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1. (WO2007005935) NOREPINEPHRINE TRANSPORTER RADIOTRACERS AND METHODS OF SYNTHESES THEREOF
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TITLE OF THE INVENTION
NOREPINEPHRINE TRANSPORTER RADIOTRACERS AND METHODS OF SYNTHESES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the priority of U.S. Provisional Application No. 60/696,979 filed My 6, 2005 and entitled NOREPINEPHRINE TRANSPORTER RADIOLIGAND AND METHODS OF SYNTHESIS, the contents of which are hereby incorporated by reference herein.

BACKGROUND OF THE INVENTION
Norepinephrine (NE) is a monoamine neurotransmitter found in both the peripheral and central nervous system (CNS). NE is responsible for regulating a vast assortment of
physiological processes. Generally, NE is released in the peripheral from sympathetic neurons that coordinate responses from the endocrine system and other tissues. In the CNS, NE neurons project diffusely throughout the brain innervating the cerebral cortex, hippocampus, thalamus, midbrain, brainstem and cerebellum and play a prominent role in regulating behavioral responses such as arousal, aggression, stress responses, anxiety, sleep-wake cycle, vigilance and emotion.
Furthermore, norepinephrine transporters (NET) are monoamine transporters that sequester NE into storage vesicles. NET contain a 12 membrane-spanning domain that is selectively expressed on NE terminals, exerting control over synaptic NE. NET may also be involved in transporting other neurotransmitters such as dopamine or serotonin. Given their strategic and diffuse locations, NET have turned out to be important pharmacotherapeutic targets for a wide variety of clinical diseases, disorders, conditions and maladies including depression, anxiety, ADHD and drug dependency. To date, a need exists for compounds that are selective for NET and can be used to effectively treat or study diseases, disorders, conditions or maladies characterized by NET or NE abnormalities.

SUMMARY OF THE INVENTION
The present invention provides compounds and radiotracers thereof for locating, diagnosing, identifying, evaluating, detecting or quantitating NET by in vivo imaging. The invention also provides methods for locating, diagnosing, identifying, evaluating, detecting or quantitating NET, using radiotracers of high-affinity or labeled compounds of the invention that exhibit low toxicity, can cross the blood-brain barrier and, preferably, distinguish among normal and abnormal brains. For example, a radiotracer of the invention can be administered to a patient in an amount suitable for in vivo imaging thereof. Preferably, radiotracers of the invention can also be used to locate, diagnose, identify, evaluate, detect and quantitate NET in such diseases, disorders, conditions or maladies as, without limitation, depression, anxiety, ADHD and drug dependency.
hi one embodiment, the compounds of the invention can be used in the treatment or prophylaxis of such diseases, disorders, conditions or maladies as, for example, depression, anxiety, ADHD and drug dependency. The compounds of the invention can also be used in the treatment or prophylaxis of a disease, disorder, condition or malady characterized by NET or NE abnormalities. Generally, prophylactic or prophylaxis relates to a reduction m. the likelihood of the patient developing a disease, disorder, condition or malady or proceeding to a diagnosis state therefor. For example, the compounds of the invention can be used prophylacticly as a measure designed to preserve health and prevent the spread or maturation of a disease, disorder, condition or malady in a patient. The invention also provides methods of administering one or more compounds of the invention to a patient in an effective amount for the treatment or prophylaxis of a disease, disorder, condition or malady.
The compounds of the invention can also be administered to a patient along with other conventional therapeutic measures, protocols or agents that may be useful in the treatment or prophylaxis of a disease, disorder, condition or malady. In one embodiment, a method is provided for administering an effective amount of one or more compounds of the invention to a patient suffering from or believed to be at risk of suffering from a disease, disorder, condition or malady characterized by NET or NE abnormalities. For example, a person of ordinary skill in the art can locate, diagnose, identify, evaluate, detect or quantitate such abnormalities by comparing in vivo images from a patient to that of at least one normal subject. The method also comprises administering, either sequentially or in combination with one or more compounds of the invention, a conventional therapeutic measure, protocol or agent that can potentially be effective for the treatment or prophylaxis of a disease, disorder, condition or malady.
The compounds and radiotracers of the invention also include analogs, salts,
compositions, derivatives, prodrugs or racemic mixtures thereof. Moreover, methods, kits or uses such as, for example, those herein, involving a compound or radiotracer of the invention can be performed with or employ one or more such analogs, salts, compositions, derivatives, prodrugs or racemic mixtures. In one embodiment, a composition can also comprise a pharmaceutically acceptable carrier and compound or radiotracer of the invention. A composition of the invention can be administered to a patient by conventional techniques including, without limitation, a bolus intravenous injection or bolus plus constant infusion paradigm.
The compounds of the invention can comprise one of the following structures, which are capable of being modified to include a detectable marker by adaptation of techniques known to a person of ordinary skill in the art. Ellis et al, Aust. J. Chem., 26: 907 (1973); Wilson et al., J. Org. Chem., 51 : 4833 (1986); Wilbur et al., J. Label. Compound. Radiopharm., 19: 1171 (1982); Chumpradit et al., J. Med. Chem., 34: 877 (1991); Chumpradit et al., J. Med. Chem., 32: 1431 (1989); Kabalka et al., J. Label. Compound. Radiopharm., 19: 795 (1982); Koch et al., Chem. Ber., 124: 2091 (1991); Mach et al., J. Med. Chem., 36: 3707 (1993); Arora et al., J. Med. Chem., 30: 918 (1987); March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).


in which A can be O, S, Se or Te, Y can be O, S, Se or Te and X can be aryl, heteroaryl, benzofused bicyclic, substituted heteroaryl or substituted aryl. Optionally, a substituted heteroaryl or substituted aryl for X can be substituted with, for example, a straight or branched alkyl, alkenyl, substituted alkenyl or halosubstituted alkenyl group or halo. In one embodiment, Ri through R5 can be independently selected from H, alkyl, aryl, alkenyl, O-aryl, O-alkyl, O-alkenyl, S-aryl, S-alkyl, S-alkenyl, NR6-aryl, NR6-alkyl, NRβ-alkenyl, halosubstituted alkyl, halosubstituted aryl, halosubstituted alkenyl, halosubstituted O-aryl, halosubstituted O-alkyl, halosubstituted O-alkenyl, halosubstituted S-aryl, halosubstituted S-alkyl, halosubstituted S-alkenyl, halosubstituted NR6-aryl, halosubstituted NR6-alkyl, halosubstituted NRe-alkenyl or halo. Moreover, R6 can be alkyl, alkenyl or halosubstituted alkenyl and R7 can be alkyl, alkenyl or halosubstituted alkenyl. Preferably, alkyl can comprise both straight and branched chain radicals of up to 8 carbons such as, without limitation, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and isobutyl. @ and * can also independently denote an R or S configuration.

In one embodiment, a compound of the invention can comprise one of the following structures


in which A can be O, S, Se or Te, Y can be O, S, Se or Te and X can be aryl, heteroaryl, benzofused bicyclic, substituted heteroaryl, substituted aryl, alkyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, halo, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, aralkyl or arylalkyl. Optionally, an aryl, heteroaryl, benzofused bicyclic, substituted heteroaryl, substituted aryl, alkyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, aralkyl or arylalkyl for X can be substituted with, for example, a straight or branched alkyl, alkenyl, substituted alkenyl or halosubstituted alkenyl group or halo, hi one embodiment, R1 through R5 can be independently selected from H, alkyl, aryl, alkenyl, O-aryl, O-alkyl, O-alkenyl, S-aryl, S-alkyl, S-alkenyl, NR6-aryl, NR6-alkyl, NR6-alkenyl, halosubstituted alkyl, halosubstituted aryl, halosubstituted alkenyl, halosubstituted O-aryl, halosubstituted O-alkyl, halosubstituted O— alkenyl, halosubstituted S— aryl, halosubstituted S-alkyl, halosubstituted S-alkenyl, halosubstituted NRr-aryl,
halosubstituted NR6-alkyl, halosubstituted NRe-alkenyl, halo, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, heteroaryl, aralkyl or arylalkyl. Moreover, R6 can be alkyl, alkenyl or halosubstituted alkenyl and R7 can be alkyl, alkenyl, halosubstituted alkenyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, halo, haloalkyl, alkylthio, alkylsulfonyl, aryl, heterocycle, heteroatom, heteroaryl, aralkyl or arylalkyl. Preferably, alkyl can comprise both straight and branched chain radicals of up to 8 carbons such as, without limitation, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and isobutyl. @ and * can also independently denote an R or S configuration.
Preferably, a compound of the invention can comprise 2-[(2-Wphenoxy)(phenyl) methyl]morpholine in which W is halo. For example, a compound of the invention can be selected from one of those provided in Table 1.

Table 1
Compounds of the invention
2(S)-[(S)-(2-iodophenoxy)(phenyl)methyl]morpholine
2(S)-[(R)-(2-iodophenoxy)(plienyl)methyl]morpholine
2(R)-[(S)-(2-iodophenoxy)(phenyl)metliyl]morpholine
2(R)-[(R)-(2-iodophenoxy)(phenyl)methyl]moφholine
2(S)-[(S)-(2-chlorophenoxy)(phenyl)methyl]morpholine
2(S)-[(R)-(2-chlorophenoxy)(phenyl)metliyl]morpholine
2(R)-[(S)-(2-clilorophenoxy)(phenyl)methyl]morpholine
2(R)-[(R)-(2-chlorophenoxy)(phenyl)methyl]moφholine
2(S)-[(S)-(2-bronioplienoxy)(phenyl)methyl]morpholine
2(S)-[(R)-(2— bromophenoxy)(phenyl)methyl]morpholine
2(R)-[(S)-(2-bromopb.enoxy)(plienyl)methyl]morpholine
2(R)-[(R)-(2-bromoplienoxy)(phenyl)methyl]morpholine
2(S)-[(S)-(2-fluorophenoxy)(phenyl)methyl]morpholine
2(S)- [(R)-(2— fluorophenoxy)(phenyl)methyl]morpholine
2(R)-[(S)-(2-fluorophenoxy)(phenyl)methyl]moφholine
2(R)-[(R)-(2-fluoroplienoxy)(phenyl)methyl]moφholine

Exemplary compounds of the invention can comprise one of the following structures including any enantiomers thereof in which n can be from 0 to 8 carbons and Z can be halo.



or

Compounds of the invention can also comprise the following structure including any
enantiomers thereof in which Ar can be aryl, substituted aryl, haloaryl, subsumed haloaryl, thiophene, substituted thiophene, halothiophene or substituted halothiophene and R1 and R2 can independently be alkyl, alkoxy, halo, H or OCH2CH2F.


In one embodiment, the invention provides a composition for locating, diagnosing, identifying, evaluating, detecting or quantitating NET. For example, the composition can
comprise a compound of the invention and at least one detectable marker. Preferably, a
detectable marker of the composition can be a substituent to a compound of the invention.
Exemplary detectable markers for a composition of the invention can include 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F, 19F, 20F, 11C, 13C, 150, 35S, 3H and 99raTc. The composition can also comprise a pharmaceutically acceptable carrier. The composition can be administered to a subject to locate, diagnose, identify, evaluate, detect or quantitate NET in vivo. Conventional imaging modalities maybe used with a composition of the invention to locate, diagnose,
identify, evaluate, detect or quantitate NET.
Radiotracers of the invention can comprise one of the following structures


in which A can be O, S, Se or Te, Y can be O, S, Se or Te and X can be a detectable marker, aryl, heteroaryl, benzofused bicyclic, substituted heteroaryl or substituted aryl. Optionally, a substituted heteroaryl or substituted aryl for X can be substituted with, for example, a detectable marker, straight or branched alkyl, alkenyl, substituted alkenyl or halosubstituted alkenyl group or halo. Without limitation, a substituted heteroaryl or substituted aryl for X can comprise 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F or 11C. In one embodiment, R1 through R5 can be independently selected from a detectable marker, H, alkyl, aryl, alkenyl, O-aryl, O-alkyl, O-alkenyl, S-aryl, S-alkyl, S-alkenyl, NRe-aryl, NR6-alkyl, NR6-alkenyl, halosubstituted alkyl, halosubstituted aryl, halosubstituted alkenyl, halosubstituted O-aryl, halosubstituted O-alkyl, halosubstituted O-alkenyl, halosubstituted S-aryl, halosubstituted S-alkyl, halosubstituted S— alkenyl, halosubstituted NRό-aryl, halosubstituted NRδ-alkyl, halosubstituted NRg-alkenyl, halo, 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F or 11C. Moreover, R6 can be alkyl, alkenyl or halosubstituted alkenyl and R7 can be alkyl, alkenyl or halosubstituted alkenyl. Preferably, alkyl can comprise both straight and branched chain radicals of up to 8 carbons such as, without limitation, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and isobutyl. @ and * can also independently denote an R or S configuration. An exemplary detectable marker can be a radionuclide, radioisotope or isotope.
In one embodiment, a radiotracer of the invention can comprise one of the following structures


in which A can be O, S, Se or Te, Y can be O, S, Se or Te and X can be a detectable marker, aryl, heteroaryl, benzofused bicyclic, substituted heteroaryl, substituted aryl, alkyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, halo, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, aralkyl or arylalkyl. Optionally, an aryl, heteroaryl, benzofused bicyclic, substituted heteroaryl, substituted aryl, alkyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, aralkyl or arylalkyl for X can be substituted with, for example, a detectable marker, straight or branched alkyl, alkenyl, substituted alkenyl or halosubstituted alkenyl group or halo. Without limitation, an aryl, heteroaryl, benzofused bicyclic, substituted heteroaryl, substituted aryl, alkyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, aralkyl or arylalkyl for X can comprise 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F or * 1C. In one embodiment, R1 through R5 can be independently selected from a detectable marker, H, alkyl, aryl, alkenyl, O-aryl, O-alkyl, O-alkenyl, S-aryl, S-alkyl, S-alkenyl, NR6-aryl, NR6-alkyl, NRβ-alkenyl, halosubstituted alkyl, halosubstituted aryl, halosubstituted alkenyl, halosubstituted O-aryl, halosubstituted O-alkyl, halosubstituted O-alkenyl, halosubstituted S-aryl, halosubstituted S-alkyl, halosubstituted S-alkenyl, halosubstituted NRό-aryl,
halosubstituted NRβ-alkyl, halosubstituted NRg-alkenyl, halo, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, heteroaryl, aralkyl, arylalkyl, 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F or 11C. Moreover, R6 can be alkyl, alkenyl or halosubstituted alkenyl and R7 can be alkyl, alkenyl, halosubstituted alkenyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, detectable marker, halo, haloalkyl, alkylthio, alkylsulfonyl, aryl, heterocycle, heteroatom, heteroaryl, aralkyl or arylalkyl.
Preferably, alkyl can comprise both straight and branched chain radicals of up to 8 carbons such as, without limitation, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and isobutyl. @ and * can also independently denote an R or S configuration.
Preferably, a radiotracer of the invention can comprise 2-[(2-Wphenoxy)(phenyl) methyl]morpholine in which W is a detectable marker. For example, a radiotracer of the invention can be selected from one of those provided in Table 2.

Table 2
Radiotracers of the invention
2(SH(S)-(2-[123I]iodophenoxy)(phenyl)methyl]morpholine
2(S)-[(R)-(2-[123I]iodoρhenoxy)(phenyl)methyl]morpholine
2(R)-[(R)-(2-[123I]iodoρhenoxy)(phenyl)methyl]morpholine
2(R)-[(S)-(2-[123I]iodophenoxy)(phenyl)methyl]morpholine
2(SH(SH2-[131I]iodophenoxy)(phenyl)methyl]morpholine
2(S)-[(R>-(2-[131I]iodoρhenoxy)(phenyl)methyl]morpholine
2(R)-[(R)-(2-[131I]iodophenoxy)(phenyl)methyl]morpholine
2(R)-[(S>-{2-[131I]iodophenoxy)(phenyl)methyl]morpholine 2(S)-[(S)-(2-[124I]iodoρhenoxy)(phenyl)methyl]morpholine
2(S)-[(R)-(2-[124I]iodoρhenoxy)(phenyl)methyl]morpholine
2(R)-[(R)-(2-[124I]iodoρhenoxy)(phenyl)methyl]morpholine
2(R)-[(S>-(2-[124I]iodoρhenoxy)(phenyl)methyl]morpholme
2(S)-[(S)-(2-[125I]iodophenoxy)(phenyl)methyl]morpholine
2(SH(RH2-[125I]iodoρhenoxy)(phenyl)methyl]morpholine
2(RH(RH2-[125I]iodoρhenoxy)(phenyl)methyl]morpholine
2(RH(SH2-[125I]iodophenoxy)(ρh.enyl)metliyl]morpholine
2(S)-[(S)-(2-[75Br]bromophenoxy)(phenyl)methyl]morpholine
2(S)-[(R)-(2-[75Br]bromophenoxy)(phenyl)metliyl]morplioline
2(R)-[(S)-(2-[75Br]broniophenoxy)(phenyl)methyl]morpholine
2(R)-[(R>-(2-[75Br]bromoρhenoxy)(phenyl)methyl]morpholine
2(S)-[(S)-(2-[76Br]bromophenoxy)(phenyl)methyl]morpholine
2(S)-[(RH2-[76Br]bromophenoxy)(phenyl)methyl]morpholine
2(R>-[(SH2-[76Br]bromophenoxy)(phenyl)methyl]morρholine
2(RH(RH2-[76Br]bromophenoxy)(phenyl)methyl]morpholine
2(S)-[(sH2-[77Br]bromophenoxy)(phenyl)methyl]morplioline
2(S)- [(R)-(2— [77Br]bromophenoxy)(phenyl)methyl]morpholine
2(R)-[(S)-(2-[77Br]bromophenoxy)(plienyl)methyl]morpholine
2(R)-[(R)-(2-[77Br]bromophenoxy)(phenyl)methyl]moipholine

Exemplary radiotracers of the invention can comprise one of the following structures including any enantiomers thereof in which n can be from 0 to 8 carbons and Z and Q can independently be a detectable marker.



or

A radiotracer of the invention can also comprise the following structure including any enantiomers thereof in which Ar can be a detectable marker, aryl, substituted aryl, haloaryi, substitued haloaryi, thiophene, substituted thiophene, halothiophene or substituted
halothiophene and R1 and R2 can independently be a detectable marker, alkyl, alkoxy, halo, H3 OCH2CH2F, 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F or 11C. Optionally, an aryl, substituted aryl, haloaryi, substitued haloaryi, thiophene, substituted thiophene, halothiophene or substituted halothiophene for Ar can comprise 75Br, 76Br, 77Br, 123I, 124I, 125I, 131I, 18F or 11C.


In one embodiment, a radiotracer of the invention can comprise one of the following structures in which Q can be a detectable marker



or

The invention also provides methods for syntheses of compounds and radiotracers of the invention. In one embodiment, a method comprises modifying a compound to be a radiotracer of the invention. The radiotracers of the invention are particularly useful for the in vivo diagnosis, identification, evaluation, detection and quantitation of the progression or regression of diseases, disorders, conditions or maladies in a patient. Exemplary diseases, disorders, conditions or maladies include, without limitation, depression, anxiety, ADHD and drug dependency. A radiotracer can also comprise a compound of the invention and at least one detectable marker such as, without limitation, a radionuclide, radioisotope or isotope. In one embodiment, a detectable marker can comprise a halo such as, for example, 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F, 19F or 20F. The selection of detectable markers for a radiotracer of the invention can vary depending on the modality chosen for in vivo imaging of NET.

DESCRIPTION OF THE DRAWINGS
Other features and advantages of the invention may also be apparent from the following detailed description thereof, taken in conjunction with the accompanying drawings of which:
Figure 1 shows regional brain time-activity data in a subject following an injection comprising a radiotracer of the invention and serial dynamic single-photon emission computed tomography (SPECT) acquisitions;
Figure 2 shows transaxial SPECT brain slices in a subject from baseline evaluations (upper in vivo image panel) and following intravenous pretreatment with a conventional agent, lOmin before an injection comprising a radiotracer of the invention (lower in vivo image panel);

Figure 3 shows regional brain analysis of time-activity data in a subject receiving a bolus injection of a radiotracer of the invention and repeated SPECT evaluations following pretreatment with a conventional agent; and
Figure 4 shows bolus plus constant infusion evaluation with a radiotracer of the invention in a subject.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds and radiotracers thereof comprising detectable markers for antemortem in vivo imaging of, for example, NET. hi one embodiment, the compounds and radiotracers of the invention are capable of binding to or associating with NET. The radiotracers of the invention can be used in vivo to locate, diagnose, identify, evaluate, detect or quantitate the progression or regression of such diseases, disorders, conditions or maladies as, without limitation, depression, anxiety, ADHD and drug dependency.

Preferably, a method of the invention can be used to determine the presence or location of NET in an organ or body area such as, without limitation, the brain of a subject. An exemplary method of the invention comprises administration of a detectable quantity or effective amount of a radiotracer to a patient. A radiotracer can be derived from a compound of the invention. One or more radiotracers can be administered to a patient as a composition or a pharmaceutically acceptable salt, for example, water-soluble, thereof.
"Pharmaceutically acceptable salt" refers to an acid or base salt of a compound or radiotracer of the invention, which possesses the desired pharmacological activity and is neither biologically nor otherwise undesirable. Pharmaceutically acceptable salt can also refer to those carboxylate salts or acid addition salts of the compounds or radiotracers of the invention, which are suitable for use in contact with the tissues of patients without undue toxicity, irritation or allergic response. The salt can refer to the relatively nontoxic, inorganic and organic acid addition salts of compounds or radiotracers of the present invention and may be formed with acids that include, without limitation, acetate, ascorbate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2— hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2— naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate, trifluoroacetate and undecanoate. Examples of a base salt include, without limitation, ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine and salts with amino acids such as arginine and lysine. In one embodiment, the basic nitrogen-containing groups can be quarternized with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides, dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides and aralkyl halides such as phenethyl bromides. A salt can also be derived from non-toxic organic acids such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic and alkanedioic acids, aromatic acids and aliphatic and aromatic sulfonic acids. Without limitation, these salts can be prepared in situ during the final isolation and purification of a compound of the invention or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Additional representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,
trifluoroacetate, naphthylate mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts, propionate, pivalate, cyclamate and isethionate. These may include cations based on the alkali and alkaline earth metals such as sodium, lithium, potassium, calcium and magnesium as well as nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine and ethylamine. Berge et al., Pharmaceutical Salts, J. Pharm. ScL, 66: 1 (1977).
Preferably, a compound of the invention can comprise one of the following structures


in which A can be O, S, Se or Te, Y can be O, S, Se or Te and X can be aryl, heteroaryl, benzofused bicyclic, substituted heteroaryl, substituted aryl, alkyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, halo, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, aralkyl or arylalkyl. Optionally, an aryl, heteroaryl, benzofused bicyclic, substituted heteroaryl, substituted aryl, alkyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, aralkyl or arylalkyl for X can be substituted with, for example, a straight or branched alkyl, alkenyl, substituted alkenyl or halosubstituted alkenyl group or halo. In one embodiment, R1 through R5 can be independently selected from H, alkyl, aryl, alkenyl, O-aryl, O-alkyl, O-alkenyl, S-aryl, S-alkyl, S-alkenyl, NR6-aryl, NR6-alkyl, NRό-alkenyl, halosubstituted alkyl, halosubstituted aryl, halosubstituted alkenyl, halosubstituted O-aryl, halosubstituted O-alkyl, halosubstituted O-alkenyl, halosubstituted S— aryl, halosubstituted S-alkyl, halosubstituted S-alkenyl, halosubstituted NR6-aryl,
halosubstituted NRό-alkyl, halosubstituted NR6-alkenyl, halo, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, heteroaryl, aralkyl or arylalkyl. Moreover, R6 can be alkyl, alkenyl or halosubstituted alkenyl and R7 can be alkyl, alkenyl, halosubstituted alkenyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, halo, haloalkyl, alkylthio, alkylsulfonyl, aryl, heterocycle, heteroatom, heteroaryl, aralkyl or arylalkyl. Preferably, alkyl can comprise both straight and branched chain radicals of up to 8 carbons such as, without limitation, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and isobutyl. @ and * can also independently denote an R or S configuration.
hi one embodiment, a radiotracer of the invention can be administered to a patient in an amount or dosage suitable for in vivo imaging. Generally, a unit dosage comprising a radiotracer of the invention may vary depending on patient considerations. Such considerations include, for example, age, condition, sex, extent of disease, contraindications or concomitant therapies. An exemplary unit dosage based on these considerations can also be adjusted or modified by a person of ordinary skill in the art. For example, a unit dosage for a patient comprising a radiotracer can vary from 1 x 10~15g/kg to 10g/kg, preferably, 1 x l(T15g/kg to 1.Og/kg. Moreover, a unit dosage comprising a radiotracer can also be from lμCi/kg to lOmCi/kg and, preferably, 0.1mCi/kg.
For example, a radiotracer of the invention can comprise one of the following structures


in which A can be O, S, Se or Te, Y can be O, S, Se or Te and X can be a detectable marker, aryl, heteroaryl, benzofused bicyclic, substituted heteroaryl, substituted aryl, alkyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, halo, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, aralkyl or arylalkyl. Optionally, an aryl, heteroaryl, benzofused bicyclic, substituted heteroaryl, substituted aryl, alkyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, aralkyl or arylalkyl for X can be substituted with, for example, a detectable marker, straight or branched alkyl, alkenyl, substituted alkenyl or halosubstituted alkenyl group or halo. Without limitation, an aryl, heteroaryl, benzofused bicyclic, substituted heteroaryl, substituted aryl, alkyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, aralkyl or arylalkyl for X can comprise 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F or 11C.

In one embodiment, R1 through R5 can be independently selected from a detectable marker, H, alkyl, aryi, alkenyl, O-aryl, O-alkyl, O-alkenyl, S-aryl, S-alkyl, S-alkenyl, NR6-aryl, NR6-alkyl, NR6-alkenyl, halosubstituted alkyl, halosubstituted aryl, halosubstituted alkenyl, halosubstituted O-aryl, halosubstituted O-alkyl, halosubstituted O-alkenyl, halosubstituted S-aryl, halosubstituted S-alkyl, halosubstituted S-alkenyl, halosubstituted NRe-aryl,
halosubstituted NR6-alkyl, halosubstituted NRg-alkenyl, halo, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, haloalkyl, alkylthio, alkylsulfonyl, heterocycle, heteroatom, heteroaryl, aralkyl, arylalkyl, 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F or 11C. Moreover, R6 can be alkyl, alkenyl or halosubstituted alkenyl and R7 can be alkyl, alkenyl, halosubstituted alkenyl, alkoxy, monoalkylamine, dialkylamine, hydroxy alkyl, detectable marker, halo, haloalkyl, alkylthio, alkylsulfonyl, aryl, heterocycle, heteroatom, heteroaryl, aralkyl or arylalkyl.
Preferably, alkyl can comprise both straight and branched chain radicals of up to 8 carbons such as, without limitation, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and isobutyl. @ and * can also independently denote an R or S configuration.
Administration of a compound or radiotracer of the invention to a subject may be local or systemic and accomplished intravenously, intraarterially or intrathecally (via the spinal fluid). Administration may also be intradermal or intracavitary, depending upon the body site under examination. In one embodiment, after a sufficient time has elapsed for a radiotracer of the invention to bind or associate with at least one NET, for example, 5 minutes to 48 hours, the area of the subject under investigation is examined by routine imaging techniques or modalities such as positron emission tomography (PET), SPECT, planar scintillation imaging or combinations thereof as well as emerging imaging modalities. The exact protocol can vary depending upon factors specific to the patient and depending upon the body site under examination, method of administration and type of radiotracer or detectable marker used, although the determination of specific procedures would be routine to a person of ordinary skill in the art.
For brain imaging, preferably, the amount of total or specific binding of a bound radiotracer of the invention is measured and compared as a ratio with the amount of a labeled compound of the invention. Such a ratio can then be compared to the same ratio in one or more age-matched normal brains. Without limitation, a radiotracer of the invention can be administered intravenously to a patient in an amount or dosage appropriate for in vivo imaging. The compounds and radiotracers of the invention can also be administered via a
pharmaceutically acceptable carrier, hi one embodiment, a compound of the invention can be administered for the treatment or prophylaxis of a disease, disorder, condition or malady such as those characterized by NET or NE abnormalities. To those of ordinary skill in the art, it is generally known that compounds selective for NET can be used to treat NET or NE
abnormalities. Bymaster et al., Neuropsychopharmacology, 27: 699 (2002); Biederman et al., Biol. Psychiatry, 46: 1234 (1999); Iversen et al., Molecular Psychiatry, 5: 357 (2000);
Allgulander et al., British J. Psychiatry, 179: 15 (2001); Klirnek et al., J. Neurosc, 17: 8451 (1997); Ryu et al., Neuropsychobiology, 49: 174 (2004); Brunello et al., Eur.
Neuropsychopharmacol., 12: 461 (2002); Wong et al., Biol. Psychiatry, 47: 818 (2000); Melloni et al., Eur. J. Med. Chem., 19: 235 (1984); Calla et al., Biol. Psychiatry, 53: 234 (2003).
The compounds of the invention can be used in the treatment or prophylaxis of a disease, disorder, condition or malady characterized by NET or NE abnormalities as each may be selective for NET. In one embodiment, the compounds of the invention are selective for NET such that each can be effectively used to treat or prevent diseases, disorders, conditions or maladies that include, for example, depression, anxiety, ADHD and drug dependency.
Preferably, a compound of the invention can also be included in a composition comprising at least one pharmaceutically acceptable carrier. A compound of the invention that can be selective for NET also may be used to treat dopamine or serotonin abnormalities. Bymaster et al., Neuropsychopharmacology, 27: 699 (2002); Biederman et al., Biol. Psychiatry, 46: 1234 (1999); Iversen et al., Molecular Psychiatry, 5: 357 (2000); Allgulander et al., British J. Psychiatry, 179: 15 (2001); Klimek et al., J. Neurosc, 17: 8451 (1997); Ryu et al.,
Neuropsychobiology, 49: 174 (2004); Brunello et al., Eur. Neuropsychopharmacol., 12: 461 (2002); Wong et al., Biol. Psychiatry, 47: 818 (2000); Melloni et al., Eur. J. Med. Chem., 19: 235 (1984); Calla et al., Biol. Psychiatry, 53: 234 (2003).
A radiotracer of the invention can also be a selective ligand for at least one NET. In one embodiment, a radiotracer of the invention may be used to directly locate, evaluate, detect or quantify NET, for example, by measurement of radioactivity. Generally, NET are located on NE neurons such that a radiotracer of the invention can also be used to locate, detect or quantify these neurons. Moreover, a radiotracer of the invention can be used to indirectly locate, evaluate, detect or quantify NE. Without being bound by theory, the plasticity of a subject's brain can allow for an increase or decrease in the number of NET in response to or based on NE changes. For example, a subject that is suffering from depression can experience a decrease in NE, which correspondingly decreases NET.
Given the relationships among NE and NET as understood by a person of ordinary skill in the art, the invention contemplates detenmning an in vivo level or quantity of NE for a subject. In one embodiment, a radiotracer of the invention can be used to obtain in vivo data relating to NET. Based on such data, quantitative and qualitative determinations regarding the in vivo level of NE can be made. Preferably, an in vivo level or quantity of NE can be estimated using a radiotracer of the invention to locate, evaluate, detect or quantify NET. For example, extrapolative or statistical techniques can be used to estimate the in vivo levels of NE for a subject from data obtained via a radiotracer or method of the invention. Exemplary
extrapolative or statistical techniques are well known to those of ordinary skill in the art.
The invention also provides a method comprising administering to a subject an effective amount of a radiotracer. In one embodiment, the method can comprise imaging the subject to obtain data, which may optionally be analyzed to locate, diagnose, identify, evaluate, detect or quantitate NET or abnormalities thereof. The obtained data can be stored or analyzed by conventional protocols, means, devices, apparatuses or systems known to those of ordinary skill in the art. Without limitation, the data can relate to the in vivo distribution of NET for the subject. The method can also comprise estimating an in vivo level of NE for the subject. Preferably, the in vivo level of NE can be estimated from the data obtained via imaging with the radiotracer. Estimations regarding in vivo NE levels can be determined from standard extrapolative or statistical techniques and provide for a diagnosis of a disease, disorder, condition or malady such as, for example, those characterized by NET or NE abnormalities. Such diseases, disorders, conditions or maladies can include depression, anxiety, ADHD and drug dependency. A radiotracer of the invention can also be used for in vivo imaging of dopamine and serotonin transporters.
The radiotracers of the invention can be administered in the form of injectable compositions. Alternatively, a radiotracer can also be formulated into well known drug delivery systems such as, for example, oral, rectal, parenteral, intravenous, intramuscular, subcutaneous, intracisternal, intravaginal, intraperitoneal, local or via powders, ointments, drops or as a buccal or nasal spray. As described, administration of a compound or radiotracer of the invention can be local or systemic and accomplished intravenously, intraarterially or intrathecally via the spinal fluid. A typical composition for administration can comprise a pharmaceutically acceptable carrier for the compound or radiotracer of the invention. Pharmaceutically acceptable carriers include, without limitation, aqueous solutions, non-toxic excipients comprising salts, preservatives or buffers, which are described in Remington's Pharmaceutical Sciences (15th edition) and The National Formulary XIV (14th edition).
Exemplary pharmaceutically acceptable carriers for a compound or radiotracer of the invention can also include non— aqueous solvents such as β-cyclodextrin or analogs thereof, propylene glycol, polyethylene glycol and vegetable oil or injectable organic esters such as ethyl oleate. An aqueous carrier can also comprise, without limitation, water, alcoholic solutions, aqueous solutions, saline solutions and parenteral vehicles such as sodium chloride or Ringer's dextrose. Intravenous carriers for administration of a compound or radiotracer of the invention include, for example, fluid and nutrient replenishers. Preservatives for a compound or radiotracer of the invention also may include antimicrobial solutions, anti-oxidants and inert gases. The pH and exact concentration of the various components for a composition of the invention can also be adjusted by a person of ordinary skill in the art. Goodman et al., The Pharmacological Basis for Therapeutics (7th edition).
hi one embodiment, radiotracers of the invention are those that, in addition to selectively binding in vivo and being capable of crossing the blood brain barrier, are non-toxic at appropriate dosage levels and have a satisfactory duration of effect. Moreover, a composition comprising a radiotracer can be administered to a subject in whom depression, anxiety, ADHD or drug dependency is anticipated, for example, patients clinically diagnosed with NET or NE abnormalities. A radiotracer of a composition can be derived from a compound of the invention. The invention employs radiotracers or labeled compounds which, in conjunction with noninvasive neuroimaging techniques or modalities such as magnetic resonance spectroscopy (MRS), magnetic resonance spectroscopy imaging (MRI), PET or SPECT, are used to locate, diagnose, identify, evaluate, detect and quantitate NET in vivo. The methods of the invention also involve imaging a patient to establish a baseline for NET or NE. The term "baseline" refers to the amount and distribution of NET or NE prior to initiation of a therapy. An exemplary method of the invention comprises at least one imaging session of a patient following administration of a therapy, hi one embodiment, a method of the invention may involve imaging a patient before and after treatment with at least one compound of the invention or conventional measures, protocols or agents. In vivo imaging can also be performed at any time during therapy.
The terms "in vivo imaging" or "imaging" refer to methods that permit the detection of a radiotracer of the invention or labeled compound. For gamma-based imaging, the radiation emitted from the organ or area being examined can be measured and expressed either as total binding or as a ratio in which total binding in one tissue is normalized to, for example, divided by, the total binding in another tissue of the same subject during the same in vivo imaging procedure. Total binding in vivo is defined as the entire signal detected in a tissue by an in vivo imaging technique without the need for correction by a second administration of an identical quantity of a radiotracer or labeled compound along with a large excess of an unlabeled, but otherwise chemically identical, agent. Moreover, NET can refer to an individual norepinephrine transporter or one or more norepinephrine transporters. A "subject" is a mammal, preferably, a human suspected of having a disease, disorder, condition or malady associated with NET or NE abnormalities. The term "subject" and "patient" are used interchangeably herein.
For purposes of in vivo imaging, the type of detection instrument available is a major factor in selecting a given detectable marker. For example, radioactive isotopes and 18F or 23I are particularly suitable for in vivo imaging in the methods of the invention. The type of instrument used will also guide the selection of a radionuclide or stable isotope, hi one embodiment, the radionuclide chosen can comprise a type of decay detectable by a given type of imaging means, device, apparatus or system. Moreover, other considerations such as the half-life of the radionuclide are taken into account when selecting a detectable marker for a radiotracer to be used during in vivo imaging.
The half-life of a detectable marker should be long enough such that the marker can be detectable at the time of maximum uptake by the target. Similarly, the half-life of the marker may be short enough to ensure that the subject does not sustain deleterious radiation. The radiotracers of the invention can be detected using gamma imaging in which emitted gamma irradiation of the appropriate wavelength is detected. Conventional methods of gamma imaging include, but are not limited to, SPECT and PET. Preferably, for SPECT detection, the chosen detectable marker will lack a particulate emission and provide for a large number of photons in a range of about 14O-300keV. For PET detection, the detectable marker may be a positron-emitting radionuclide such as l F, which can annihilate to form two 51 Ike V gamma rays that are then detected by a PET camera.
A radiotracer of the invention can provide for quantitative measurement of NET and sites thereof, hi one embodiment, a radiotracer can be used to locate, diagnose, identify, evaluate or detect NET or sites thereof. Without limitation, use of a radiotracer for in vivo imaging can be performed in conjunction with dosimetry calculations, metabolite analysis or kinetic modeling. Preferably, the in vivo biodistribution of a radiotracer of the invention can also be quantitated or evaluated after its administration to a subject. For example, the biodistribution of a radiotracer may be quantitated or evaluated to provide estimates for the dose of radiation absorbed by a subject. The metabolic rate of a radiotracer can optionally be quantitated or evaluated in conjunction with an exemplary biodistribution analysis.
Furthermore, an exemplary radiotracer of the invention can be administered to a subject in a composition comprising a sterile, apyrogenic solution. An exemplary compound or radiotracer of the invention can also comprise a molecular mass from about 200 to 700g/mol.

Preferably, a radiotracer of the invention can comprise a molecular mass of about 390 to 400g/mol such as, without limitation, 2(S)-[(S)-(2-[123I]iodophenoxy)(phenyl)methyl] morpholine. For example, a compound or radiotracer of the invention comprising 2(S)-[(S)-(2-Wphenoxy)(phenyl)methyl] in which W is a detectable marker can elementally include about 51.66, 4.59, 3.54 and 8.10g/mol of carbon, hydrogen, nitrogen and oxygen,
respectively. A composition of the invention can comprise a compound or radiotracer thereof and at least one pharmaceutically acceptable carrier.
In one embodiment, compounds or radiotracers of the invention, which are useful for in vivo imaging are administered to a patient. The compounds or radiotracers are to be used in conjunction with non-invasive neuroimaging techniques such as MRS, MRI, PET, SPECT and combinations thereof. Moreover, a compound of the invention may be labeled with 19F or 13C for imaging by MRS, MRI or combinations thereof by adaptation of organic chemistry techniques known to a person of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition). The compounds of the invention also may be radiolabeled with 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F or 11C for PET by adaptation of techniques well known to a person of ordinary skill in the art. Fowler et al., Positron Emission Tomography and
Autoradiography. The compounds of the invention also may be radiolabeled with 123I for SPECT by adaptation of techniques known to those of ordinary skill in the art. Kulkarni et al., Int. J. Rad. Appl. Inst, 18: 647 (1991).
In addition, the compounds of the invention may be labeled with any suitable radioactive iodine isotope such as, without limitation, 11, 125I or 123I by adaptation of techniques known to a person of ordinary skill in the art. A stable form or derivative of a compound of the invention can also be reacted with a halogenating agent comprising 75Br, 76Br, 77Br, 1231, 1241, 1251, 131I, F, F or 20F. Preferably, a stable form or derivative of a compound of the invention and analogs, salts, compositions, derivatives, prodrugs or racemic mixtures thereof can also be precursors, which are useful for the synthesis of a labeled compound or radiotracer of the invention.
The compounds of the invention also may be radiolabeled with known metal detectable markers such as, for example, 99mTc. Modification of the substituents to a compound of the invention in order to introduce ligands that bind such metal ions can be effected without undue experimentation by a person of ordinary skill in the art. The metal radiolabeled compound of the invention can then be used as a radiotracer to detect NET. Compounds comprising a detectable marker such as 99mTc can be prepared by adaptation of techniques known to those of ordinary skill in the art. Zhuang et al., Nuclear Medicine and Biology, 26: 217 (1999); Oya et al., Nuclear Medicine and Biology, 25: 135 (1998); Horn et al., Nuclear Medicine and Biology, 24: 485 (1997).
In one embodiment, a method of the invention may use detectable markers or isotopes detectable by nuclear magnetic resonance (NMR) spectroscopy for purposes of in vivo imaging and spectroscopy. Elements particularly useful in magnetic resonance spectroscopy include 19F and 13C. Suitable detectable markers for preparing a radiotracer of the invention also include beta-emitters, gamma-emitters, positron-emitters and x-ray emitters. Moreover, exemplary detectable markers include 75Br, 76Br, 77Br, 1231, 1241, 1251, 131I5 18F, 19F, 20F, 11C, 13C, 150, 35S, 3H and 99mTc. Suitable stable isotopes for use in MRI or MRS include 19F and 13C. Preferably, a radiotracer of the invention comprises 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F or 11C for use in in vivo imaging. The invention also contemplates that any type of suitable method or detectable marker for visualizing radiotracers can be used to locate, diagnose, identify, evaluate, detect or quantitate NET in vivo.
In one embodiment, a radiotracer of the invention can be used to locate, diagnose, identify, evaluate, detect or quantitate NET in biopsied tissues. Preferably, a detectable marker for a radiotracer or labeled compound of the invention is a radiolabel, although other labels such as enzymes, chemiluminescent and immunofluorescent labels are well known to those of ordinary skill in the art. Tissue containing NET will bind to the compounds or radiotracers of the invention. For biopsied tissues, the bound tissue can be separated from the unbound tissue by conventional techniques such as filtering. The bound tissue may also be quantified through approaches known to those of ordinary skill in the art. The compounds or radiotracers of the invention can specifically bind to or associate with NET in the brain of a subject.
The compounds of the invention can be modified to be used as radiotracers by labeling with suitable radioactive halogen isotopes. Although a 125I isotope can be useful for laboratory testing, it may be less practical as a detectable marker for in vivo purposes given its relatively long half-life of about 60 days and low gamma-emission, for example, about 30-65Kev. The isotope 123I has a half-life of about thirteen hours and gamma energy of about 159KeV such that radiotracers comprising it can be readily used for in vivo diagnostic purposes. Other exemplary isotopes for use with in vivo imaging techniques include 131I with a half-life of about 8.3 days. Suitable bromine isotopes for a radiotracer of the invention also include 77Br, 75Br and 76Br.
Materials for compounds and radiotracers of the invention can be provided to users in kits. For example, kits for forming the radiotracers can contain, without limitation, a vial containing a physiologically suitable solution of an intermediate of a compound of the invention in a concentration and at a pH suitable for optimal complexing conditions. The user can add to the vial an appropriate quantity of a detectable marker, for example, Na123I. The resulting radiotracer can then be administered intravenously to a patient such that NET in the brain can be imaged antemortem by a means for measuring the gamma ray or photo emissions from the detectable marker.
In one embodiment, a method of the invention may be used to locate, diagnose, identify, evaluate, detect or quantitate NET or NE abnormalities in mild or clinically confusing cases. For example, the method provides for longitudinal studies of NET or NE in high risk populations including, without limitation, patients suffering from or believed to be at risk of suffering from depression, anxiety, ADHD or drug dependency. The method of the invention can also be used to monitor the effectiveness of therapies targeted at preventing a disease, disorder, condition or malady.
The invention also provides a method for the treatment or prophylaxis of a disease characterized by NET or NE abnormalities comprising administering to a patient in need thereof an effective amount of a compound of the invention. In one embodiment, the method can include providing a patient suffering from or believed to be at risk of suffering from a disease, disorder, condition or malady characterized by, for example, NET or NE abnormalities. The method may also comprise administering to the patient an effective amount of a compound of the invention. The compound of the invention can also be administered as part of a composition comprising a pharmaceutically acceptable carrier.
In one embodiment, a method for locating, diagnosing, identifying, evaluating, detecting or quantitating NET comprises administering to a patient in need thereof an effective amount of a radiotracer of the invention. For example, the method can comprise providing a patient suffering from or believed to be at risk of suffering from a disease, disorder, condition or malady characterized by, for example, NET or NE abnormalities. The method may also comprise administering to the patient an effective amount of a radiotracer of the invention and, optionally, imaging the radiotracer in vivo. Exemplary means, devices, apparatuses or systems for imaging of a radiotracer of the invention in vivo include, without limitation, PET, SPECT or combinations thereof.
"Effective amount" refers to the amount required to produce a desired effect or result.

One example of an effective amount includes amounts or dosages that enable location, diagnosis, identification, evaluation, detection or quantitation of NET and imaging thereof either in vivo or in vitro. Another example of an effective amount includes amounts or dosages that yield acceptable toxicity and bioavailability levels for imaging and therapeutic uses including, without limitation, the treatment or prophylaxis of NET or NE abnormalities.
The invention also provides a method of distinguishing a normal brain from one comprising NET or NE abnormalities indicative of a disease, disorder, condition or malady. In one embodiment, the method comprises obtaining tissue samples from a normal subject.
Furthermore, the method includes obtaining comparable tissue samples from subjects suffering from or suspected of suffering from a disease, disorder, condition or malady such as, for example, those related to NET or NE abnormalities. These tissue samples can be made into separate homogenates using methods well known to those of ordinary skill in the art and may then be incubated with a radiotracer of the invention. The amount of tissue that binds to the radiotracer can be calculated for each tissue sample. These amounts may also be compared to each other. In one embodiment, a difference in these amounts can provide for a diagnosis of a disease, disorder, condition or malady.
hi one embodiment, a composition comprising a radiotracer can also be prepared by a user with a kit. For example, the invention provides a kit comprising materials such as a non-radiolabeled compound of the invention. The compound can be in a dry condition and, optionally, one or more inert substances or pharmaceutically acceptable carriers may be added thereto. A kit of the invention can include materials such as those comprising a detectable marker. These materials may also be combined by techniques known to a person of ordinary skill in the art. Moreover, the kit can comprise instructions for performing a method of the invention that involves reacting a compound with a detectable marker such as, for example, 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F, 19F, 20F, 11C, 13C, 150, 35S, 3H or 99mTc. A kit of the invention can also include suitable chelators such as, without limitation, dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, orthophtalic acid, malic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, β-cyclodextrin or analogs thereof, salicylic acid or derivatives thereof or phosphorus compounds such as pyrophosphates and enolates. The kit can also include instructions for performing an in vivo imaging protocol with a radiotracer prepared therefrom.
In one embodiment, a kit of the invention can comprise a compound or radiotracer of the invention. An exemplary kit can include a composition comprising a compound or radiotracer of the invention. For example, the kit may include a dosage form comprising a radiotracer of the invention. The dosage form can also comprise a sterile, pyrogen-free solution. The kit can include a vial for the dosage form. Preferably, the vial can be a 10ml sterile borosilicate vial with a butyl TEFLON-faced septa and aluminum ring seals. Moreover, the vial can also be contained within an outer lead shield to protect from gamma radiation. The kit of the invention can also comprise instructions for use of a compound or radiotracer. Without limitation, the instructions can provide a protocol for administration to a subject for treatment of a disease, disorder, condition or malady or in vivo imaging of NET. A radiotracer of the invention can retain chemical purity after several days of storage in a dosage form.
A radiotracer of the invention or composition thereof can also comprise additives such as pH controlling agents, for example, acids, bases, buffers, β-cyclodextrin or analogs thereof, stabilizers, for example, ascorbic acid or isotonizing agents, for example, sodium chloride. The invention also contemplates that additional characteristics of a subject can be diagnosed, identified, evaluated, detected or quantitated in conjunction with in vivo imaging of NET via a radiotracer. Exemplary characteristics include, without limitation, glucose metabolic activity or behavioral characteristics.
In one embodiment, a radiotracer of the invention can be introduced into a tissue or patient in a detectable quantity such as, for example, an effective amount. The radiotracer may be part of a composition and can be administered to the tissue or patient by methods well known to those of ordinary skill in the art. For example, a radiotracer or composition of the invention can be administered either orally, rectally, parenterally, intravenously, intramuscularly, subcutaneously, intracisternally, intravaginally, intraperitoheally, intravesically, locally or via powders, ointments, drops or as a buccal or nasal spray.
Preferably, a radiotracer of the invention can be introduced into a patient in a detectable quantity and after sufficient time passes for it to become associated with at least one NET, the radiotracer may be detected noninvasively inside the patient. In one embodiment, a radiotracer of the invention can be introduced into a patient, allowing it to become associated with a NET and then a sample of tissue from the patient may removed for diagnosis, identification, evaluation, detection or quantitation apart from the patient. A tissue sample can also be removed from a patient and a radiotracer introduced thereto. After a sufficient amount of time passes for the radiotracer to become bound to or associated with NET therein, it can be detected by a conventional imaging modality.
The administration of a radiotracer to a patient can be by a general or local
administration route such as, without limitation, a bolus injection. A bolus injection can comprise sterile saline, for example, 0.9% aqueous NaCl, and at least one compound or radiotracer of the invention. Without limitation, a radiotracer can be administered to the patient such that it is delivered throughout the body, hi one embodiment, the radiotracer can be administered to a specific organ or tissue of interest, preferably, the brain. The invention also contemplates locating and quantitating NET in the brain to diagnose or evaluate the progress of a disease, disorder, condition or malady including depression, anxiety, ADHD and drug dependency.
The term "tissue" means a part of a patient's body. Examples of tissues include the brain, heart, liver, blood vessels and arteries. An effective amount or detectable quantity of a radiotracer or labeled compound of the invention can be detected by a selected in vivo imaging method. For example, an effective amount of a radiotracer can be administered to a subject, enabling its detection in association with NET. The amount of a radiotracer to be introduced into a patient in order to provide for diagnosis, identification, evaluation, detection or quantitation can readily be determined by those of ordinary skill in the art. For example, increasing amounts of the radiotracer can be given to a patient until the radiotracer is detected by the selected in vivo imaging method. A detectable marker can be introduced to a compound of the invention to provide for a radiotracer that can be detected by suitable imaging modalities. In one embodiment, a method of the invention determines the presence and location of NET in an organ or body area, preferably, the brain of a patient. A person of ordinary skill in the art will also be familiar with determining the amount of time sufficient for a compound or radiotracer of the invention to become associated with at least one NET. The amount of time necessary for such association can, without limitation, be determined by introducing an effective amount of a radiotracer of the invention into a patient and then detecting it at various times after
administration.
The terms "associated" or "associating" can mean a chemical interaction between a radiotracer and NET. Examples of associations include covalent bonds, ionic bonds, hydrophilic-hydrophilic interactions, hydrophobic-hydrophobic interactions and complexes. Those of ordinary skill in the art are familiar with the various means by which to detect labeled compounds or radiotracers. For example, MRI, PET or SPECT can be used to detect compounds labeled with a detectable marker or radiotracers of the invention. The detectable marker that is introduced to a compound of the invention to yield a radiotracer can depend on the selected detection method.
In one embodiment, the radiotracer can comprise sufficient radioactivity and
concentration thereof to assure reliable diagnosis, identification, evaluation, detection or quantitation. In vivo imaging can also be performed quantitatively such that the amount of NET can be determined. In one embodiment, radiotracers for imaging include a radioisotope such as 75Br, 76Br, 77Br, 1231, 1241, 1251, 1311, 18F or 11C. The invention also provides a method of imaging NET. A radiotracer of the invention can cross the intact blood-brain barrier after, for example, a bolus intravenous injection.
Exemplary radiotracers or labeled compounds of the invention can be used to, for example, locate, diagnose, identify, evaluate, detect or quantitate NET and distributions thereof via radioscintigraphy, MRI, chemilumensence, near infrared luminescence, fluorescence, SPECT, computed tomography (CT scan), PET or combinations thereof. The invention also contemplates the use of conventional imaging protocols, means, devices, apparatuses or systems for performing radioscintigraphy, MRI, chemilumensence, near infrared luminescence, fluorescence, SPECT, CT scan, PET or combinations thereof. Exemplary imaging protocols, means, devices, apparatuses or systems include those generally described in U.S. Patent Nos. 6,072,177, 6,803,580, 5,900,636, 6,271,524, 5,532,489, 5,272,343, 5,241,181, 5,512,755, 5,345,082, 5,023,895, 4,864,140, 5,323,006, 4,675,526 and 4,395,635, the contents of which are hereby incorporated by reference herein.
In one embodiment, the invention provides a method for in vivo imaging comprising administering to a subject an effective amount of a radiotracer. Preferably, the method can comprise administering a radiotracer of the invention to a subject orally, rectally, parenterally, intravenously, intramuscularly, subcutaneously, intracisternally, intravaginally, intraperitoneally, intravesically, locally or via powders, ointments, drops or as a buccal or nasal spray. The method also comprises detecting the radiotracer. For example, the radiotracer can be detected in vivo with conventional or emerging imaging modalities. Conventional imaging modalities include, without limitation, PET, SPECT, planar scintillation imaging or combinations thereof. An exemplary imaging modality can be capable of locating, diagnosing, identifying, evaluating, detecting or quantitating a radiotracer of the invention in vivo.
A method for in vivo imaging can also comprise detecting radioactivity of a radiotracer of the invention. Preferably, the radioactivity of a radiotracer can be measured in vivo. Without limitation, the radioactivity of a radiotracer of the invention can be measured qualitatively or quantitatively. In one embodiment, a radiotracer of a method of the invention can be associated with at least one NET in vivo. For example, a method for in vivo imaging can comprise administering to a subject an effective amount of a radiotracer of the invention. The method can also comprise allowing a sufficient time for the radiotracer to be associated with at least one NET and then detecting the radiotracer such as with conventional or emerging imaging modalities.
Furthermore, a method for in vivo imaging can comprise administering to a subject an effective amount of a radiotracer of the invention and imaging the subject. In one embodiment, the subject can be imaged to detect a distribution of NET. For example, the distribution of NET can be within the brain of the subject. Preferably, a method for in vivo imaging can comprise administering to a subject suffering from or believed to be at risk of suffering from NET or NE abnormalities an effective amount of a radiotracer of the invention. Without limitation, the method can also comprise imaging the subject to obtain data, which may optionally be analyzed to locate, diagnose, identify, evaluate, detect or quantitate NET and abnormalities thereof. The radiotracer can be imaged in vivo with conventional or emerging imaging modalities including PET, SPECT, planar scintillation imaging or combinations thereof.
The data obtained from imaging during a method of the invention can be stored or analyzed by conventional protocols, means, devices, apparatuses or systems known to those of ordinary skill in the art. The invention also provides a method for tissue imaging. In one embodiment, the method includes contacting a tissue comprising at least one NET with the radiotracer of the invention. Moreover, the method comprises detecting the radiotracer, which can be performed in vitro or in vivo. Preferably, the tissue of a method of the invention can comprise brain tissue. Brain tissue can be obtained from the subject by conventional techniques known to those of ordinary skill in the art.
In one embodiment, a method for in vivo imaging can comprise administering to a subject suffering from or believed to be at risk of suffering from NET or NE abnormalities an effective amount of a radiotracer of the invention and imaging the subject. The method can also comprise administering to the subject in need thereof a therapeutic agent Without limitation, the therapeutic agent can be a conventional or emerging agent for treating NET or NE abnormalities or comprise a compound of the invention. Subsequently, the method can comprise administering to the subject an effective amount of the radiotracer and imaging the subject. The method can then provide for a comparison of the extent of NET or NE abnormalities in the subject before and after administering the therapeutic agent. For example, comparing the extent of NET or NE abnormalities in a method of the invention can be performed qualitatively or quantitatively. An exemplary comparison can also be performed by conventional protocols, means, devices, apparatuses or systems known to those of ordinary skill in the art.
Moreover, the invention provides a method for treating depression, anxiety, ADHD, drug dependency or combinations thereof. In one embodiment, the method comprises administering to a subject in need thereof an effective amount of a compound of the invention. A method of the invention can also be performed to treat NET or NE abnormalities. Preferably, the method of treating NET or NE abnormalities can comprise administering to a subject in need thereof an effective amount of a compound of the invention. For example, the compound can be administered to the subject as a composition comprising at least one pharmaceutically acceptable carrier.
The invention also provides a method of assessing, evaluating or determining whether a conventional or emerging therapeutic agent for NET or NE abnormalities can be selective for at least one NET. For example, the method can be used to determine at which dosage
concentration the agent should be administered to a subject in order to treat a disease, disorder, condition or malady such as, without limitation, depression, anxiety, ADHD and drug dependency. In one embodiment, the method comprises administering an effective amount of a radiotracer of the invention to a subject not suffering from or believed to be at risk of suffering from NET or NE abnormalities and imaging the subject. Subsequently, the conventional or emerging agent can be administered to the subject at a first dosage concentration. The subject can then be imaged using a radiotracer of the invention. The method also comprises
administering the conventional or emerging agent to the subject at a second dosage
concentration, followed by imaging the subject with a radiotracer of the invention.
Exemplary administrations of the conventional or emerging agent to the subject can also be performed at several different dosage concentrations. After each administration, the subject can be imaged using a radiotracer of the invention. Data obtained from imaging the subject can provide a basis for assessing, evaluating or determining at which dosage concentration the conventional or emerging agent may be active or effective for selecting at least one NET.
Without limitation, the conventional or emerging agent can comprise a compound of the invention, hi one embodiment, data obtained from imaging the subject may also provide a basis for assessing, evaluating or determining NET occupancy achieved by the conventional or emerging agent. Similarly, the method of the invention can be used to assess, evaluate or determine whether a maximum dosage concentration of the conventional or emerging agent exists for the subject. The invention also contemplates using data obtained from imaging and maximum dosage concentrations to establish dosage levels, regimes or protocols for conventional or emerging agents, which can be routine for those of ordinary skill in the art.
Furthermore, the invention provides a method for longitudinally assessing, evaluating or deteraiining the efficacy of a conventional or emerging therapeutic agent in treating NET or NE abnormalities, hi one embodiment, the method comprises administering to a subject suffering from or believed to be at risk of suffering from NET or NE abnormalities an effective amount of a radiotracer of the invention. The method also comprises imaging the subject. The subject can then be administered the conventional or emerging agent for a longitudinal period that may include, for example, days, weeks, months or years. Subsequent to the longitudinal period, the subject can be administered an effective amount of a radiotracer of the invention and imaged. The method also comprises comparing data obtained from imaging the subject before and after administering the conventional or emerging agent to assess, evaluate or determine its efficacy in treating NET or NE abnormalities of the subject. The invention also contemplates performing additional imaging of the subject with varying longitudinal periods that include administering the conventional or emerging agent as well as absences thereof.
In one embodiment, the invention provides a protocol for in vivo imaging using a radiotracer of the invention. A subject can receive, without limitation, about 5 to 50 drops of a Lugol solution about 30 minutes prior to an injection comprising a radiotracer of the invention. The Lugol solution can minimize radioactive uptake by the thyroid. Body imaging can be performed with any suitable gamma camera, for example, a dual or triple headed gamma camera. Following an exemplary bolus intravenous administration of about 1 to 5OmCi of a radiotracer, for example, 2(S)-[(S)-(2-[123I]iodophenoxy)(phenyl) methyljmorpholine, over about 10 seconds, simultaneous anterior and posterior planar images of a subject's whole body may be obtained. For example, a protocol for in vivo imaging using a radiotracer of the invention can comprise a series of one to eleven whole body images obtained at various post injection time points. Such post injection time points can be, without limitation, 1 minute, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours and from about 18 to 24 hours. Counts can be acquired, for example, into a 128 x 128 matrix with a 20% symmetric energy window centered on 159kEv.
An exemplary protocol of the invention can also comprise, prior to use of a 2(S)-[(S)-(2— [123I]iodophenoxy)(phenyl)methyl]moφholine radiotracer, one to ten calibration sources containing 10-30μCi of 12 I that can be placed over the body of a subject as well as on the imaging table, providing a calibration factor for expression of counts as absolute units of radioactivity and estimating attenuation over different body regions for correction of counts. Commencing with a radiotracer injection, a 24 hour urine collection may also be initiated at several sampling periods such as, without limitation, about 0 to 4 hours, 4 to 8 hours, 8 to 12 hour, 12 to 16 hours and 16 to 24 hours. Moreover, blood aliquots, for example, about 1 to

20ml, can be sampled at the start of each image acquisition for the purposes of determining the amount of the radiotracer present in plasma. Blood aliquots may also be sampled in order to determine the amount, metabolic rate or pathway of the injected radiotracer.

Optionally, a protocol of the invention can also comprise assessing vital signs of the subject at pre-injection baseline and, for example, 15, 30, 60 and 90 minutes after administration of the radiotracer. An EKG can also be obtained at baseline and, without limitation, at 20 and 40 minutes post radiotracer injection. Adverse events can be assessed as vital signs are obtained. Clinical laboratory tests can be performed at baseline and after each injection including, without limitation, serum chemistry battery, complete blood count with differential and urinalysis. Anterior and posterior planar images can be transferred to a dedicated workstation and reviewed visually for assessment of body organ distribution of radioactivity. Regions of interest can be placed on the anterior and posterior source organ and the whole body. Moreover, the geometric mean of total counts may be calculated and converted into units of radioactivity using calibration sources determined or obtained at the onset of each imaging session. Radioactivity can also be corrected for body attenuation.
For a protocol of the invention, following the last imaging time point, residual radioactivity can be assumed to undergo physical decay only. A residence time may be determined for each source organ based on the area under the curve and time activity data divided by the injected dose. These data can be utilized in MERD calculations of target organ specific radiation absorbed doses with correction from urine assays and standard gastrointestinal kinetic models, hi one embodiment, a protocol of the invention can also comprise evaluating total source organ counts determined as the geometric mean of total counts in the anterior and posterior planar image, source organ uptake and washout with calculation of residence time as the area under the time activity curve divided by the injected dose of a radiotracer, radiation absorbed dose estimates based on using an MIRD method utilizing urine data in the model to increase the accuracy of bladder wall doses and ICRP 30 gastrointestinal tract kinetics or characterization of venous plasma for a compound or radiotracer, preferably, those protein bound and free, and metabolites.
In one embodiment, a SPECT imaging protocol of the invention can comprise use of fiducial markers such as, without limitation, 5 fiducial markers filled with, for example, about 1 to lOμCi of a radiotracer attached to both sides of a subject's head including, preferably, the canthomeatal line prior to imaging. The markers facilitate post hoc computer reorientation of transaxial images to aid in the standardization of brain orientation. Subjects can also be dosed by intravenous injection of, without limitation, about 5mCi of a radiotracer. Serial dynamic SPECT projection data can be acquired using any suitable gamma camera such as, for example, a three-headed detector SPECT system fitted with low-energy, high-resolution fanbeam collimators. Scans may be acquired, without limitation, for about 10 minutes at acquisition times x 6 scans, then 15 minutes x 4 scans and 20 minutes x 3 scans for a total of 13 SPECT scans acquired over 3 hours. Projection data can also be acquired, for example, into a 20% symmetric photopeak window centered on 159keV for a total of 120 raw projection images sampled every 3 degrees.
Preferably, uniformity corrected projection data can be reconstructed using, without limitation, filtered back-projection and a ramp filter. A standardized three dimensional
Butterworth filter can also be applied to the reconstructed images. Images may be reoriented to obtain an axial image set aligned parallel to the canthomeatal line. Attenuation correction can also be performed using, for example, a Chang zero order (homogeneous) correction applied to the reconstructed data via an empiric μ determined for a distributed radiosource in an anthropomorphic brain phantom. Venous sampling can be performed, without limitation, at the end of each SPECT acquisition for measurement of the radiotracer in plasma, for example, both protein bound and free.
In one embodiment, for bolus injection radiotracer SPECT protocols, parameters for evaluation include time to peak specific uptake for all brain regions, amplitude of specific peak for all brain regions, peak specific washout rates (linear and monoexponential fits of time-activity data) for all brain regions, ratio of early to late regional count density for all brain regions, standardized area under the time activity curve for all brain regions, brain to white matter DV ratio for all brain regions, brain to striatal (low density region) DV ratio for all brain regions, characterization of venous plasma and metabolites and pixel-wise parametric parameter estimates using, for example, a Ichise model for estimation of distribution volume. Preferably, the use of 123I can be effective for imaging with conventional nuclear medicine gamma cameras including, without limitation, those for SPECT imaging. 123I is a safe and routinely used detectable marker for thyroid scanning. For example, 123I has a relatively short half-life (13 hours) and is generally associated with low levels of radiation exposure to the subject. Emitted 123I gamma photons have an energy of 159keV.
For the treatment or prophylaxis of NET or NE abnormalities, a compound of the invention can be administered to a patient at dosage levels in the range of about 0.1 to about l,000mg per day. For a normal human adult with a body weight of about 70kg, a dosage in the range of about 0.01 to about 1 OOmg per kilogram of body weight per day can be sufficient. The specific dosage used may vary or can be adjusted as considered appropriate by those of ordinary skill in the art. For example, the dosage can depend on a number of factors including the requirements of the patient, severity of a disease, disorder, condition or malady being treated and pharmacological activities of the compound being used. The determination of practical dosages for a patient is well known to those of ordinary skill in the art.
The term "alkyl" as employed herein by itself or as part of another group refers to both straight and branched chain radicals of up to 8 carbons, preferably, 6 carbons such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and isobutyl. A compound or radiotracer of the invention can also comprise one or more alkyl substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al, Organic Chemistry (6th edition).
The term "alkoxy" is used herein to mean a straight or branched chain alkyl radical, as indicated, bonded to an oxygen atom including, but not limited to, methoxy, ethoxy, n-propoxy and isopropoxy. For example, the alkoxy chain is 1 to 6 carbon atoms in length and, preferably, 1—4 carbon atoms in length. A compound or radiotracer of the invention can also comprise one or more alkoxy substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I

Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).
The term "monoalkylamine" as employed herein by itself or as part of another group refers to an amino group that is substituted with one alkyl group as indicated. Thus, the term "methylamino" refers to a neutral group or ring substituent in which N is connected to a compound of the invention via the ring or a chain of the compound and N is further bound to a methyl and a hydrogen. Moreover, the N may be charged and may form a salt. A compound or radiotracer of the invention can also comprise one or more monoalkylamine substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).
The term "dialkylamine" as employed herein by itself or as part of another group refers to an amino group that is substituted with two alkyl groups as indicated. Thus, the term
"dimethylamino" refers to a neutral group or ring substituent in which N is connected to a compound of the invention via the ring or a chain of the compound and N is further bound to two methyl groups. In addition, the N may be charged and may form a salt. A compound or radiotracer of the invention can also comprise one or more dialkylamine substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al, Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).
The term "hydroxyl alkyl" as employed herein refers to an alkyl chain connected to a compound of the invention via the ring or a chain of the compound in which the distal portion of the alkyl chain of the group contains a hydroxy moiety. The alkyl chain can contain any number of carbons, but, preferably, the number of carbons in the alkyl chain is from 1 to 6. A compound or radiotracer of the invention can also comprise one or more hydroxyl alkyl substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).
The term "halo" employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine. A compound or radiotracer of the invention can also comprise one or more halo substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).
The term "haloalkyl" as employed herein refers to any of the mentioned alkyl groups substituted by one or more chlorine, bromine, fluorine or iodine with fluorine and chlorine such as chloromethyl, iodomethyl, trifluoromethyl, 2,2,2-trifluoroethyl and 2-chloroethyl. A compound or radiotracer of the invention can also comprise one or more haloalkyl substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).
The term "alkylthio" as employed herein by itself or as part of another group refers to a thioether of the structure: Rx-S in which Rx is a C1^ alkyl. A compound or radiotracer of the invention can also comprise one or more alkylthio substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).
The term "alkylsulfonyl" as employed herein by itself or as part of another group refers to a sulfone of the structure: Ry-SO2 in which Ry is a C1-^ alkyl. A compound or radiotracer of the invention can also comprise one or more alkylsulfonyl substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).
The term "aryl" as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably, 6-10 carbons in the ring portion such as phenyl, naphthyl or tetrahydronaphthyl. A compound or radiotracer of the invention can also comprise one or more aryl substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).
The term "heterocycle" or "heterocyclic ring", as used herein unless noted otherwise, represents a stable 4 to 7 membered monc—heterocycric ring system that may be saturated or unsaturated, and consist of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S. Moreover, the nitrogen and sulfur heteroatom may optionally be oxidized. Especially useful are rings containing one nitrogen combined with one oxygen or sulfur or two nitrogen heteroatoms. Examples of such heterocyclic groups include piperidinyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, homopiperidinyl, homopiperazinyl, pyridazinyl, pyrazolyl, and pyrazolidinyl, most preferably thiamoφholinyl, piperazinyl and morpholinyl. A compound or radiotracer of the invention can also comprise one or more heterocycle or heterocyclic ring substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).
The term "heteroatom" is used herein to mean an oxygen atom ("O"), a sulfur atom ("S") or a nitrogen atom ("N"). It will also be recognized that when the heteroatom is nitrogen, it may form an NRaRb moiety in which Ra and Rb are independently hydrogen, C1-^ alkyl, C2_6 aminoalkyl, C1^ halo alkyl or halo benzyl. Moreover, Ra and Rb can be taken together to form a 5 to 7 membered heterocyclic ring that optionally comprises O, S or NR0 in which Rc is hydrogen or C1-^ alkyl. A compound or radiotracer of the invention can also comprise one or more heteroatom substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).

The term "heteroaryl" as employed herein refers to groups having 5 to 14 ring atoms, 6, 10 or 14 n-electrons shared in a cyclic array and containing carbon atoms and 1 , 2 or 3 oxygen, nitrogen or sulfur heteroatoms in which examples of heteroaryl groups are thienyl,
benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H- quinolizinyl, isoquinolyl, quinolyl, phtlialazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carboliiiyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups. A compound or radiotracer of the invention can also comprise one or more heteroaryl substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).
The term "aralkyl" or "arylalkyl" as employed herein by itself or as part of another group refers to C[_6 alkyl groups as indicated having an aryl substituent such as benzyl, phenylethyl or 2-naphthylmethyl. A compound or radiotracer of the invention can also comprise one or more aralkyl or arylalkyl substituents included via adaptation of general organic chemistry techniques known to those of ordinary skill in the art. March et al., Advanced Organic Chemistry: I Reactions, Mechanisms and Structure (3rd edition); Morrison et al., Organic Chemistry (6th edition).
The examples herein are provided to illustrate advantages of the present invention that have not been previously described and to further assist a person of ordinary skill in the art with that set forth herein. The examples can include or incorporate any of the variations or embodiments of the invention described above. For example, a composition of the invention can comprise at least one compound or radiotracer thereof for administration to a subject. The composition can be used for prophylaxis or treatment of a disease, disorder, condition or malady or in vivo imaging of NET. The embodiments described above may also further each include or incorporate the variations of any or all other embodiments of the invention.

EXAMPLE I
Synthesis I

lOOg of AD-Mix-α was prepared by mixing 69.2Og OfK3Fe(CN)6, 29.0Og K2CO3, 0.16Og OfOsO4, 2H2O and 1.64Og of (DHQ)2PHAL.

(2R,3S)-ethyl 2,3-dihydroxy-3-phenylρropanoate (2a)
In a mixture tBuOH/H2O (1 Oml/1 OmI) was dissolved AD-Mix- α (11.2g, 1 Ag for lmmol of ethyl cinnamate) and methanesulfonamide (760mg, leq), then at 00C was added dropwise (E)-ethyl cinnamate Ia (1.34ml, 1 eq) and the resulting mixture was vigorously stirred for 2 hours (h) at room temperature (RT). A saturated solution of sodium thiosulfate (100ml) was added to the mixture, extracted with AcOEt (3 x 75ml) and dried over Na2SO4.
Evaporation and chromatography (SiO2, Hexane/AcOEt 7/3) of the residue provided 2a as a white solid in 78% yield.
NMR 1H (CDCl3), δ=0.97 (t, 3H, J=6.5Hz, CH3); 3.31 (d, IH, J=6.5Hz5 OH); 3.47 (d, IH5 J=6.5Hz, OH); 3.94-3.96 (m, 2H, CH2); 4.06 (dd, IH, J=6.5, 3.5Hz, CH); 4.71 (dd, IH, J=6.5, 3.5Hz, CH); 7.06-7.15 (m, 5H, CHAr). NMR 13C (CDCl3), δ=14.4 (1C, CH3); 62.3 (1C, CH2); 75.1 (1C, CH); 75.4 (1C, CH); 126.7 (2C, CHAr); 128.3 (1C, CHAr); 128.7 (2C5 CHAr); 140.4 (1C, Cq); 173.1 (IC5 Cq).

(4R55S)-€thyl 2,2-dimethyl-5-phenyl-l ,3-dioxolane-4-carboxylate (3a)
In 40ml OfCH2Cl2 was dissolved 2a (Ig, leq) then were added 2,2-dimethoxypropane (2.3ml, 4eq) and PTSA (20mg, catalyst). The resulting solution was stirred for 1 night at RT5 hydrolyzed with 30ml of saturated K2CO3, extracted with CH2Cl2, dried over Na2SO4 and concentrated in vacuum, yielding 3 a in 98% as a colorless oil.
NMR 1H (CDCl3), δ=l .27 (t, 3H5 J=7.15Hz, CH3); 1,58 (s, 3H5 CH3); 1.63 (s, 3H5 CH3);

4.22-4.27 (m, 2H5 CH2); 4.35 (d, IH5 J=7.6Hz, CH); 5.17 (d, IH, J=7.6Hz, CH); 7.33-7.46 (m, 5H, CHAr). NMR 13C (CDCl3), δ=14.5 (1C, CH3); 26.1 (1C, CH3); 27.3 (1C, CH3) 42.8 (1C, Cq); 61.8 (1C, CH2); 81.2 (1C, CH); 81.7 (1C, CH); 111.9 (IC5 CHAr); 126.9 (2C5 CHAr); 128.9 (2C5 CHAr); 138.1 (1C, Cq); 170.6 (1C, Cq).

((4S,5S)-2,2-dimethyl-5-phenyl-l ,3-dioxolan-^-yl)methanol (4a)
In 30ml of THF was dissolved 3a (1.15g, leq) then at O0C was added by portions LiAlH4 (346mg, 2eq) and the resulting solution was refluxed for 2h. After cooling to 0°C, the reaction was hydrolyzed with 10ml of IN NaOH, extracted with AcOEt, washed with H2O, dried over Na2SO4 and concentrated in vacuum, affording 4a in 78% yield as a colorless oil.
NMR 1U (CDCl3), δ=1.41 (s, 3H, CH3); 1,46 (s, 3H, CH3); 2.79 (bs, IH, OH); 3.48-3.52 (m, IH); 3.68-3.76 (m, 2H); 4.76 (d, IH, J=8.8Hz, CH); 7.18-7.28 (m, 5H, CHAr). NMR 13C (CDCl3), δ=27.5 (2C5 CH3); 60.8 (IC5 CH2); 79.1 (IC5 CH); 84.2 (1C, CH); 109.6 (IC5 Cq); 126.9 (2C5 CHAr); 128.7 (IC5 CHAr); 128.9 (2C5 CHAr); 138.1 (1C, Cq).

(1 S,2R)-3-chloro-l-phenylpropane-l 52-diol (6a)
In a mixture tBuOH/H2O (25ml/25ml) was dissolved AD-Mix-α (11.2g5 1.4g for lmmol of l-((E)-3-chloroprop-l-enyl)benzene) and methanesulfonamide (760mg, leq), then at O0C was added dropwise l-((E)-3-chloroprop-l-enyl)benzene 5a (1.1 ImI, leq) and Hie resulting mixture was vigorously stirred for 16h at 00C. A saturated solution of sodium thiosulfate (100ml) was added to the mixture, extracted with AcOEt (3 x 75ml) and dried over Na2SCH. Evaporation and chromatography (SiO2, Hexane/AcOEt 7/3) of the residue provided 6a as a colorless oil in 93% yield.
NMR 1H (CDCl3), 5=3.15-3.19 (m, IH); 3.34-3.38 (m, IH); 3.68-3.73 (m, IH); 3.80 (d, IH, J=5.1Hz, OH); 3.87 (d, IH, J=3.8Hz, OH); 4.51-4.54 (m, IH); 7.02-7.24 (m, 5H, CHAr). NMR 13C (CDCl3), 6=47.0 (1C, CH2); 75.4 (1C, CH); 76.2 (1C, CH); 127,7 (2C, CHAr); 129.1 (1C, CHAr); 129.4 (2C, CHAr); 141.1 (1C, Cq).

(4R,5S)-4-(chloromethyl)-2,2-dimethyl-5-phenyl-l,3-<iioxolane (7a), from 4a
In CHCl3 15ml was dissolved 4a (743mg, leq) and Et3N (978μl, 3eq), then at 0°C was added dropwise POCl3 (1.49ml, 3eq) and the resulting mixture was refluxed for 2h. After evaporation of the reaction, the residue was dissolved in CHCl3, washed with saturated NaHCO3 and dried over Na2SO4. Evaporation and chromatography (SiO2, Hexane/AcOEt 8/2) of the residue provided 7a as a colorless oil in 71% yield.

(4R,5S)-4-(chloromethyl)-2,2-dimethyl-5-phenyl-l,3-dioxolane (7a), from 6a
In 40ml OfCH2Cl2 was dissolved 6a (Ig, leq) then were added 2,2-dimethoxypropane (2.6ml, 4eq) and PTSA (20mg, catalyst). The resulting solution was stirred for 1 night at RT, hydrolyzed with 30ml of saturated K2CO3, extracted with CH2Cl2, dried over Na2SO4 and concentrated in vacuum, yielding 7a in 99% as a colorless oil.
NMR 1H (CDCl3), δ=1.43 (s, 3H, CH3); 1.47 (s, 3H, CH3); 3.46 (dd, IH, J=IZO, 4.8Hz,

CH2a); 3.60 (dd, IH, J=12.0, 3.5Hz, CH2b); 3.90 (qint, IH, J=3.5Hz, CH); 4.77 (d, IH, J=8.2Hz, CH); 7.20-7.29 (m, 5H, CHAr). NMR 13C (CDCl3), δ=27.4 (1C, CH3); 27.6 (1C, CH3); 43.3

(1C, CH2); 80.8 (1C, CH); 82.7 (1C, CH); 110.1 (1C, Cq); 127.3 (2C, CHAr); 129.0 (1C,

CHAr); 129.1 (2C, CHAr); 137.5 (1C, Cq).

2-(N-benzyl-N-(((4S,5S)-2,2-dimethyl-5-phenyl-l,3-dioxolan-4-yl)methyl)amino)ethanol (8a)
In a sealed tube were mixed 7a (1.0Ig, leq) and N-benzylethanolamine (2.02g, 3eq) and the resulting solution was heated at 150°C for 24h. After cooling the reaction was diluted with

-Al- AcOEt, washed with NaOH 30% and dried over Na2SO4. Evaporation and chromatography

(SiO2, Hexane/AcOEt 8/2) of the residue provided 8a as a colorless oil in 91% yield.
NMR 1H (CDCl3), δ=l .40 (s, 3H, CH3); 1.46 (s, 3H, CH3); 2.51-2.55 (m, IH); 2.59-2.64

(m, IH); 2.67-2.70 (m, 3H); 3.39-3.45 (m, 2H); 3.53 (s, 2H); 3.85-3.89 (m, IH); 4.42 (d, IH, J=8.5Hz); 6.89-7.05 (m, 2H, CHAr); 7.13-7.17 (m, 5H, CHAr); 7.22-7.27 (m, 3H, CHAr).

NMR 13C (CDCl3), 5=27.5 (1C, CH3); 27.7 (1C, CH3); 54.9 (1C, CH2OH); 56.6 (1C, CH2); 59.5

(1C, CH2); 59.7 (1C, CH2); 82.0 (1C, CH); 82.2 (1C, CH); 109.6 (1C, Cq); 127.2 (2C, CHAr);

127.5 (1C, CHAr); 128.7 (2C, CHAr); 128.8 (1C, CHAr); 129.0 (2C, CHAr); 129.4 (2C,

CHAr); 138.0 (1C, Cq); 138.8 (1C, Cq).

N-benzyl-2-chloro-N-(((4S,5S)-2,2-dimethyl-5-phenyl-l,3-dioxolan-4-yl)methyl) ethanamine (9a)
In CHCl3 10ml was dissolved 8a (800mg, leq) and Et3N (976μl, 3eq), then at 00C was added dropwise POCl3 (640ml, 3eq) and the resulting mixture was refluxed for 2h before evaporation in vacuum. The residue was dissolved in CHCl3, washed with NaHCO3 and dried over Na2SO4. Evaporation and chromatography (SiO2, Hexane/AcOEt 8/2) of the residue provided 9a as a colorless oil in 93% yield.
NMR 1H (CDCl3), δ=1.39 (s, 3H, CH3); 1.44 (s, 3H, CH3); 2.70-2.77 (m, 3H); 3.02- 3.06 (m, IH); 3.31-3.38 (m, 2H); 3.51-3.60 (m, 2H); 3.84-3.88 (m, IH); 4.52 (d, IH, J=8.5Hz); 7.06-7.19 (m, 1OH, CHAr). NMR 13C (CDCl3), 5=27.5 (1C, CH3); 27.7 (1C, CH3); 42.1 (1C,

CH2Cl); 54.8 (1C, CH2); 56.8 (1C, CH2); 59.9 (1C, CH2); 81.8 (1C, CH); 82.6 (1C, CH); 109.5

(1C, Cq); 127.2 (2C, CHAr); 127.5 (1C, CHAr); 128.6 (1C, CHAr); 128.7 (2C, CHAr); 128.9

(2C, CHAr); 129.4 (2C, CHAr); 138.3 (1C, Cq); 139.9 (1C, Cq).

(1 S,2S)-3-(N-benzyl-N-(2-chloroethyl)amino)-l-ρhenylρropane-l ,2-diol (1 Oa)
In a mixture THF/H2O (2/1) 30ml was dissolved dioxolane 9a (843mg) and at 00C was added TFA 5ml and the resulting solution was stirred at RT for 1 night. After cooling at 0°C, a saturated solution OfK2CO3 was added dropwise to pH=8, extracted with AcOEt, washed with H2O and dried over Na2SO4. Evaporation provided 1 Oa as a brownish oil in 87% yield.
NMR 1H (CDCl3), 5=2.35-2.36 (m, IH); 2.45-2.51 (m, IH); 2.64-2.69 (m, IH); 2.75- 2.80 (m, IH); 3.37-3.44 (m, 2H); 3.65-3.70 (m, 2H); 4.32^.35 (m, IH); 7.12-7.21 (m, 1OH, CHAr). NMR 13C (CDCl3), 5=42.1 (1C, CH2); 56.1 (1C, CH2); 57.0 (1C, CH2); 59.4 (1C, CH2);

72.1 (1C, CH); 76.1 (1C, CH); 127.1 (2C, CHAr); 128.0 (1C, CHAr); 128.3 (1C, CHAr); 128.7 (2C, CHAr); 129.0 (2C, CHAr); 129.5 (2C, CHAr); 141.2 (2C, Cq).

(S)-((S)-4-benzylmorpliolin-2~yl)(phenyl)methanol (1 Ia)
In 5ml of dry DMF was dissolved 10a (250mg, leq) and NaH (56mg, 3eq) was added by portions over 30 minutes (min) and the resulting mixture was stirred at RT for 3h. Thereafter, the reaction was portioned between H2O and AcOEt and the organic layer was washed with H2O and dried over Na2SO4. Evaporation and chromatography (SiO2, Hexane/ AcOEt 1/1) of the residue provided 1 Ia as a colorless oil in 61% yield.
NMR 1H (CDCl3), δ=l .90-2.03 (m, 2H); 2.32 (d, IH, J=I 1.2Hz); 2.43 (d, IH,
J=I 1.2Hz); 3.16 (d, IH, J=13.0Hz); 3.40 (d, IH, J=13.0Hz); 3.50-3.58 (m, 2H); 3.78 (dt, IH, J=I 1.2, 2.6Hz); 4.44 (d, IH, J=7.3Hz); 7.10-7.22 (m, 1OH, CHAr). NMR 13C (CDCl3), δ-52.6 (1C, CH2); 55.5 (1C, CH2); 63.6 (1C, CH2); 66.9 (1C, CH2); 75.8 (1C, CH); 79.8 (1C, CH); 127.4 (2C, CHAr); 127.6 (1C, CHAr); 128.4 (1C, CHAr); 128.7 (2C, CHAr); 128.8 (2C, CHAr); 129.6 (2C, CHAr); 137.7 (1C, Cq); 140.5 (1C, Cq).

EXAMPLE II
Synthesis II



1b 2b 3b


lOOg of AD-Mix-β was prepared by mixing 69.2Og OfK3Fe(CN)6, 29.0Og K2CO3, 0.16Og OfOsO4, 2H2O and 1.64Og Of(DHQD)2PHAL.

(2R,3R)-ethyl 2,3-dihydroxy-3-phenylpropanoate (2b)
In a mixture tBuOH/H2O (lOml/lOml) was dissolved AD-Mix-β (11.2g, 1.4g for lmmol of ethyl cinnamate) and methanesulfonamide (760mg, leq), then at O0C was added dropwise (Z)-ethyl cinnamate Ib (1.34ml, leq) and the resulting mixture was vigorously stirred for 2h at RT. A saturated solution of sodium thiosulfate (100ml) was added to the mixture, extracted with AcOEt (3 x 75ml) and dried over Na2SO4. Evaporation and chromatography (SiO2, Hexane/AcOEt 7/3) of the residue provided 2b as a white solid in 78% yield. m/z=211.2 (m + 1).

(4R,5R)-ethyl 2,2-dimethyl-5-phenyl-l,3-dioxolane-Φ-carboxylate (3b)
hi 40ml OfCH2Cl2 was dissolved 2b (Ig, leq) then were added 2,2-dimethoxypropane (2.3ml, 4eq) and PTSA (20mg, catalyst). The resulting solution was stirred for 1 night at RT, hydrolyzed with 30ml of saturated K2CO3, extracted with CH2Cl2, dried over Na2SO4 and concentrated in vacuum to yield 3b in 96% as a colorless oil. m/z=251.3 (m + 1).

((4S,5R>-2,2-dimethyl-5-phenyl-l ,3-dioxolan-4-yl)methanol (4b)
In 30ml of THF was dissolved 3b (1.15g, leq) then at 0°C was added by portions LiAlH4 (346mg, 2eq) and the resulting solution was refluxed for 2h. After cooling to 0°C, the reaction was hydrolyzed with 1 OmI of IN NaOH, extracted with AcOEt, washed with H2O, dried over Na2SO4 and concentrated in vacuum, affording 4b in 75% yield as a colorless oil. m/z=209.2 (m + l).

(4R,5R)-4-(chloromethyl)-2,2-dimethyl-5-phenyl-l ,3-dioxolane (7b)
In CHCl3 15ml was dissolved 4b (743mg, leq) and Et3N (978μl, 3eq), then at 00C was added dropwise POCl3 (1.49ml, 3eq) and the resulting mixture was refluxed for 2h. After evaporation of the reaction, the residue was dissolved hi CHCl3, washed with saturated NaHCO3 and dried over Na2SO4. Evaporation and chromatography (SiO2, Hexane/ AcOEt 8/2) of the residue provided 7b as a colorless oil in 67% yield. m/z=227.6 (m + 1).

2-(^-beiizyl-N-(((4S,5R)-2,2-^imethyl--5-phenyl-l,3-dioxolan-4-yl)methyl)ammo)ethanol

(8b)
In a sealed tube were mixed 7b (l.Olg, leq) and N-benzylethanolamine (2.02g, 3eq) and the resulting solution was heated at 15O0C for 24h. After cooling, the reaction was diluted with AcOEt, washed with NaOH 30% and dried over Na2SO4. Evaporation and chromatography

(SiO2, Hexane/AcOEt 8/2) of the residue provided 8b as a colorless oil in 91% yield. m/z=342.4

(m+ 1).

N-benzyl-2-chloro-N-(((4S,5R)-2,2-dimethyl-5-phenyl-l,3-dioxolan-^-yl)methyl) ethanamine (9b)
In CHCl3 10ml was dissolved 8b (800mg, leq) and Et3N (976μl, 3eq), tlien at 0°C was added dropwise POCl3 (640ml, 3eq) and the resulting mixture was refluxed for 2h before evaporation in vacuum. The residue was dissolved in CHCl3, washed with NaHCO3 and dried over Na2SO4. Evaporation and chromatography (SiO2, Hexane/AcOEt 8/2) of the residue provided 9b as a colorless oil in 78% yield. m/z=361.0 (m + 1).

(lR,2S)-3-(N-benzyl-N-(2-chloroethyl)amino)-l-ρhenylρroρane-l ,2-diol (1 Ob)
In a mixture THF/H2O (2/1) 30ml was dissolved dioxolane 9b (843mg) and at 00C was added TFA 5ml and the resulting solution was stirred at RT for 1 night. After cooling at 00C, a saturated solution OfK2CO3 was added dropwise to pH=8, extracted with AcOEt, washed with H2O and dried over Na2SO4. Evaporation provided 10b as a brownish oil in 89% yield.
m/z=320.7 (m + l).

(RH(S)-4-benzylmorpholin-2-yl)(phenyl)methanol (1 Ib)
hi 5ml of dry DMF was dissolved 10b (250mg, leq) and NaH (56mg, 3eq) was added by portions over 30min and the resulting mixture was stirred at RT for 3h. Thereafter, the reaction was portioned between H2O and AcOEt and the organic layer was washed with H2O and dried over Na2SO4. Evaporation and chromatography (SiO2, Hexane/ AcOEt 1/1) of the residue provided 1 Ib as a colorless oil in 61% yield. m/z=284.3 (m + 1).

EXAMPLE III
Synthesis III


((2R,3R)-3-phenyloxiran-2-yl)methanol (15)
To 50ml OfCH2Cl2 at -100C was added successively 0.9g of crush 4A activated molecular sieves, D-(-)-diethyl tartarate (0.5g, 7mol percent), Ti(OiPr)4 (0.45g, 5mol percent) and tBuOOH 6.2M in CH2Cl2 (7.8ml, 1.5eq). After lOmin, the mixture was cooled at -2O0C and trans cinnamylalcohol (4.35g, leq) was added dropwise in 10ml OfCH2Cl2. The resulting mixture was stirred for Ih at -2O0C and Ih at 0°C before addition of 10ml of H2O. Thereafter, 2.5ml of NaOH 30% were added and after lOmin of stirring the organic phase was separated, washed with H2O and dried over Na2SO4. Evaporation and chromatography (SiO2,
Hexane/Et2O 9/1) of the residue provided 15 as a white solid in 81% yield.
NMR 1H (CDCl3), δ=1.84 (bs, IH); 3.20 (d, J=4.2, 2.2Hz, IH); 3.74 (dd, J=12.7, 4.2Hz, IH); 3.88 (d, J=2.2Hz, IH); 4.01 (dd, J-12.7, 2.2Hz, IH); 7.27-7.38 (m, 5H). NMR 13C (CDCl3), δ=55.8; 61.7; 62.8; 116.7; 126.1; 128.5; 128.8.

(2S,3R)-2-(chloromethyl)-3-phenyloxirane (17)
In CHCl3 10ml was dissolved 15 (Ig, leq) and Et3N (2.78ml, 3eq), then at O0C was added dropwise POCl3 (1.86ml, 3eq). The resulting mixture was refluxed for 2h before evaporation in vacuum. The residue was dissolved in CHCl3, washed with NaHCO3 and dried over Na2SO4. Evaporation and chromatography (SiO2, Hexane/Et2O 95/5) of the residue provided 17 as a colorless oil in 90% yield.
NMR 1H (CDCl3), δ=3.28 (ddd, J=5.8, 4.8, 1.9Hz, IH); 3.66 (dd, J=I 1.8, 5.8Hz, IH); 3.72 (dd, J=I 1.8, 4.8,Hz, IH); 3.82 (d, J=I .9Hz, IH); 7.26-7.38 (m, 5H). NMR 13C (CDCl3), δ=44.3; 58.5; 60.9; 116.6; 125.6; 128.6; 135.9.

(2S,3R)-3-phenyloxirane-2-carbaldehyde (16)
hi 60ml OfCHCl3 was dissolved trans-cinnaldehyde (3.1ml, leq), a,a-diphenyl-L-trimethylsilylprolinol (800mg, lOmol percent) and H2O2 30% (3.05ml, 1.2eq). The resulting mixture was stirred at RT for 2h. Thereafter, 30ml of H2O were added, extracted with CH2Cl2 and dried over Na2SO4. Evaporation and chromatography (SiO2, Hexane/AcOEt 95/5) of the residue provided 16 as a colorless oil in 80% yield.
NMR 1H (CDCl3), δ=3.5 (dd, IH, J=5.8, 1.8Hz, CH); 4.22 (d, IH, J=I.8Hz, CH); 7.32- 7.44 (m, 5H, CHAr); 9,23 (d, IH, J=5.8Hz, CHO). NMR 13C (CDCl3), δ=57.2 (1C, CH); 63.2 (1C, CH); 126.2 (2C, CHAr); 129.1 (1C, CHAr); 129.5 (1C, CHAr); 134.8 (1C, Cq); 197.3 (1C,

CHO).

2-(N-benzyl-N-(((2R,3R)-3-ρhenyloxiran-2-yl)methyl)amino)ethanol (18), from 17
In a sealed tube were mixed 17 (Ig, leq) and N-benzylethanolamine (3.33g, 3eq). The resulting solution was heated at 50°C for 24h. After cooling, the reaction was diluted with AcOEt, washed with NaOH 30% and dried over Na2SO4. Evaporation and chromatography (SiO2, Hexane/ AcOEt 8/2) of the residue provided 18 as a colorless oil in 53% yield.

2-(N-benzyl-N-(((2R,3R)-3-ρhenyloxiran-2-yl)methyl)amino)ethanol (18), from 16
hi 30ml of MeOH was dissolved 16 (2.9g, 1 eq) and N-benzylethanolamine (4.Og,

1.1 eq). Thereafter, at 0°C was added NaBH3CN and the resulting mixture was stirred at RT for 1 night. 30ml of H2O were also added, extracted with AcOEt and dried over Na2SO4.
Evaporation and chromatography (SiO2, Hexane/ AcOEt 7/3) of the residue provided 18 as a colorless oil in 80% yield.
NMR 1H (CDCl3), 5=2.52-2.63 (m, 2H); 2.70-2.76 (m, IH); 2.81-2.89 (m, 2H); 2.98- 3.00 (m, IH); 3.47-3.52 (m, 3H); 3.58 (d, IH, J=13.5Hz); 3.68 (d, IH, J=13.5Hz); 7.08-7.20 (m, 1OH, CHAr). NMR 13C (CDCl3), δ=55.7 (1C, CH2); 56.5 (1C, CH2); 57.1 (1C, CH); 59.4 (1C, CH2); 59.7 (1C, CH2); 61.7 (1C, CH); 126.0 (2C, CHAr); 127.8 (1C, CHAr); 128.7 (1C, CHAr); 128.9 (2C, CHAr); 129.0 (2C, CHAr); 129.4 (2C, CHAr); 137.4 (1C, Cq); 138.9 (1C, Cq).

(RH(S)-4-benzylmorpholin-2-yl)(phenyl)methanol (1 Ib)
In 5ml of dry DMF was dissolved 18 (250mg, leq) and NaH (63mg, 3eq) was added by portions over 30min. The resulting mixture was stirred at RT for 24h. Thereafter, the reaction was portioned between H2O and AcOEt and the organic layer was washed with H2O and dried over Na2SO4. Evaporation and chromatography (SiO2, Hexane/AcOEt 6/4) of the residue provided 1 Ib as a colorless oil in 32% yield. m/z=284.3 (m + 1).

EXAMPLE IV
Synthesis IV



hene


H

R2=H

For a person of ordinary skill in the art, the exemplary syntheses of compounds 24 and 25 are generally related to that for compounds 24a through 24c and 25a through 25c, respectively. Moreover, the exemplary synthesis of compound 29 is generally related to that for compounds 29a through 29h. The exemplary synthesis of compound 30 is also generally related to that for compounds 30a through 30c.

2-chloro-N-((S)-2,3-dihydroxypropyl)acetamide (19)
To a solution of (S)—3-amino-l,2— propanediol (5.24g, 57.51mmol, leq) in amixture

CH3CNZMeOH (190ml/33ml) at-10°C was added triethylamine (9.60ml, 69.0mmol, 1.2eq). Chloroacetyl chloride (5.10ml, 63.3mmol, l.leq) was then added dropwise at -1O0C over 1.5h under nitrogen. The mixture was allowed to reach RT and stirred overnight (16h). The crude was concentrated under vacuum and purified by flash chromatography on silica gel with MeOH/EtOAc (8 :92) to provide 19 as a white solid (9.05g, 94%).
NMR 1H (DMSCM6), δ=8.02 (s, IH, NH); 4.27 (s, IH, OH); 4.48 (s, IH, OH); 4.06 (s, 2H, CH2Cl); 3.56-3.50 (m, IH); 3.38-3.23 (m, 3H); 3.07-2.99 (m, IH, CH2NH). NMR 13C (DMSO-d6), 5=166.1 (CO); 70.0 (CHOH); 63.8 (CH2OH); 42.7 (CH2); 42.6 (CH2).

6-(hydroxymethyl)morpholin-3-one (20)
To a stirred solution of potassium tert-butoxide (14.49g, 129.1mmol, 2.5eq) in 100ml tert-amyl alcohol at RT was added 19 (8.65g, 51.6mmol, leq) in 215ml tert-amyl alcohol over 2h under nitrogen. After one more hour, MeOH (50ml) and H2O (3ml) were added and the mixture was stirred for an additional 20min. The crude was concentrated under vacuum and purified by flash chromatography on silica gel with MeOH/EtOAc (20:80) to provide 20 as a white solid (6.22g, 92%).
NMR 1H (DMSO-d6), δ=7.93 (s, IH, NH); 4.85 (t, IH, CH2OH, J=5.5Hz), 4.00 (m, 2H, CH2O); 3.68-3.61 (m, IH); 3.52-3.38 (m, 2H); 3.21-3.15 (m, IH, CH2NH); 3.11-3.04 (m, IH, CH2NH). NMR 13C (DMSO-d6), 5=167.6 (CO); 73.5 (CH); 66.8 (CH2O); 61.7 (CH2OH); 42.6 (CH2NH).

(S)-2-(hydroxymethyl)morpholine (21)
To a suspension of 20 (previously crushed) (11.75g, 89.69mmol, leq) in anhydrous THF (450ml) at O0C was slowly added a solution of red-Al (bis(2-methoxyethoxy)aluminum hydride) at 65 wt percent in toluene (11 OmI, 359mmol, 4eq) over Ih under nitrogen. The mixture was stirred overnight (16h) at RT and then cooled at 0°C before addition of 7ml of water followed by 14ml of a 4N potassium hydroxide solution. The precipitate obtained was filtered through Celite and rinsed with CH2Cl2. The filtrate was concentrated under vacuum and purified by flash chromatography on silica gel with MeOH/CHCl3 (25:75) to provide 21 as a pale yellow oil (8.93g, 85%).
NMR 1H (DMSO-d6), 8=4-12-4.02 (br, 2H); 3.74-3.68 (m, IH); 3.45-3.38 (m, IH); 3.36-3.31 (m, 2H); 3.28-3.22 (m, IH); 2.84-2.76 (m, IH); 2.70-2.57 (m, 2H); 2.38-2.32 (m, IH). NMR 13C (DMSO<i6), 5=76.8 (CH); 66.6 (CH2O); 62.7 (CH2OH), 47.8 (NCH2CH2); 45.2 (NCH2CH).

(S)-2-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (22)
To a vigorously stirred solution of 21 (5.73g, 48.97mmol, leq) in a mixture OfCH2Cl2 (50ml) and water (36ml) was added at RT (13.50ml, 53.87mmol, l.leq) a 4N sodium hydroxide solution. Di-tert-butyl dicarbonate (10.69g, 48.97mmol, leq) was then added dropwise to the mixture. After 3h, the mixture was extracted three times with CH2Cl2, the extracts were combined, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel with EtOAc/hexane (50:50) to provide 22 as a white solid (8.86g, 83%).
NMR 1H (CDCl3), 5=3.98-3.76 (m, 3H); 3.70-3.48 (m, 4H); 3.02-2.87 (br, IH); 2.84-2.69 (m, 2H); 1.47 (s, 9H, 3CH3). NMR 13C (CDCl3), 5=154.8 (CO); 80.1 (C(CH3)3); 75.9 (CH); 66.4 (CH2OH); 63.4 (CH2O); 44.8 (br, NCH2CH); 43.5 (br, NCH2CH2); 28.4 (CH3).

(S)-2-formylmorpholine-4-carboxylic acid tert-butyl ester (23)
To a solution of alcohol 22 (2.17g, lO.Ommol, leq) and TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, 16mg, O.lOmmol, lmol percent) in 25ml EtOAc under nitrogen, was added NaHCO3 (2.52g, 30mmol, 3eq). The mixture was cooled at -50C and trichloroisocyanuric acid (2.44g, 10.5mmol, 1.05eq) in 40ml EtOAc was added dropwise over a period of Ih. After stirring Ih at — 5°C, 100ml of a IM solution of sodium iodide were added and the mixture extracted three times with EtOAc. The organic layers were combined before addition of 150ml OfNa2SO3 10%. The aqueous layer was washed twice with EtOAc, then the organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. Filtration through a Whatman 0.45μm PFTE filter and evaporation of the solvent provided the aldehyde 23 as a yellow oil (1.92g, 89%).
NMR 1H (CDCl3), 5=9.62 (s, IH, HCO); 4.15-3.71 (m, 4H); 3.68-3.52 (m, IH); 3.12-2.79 (m, 2H); 1.45 (s, 9H, 3CH3). NMR 13C (CDCl3), 5=200.1 (HCO); 154.5 (NCO); 80.6 (C(CH3)3); 79.0 (CH); 66.3 (CH2O); 43.7 (br, NCH2CH); 42.9 (br, NCH2CH2); 28.4 (CH3).

(2S,3S)-2-[hydroxy(phenyl)methyl]morpholine-4-carboxylic acid tert-butyl ester (24a) and (2S,3R)-2-[hydroxy(phenyl)methyl]morpholine-4-carboxylic acid tert-butyl ester (25a)
To a suspension of magnesium (709mg, 29.20mmol, 4eq) in the presence of a crystal of I2 in 45ml THF, was added dropwise, over 45min5 bromobenzene (3.10ml, 29.2mmol, 4eq) at RT (the reaction was initiated with a heat gun) under nitrogen. After Ih, the solution was cooled to -100C and ZnBr2 (3.6Ig, lθ.lmmol, 2.2eq) in 10ml THF was added dropwise. The mixture was allowed to reach RT. After 20min, the mixture was cooled to -1O0C and 23 (1.57g, 7.30mmol, leq) in 12ml THF was added dropwise to the mixture. The mixture was stirred overnight (18h) at RT, then cooled at 00C before addition of 100ml saturated aqueous NH4Cl. The mixture was extracted three times with EtOAc, the extracts were combined, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude products were purified by flash chromatography on silica gel (average size 40μm) with EtOAc/hexane (gradient 20:80 to 45:55) to provide 25a (less polar diastereoisomer) (406mg, 19%) and 24a (1.28g, 60%) as white solids.
Data for (2S,3R)-25a (less polar diastereomer) include NMR 1H (CDCl3), 5=7.43-7.28 (m, 5H, ArH); 4.81 (s, IH, CHOH); 3.93-3.72 (m, 3H); 3.63-3.49 (m, 2H); 2.98-2.78 (m, 3H); 1.41 (s, 9H, 3CH3). NMR 13C (CDCl3), 6=154.9 (NCO); 139.7 (C); 128.4 (CHAr); 127.9 (CHAr); 126.4 (CHAr); 80.0 (C(CH3)3); 78.7 (CHOH); 74.4 (CHO); 66.8 (CH2O); 44.2 (br, NCH2CH2); 42.8 (br, NCH2CH); 28.4 (CH3).
Data for (2S,3S)-24a (more polar diastereomer) include NMR 1H (CDCl3), 5=7.41-7.28 (m, 5H, ArH); 4.53 (d, IH, J=7.3Hz, CHOH); 4.01-3.94 (m, IH); 3.87-3.76 (m, IH); 3.72-3.42 (m, 3H); 3.27-2.92 (m, 2H); 2.82-2.61 (br, IH); 1.39 (s, 9H, 3CH3). NMR 13C (CDCl3), 5=154.7 (NCO); 139.3 (C); 128.6 (CHAr); 128.4 (CHAr); 126.9 (CHAr); 80.1 (C(CH3)3); 79.4 (CHOH); 75.1 (CHO); 66.5 (CH2O); 44.6 (br, NCH2CH2); 43.0 (br, NCH2CH); 28.3 (CH3).

η -(l-ethoxy-2- ^fluorobenzene)tricai'bonylchromium (27a)
A mixture of l-ethoxy-2-fluorobenzene (26) (2.48g, 17.7mmol, leq) and chromium hexacarbonyl (5.87g, 26.57mmol, 1.5eq) in di-n-butyl ether (120ml) and THF (5ml) was refiuxed for 6Oh under nitrogen in the dark. After evaporation of the solvent under reduced pressure, the crude product was purified by flash chromatography on silica gel with
EtOAc/hexane (15:85) to provide 27a as a yellow crystalline solid (2.29g, 47%).

NMR 1H (CDCl3), 5=5.68-5.61 (m, IH, ArH); 5.34-5.26 (m, IH3 ArH); 5.15-4.98 (m, 2H, ArH); 4.17-3.98 (m, 2H5 CH2); 1.48 (t, 3H, J=6.95Hz, CH3). NMR 13C (CDCl3), δ=232.3 (CrCO); 136.0 (d, J=264Hz, CF), 131.3 (d, J=9.8Hz, COCH2); 88.9 (CHAr); 85.6 (d, J=5.5Hz, CHAr); 82.5 (d, J=I 8.2Hz, CHAr); 78.4 (CHAr); 67.0 (CH2); 14.7 (CH3).

η6-(l— methoxy-2— fluorobenzene)tricarbonylchromium (27b)
Compound 27b was obtained based on the exemplary synthesis of compound 27a.
NMR 1H (CDCl3), δ=3.86 (s, 3H, CH3); 5.02-5.12 (m, 2H, CHAr); 5.29-5.32 (m, IH, CHAr); 5.61-5.65 (m, IH, CHAr). NMR 13C (CDCl3), 5=57.5 (1C, CH3); 77.5 (1C, CHAr); 82.3 (d, J=18Hz, CHAr); 85.8 (d, J=5Hz, CHAr); 88.6 (1C, CHAr); 131.9 (d, J=9Hz, Cq); 136.1 (d, J=263Hz, Cq); 232.1 (3C, CrCO).

η6-(l-methoxy-2-fluorobenzene)tricarbonylchromium (27c)
Compound 27c was obtained based on the exemplary synthesis of compound 27a.
NMR 1H (CDCl3), 5=2.25 (s, 3H, CH3); 4.96 (s, IH, CHAr); 5.36 (s, IH, CHAr); 5.45

(s, 2H, CHAr). NMR 13C (CDCl3), 5=14.6 (1C, CH3); 80.4 (d, J=20Hz, CHAr); 88.0 (1C, CHAr); 91.7 (d, J=8Hz, CHAr); 94.9 (d, J=3Hz, CHAr); 96.1 (d, J=16Hz, Cq); 144.6 (d, J=260Hz, Cq); 232.2 (3C, CrCO).

(2S,3S)-2-[(2-emoxyphenoxy)phenylmethyl]morpholine-4-carboxylic acid tert-butyl ester

(29a), preparation from diastereomer 24a
To a suspension of NaH (60% oil dispersion, 59mg, 1.46mmol, 1.5eq, washed once with hexane) in ImI DMF was added dropwise 24a (287mg, 0.979mmol, leq) in 3ml DMF at RT under nitrogen atmosphere. After Ih, tricarbonylchromium complex 27a (405mg, 1.46mmol, 1.5eq) in 3ml DMF was added to the mixture. The mixture was stirred for 2h at RT and then cooled at O0C before addition of a solution of I2 (1.49g, 5.87mmol, 6eq) in 5ml THF over 30min. The mixture was stirred for 30min at RT, then 40ml of 10% (w/v) Na2S2O3 solution was added. The mixture was extracted three times with EtOAc. The extracts were combined and washed twice with 30ml H2O. The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel with EtOAc/hexane (15:85) to provide 29a as a colorless oil (386mg, 95%).

(2S,3S)-2-[(2-ethoxyphenoxy)phenylmethyl]morpholine-4— carboxylic acid tert-butyl ester

(29a), preparation from diastereomer 25a
To amixture of alcohol 25a (356mg, 1.21mmol, leq), triphenylphosphine (637mg,

2.43mmol, 2eq) and 2-ethoxyphenol (28a) (0.31ml, 2.43mmol, 2eq) in 7ml THF at 00C was added diisopropyl azodicarboxylate (0.47ml, 2.43mmol, 2eq). The mixture was allowed to reach RT and stirred for 24h. The crude was concentrated under reduced pressure and purified by flash chromatography on silica gel with EtOAc/hexane (15:85) to provide 29a as a colorless oil (267mg, 53%).
NMR 1H (CDCl3), 5=7.47-7.41 (m, 2H, ArH); 7.38-7.24 (m, 3H, ArH); 6.91-6.79 (m, 3H, ArH); 6.75-6.68 (m, IH, ArH); 5.19 (d, IH, J=3.5Hz, CHOAr); 4.13-4.04 (m, 2H); 4.02- 3.94 (m, IH); 3.92-3.71 (m, 3H); 3.61-3.51 (m, IH); 3.05-2.80 (m, 2H); 1.45 (s, 12H, CH3,

3CH3). NMR 13C (CDCl3), 5=154.7 (NCO); 150.0 (C); 147.7 (C); 137.6 (C); 128.2 (CHAr);

128.1 (CHAr); 127.4 (CHAr); 122.5 (CHAr); 120.8 (CHAr); 118.6 (CHAr); 114.2 (CHAr); 82.4

(br, CHO); 79.9 (C(CH3)3); 78.0 (CHO); 66.6 (CH2O); 64.5 (CH2O); 44.7 (br, NCH2CH2); 42.9 (br, NCH2CH); 28.3 (3CH3); 15.0 (CH2CH3).

(2 S ,3 S)-2-[(2-ethoxyphenoxy)phenylmethyl]morpholine (3 Oa)
Trifluoroacetic acid (0.74ml, 9.69mmol, 15eq) was added dropwise to a solution of 29a (267mg, 0.646mmol, leq) in 5ml of dry CH2Cl2 at 0°C. The mixture was allowed to reach RT and stirred for 1.5h. 15ml of a IM NaOH solution were then slowly added at 00C and the mixture was extracted three times with EtOAc/MeOH (95:5). The extracts were combined, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel with MeOH/CHCl3 (10:90) to provide 30a as a colorless oil (198mg, 98%).
NMR 1H (MeOH-d4), 5=7.47-7.43 (m, 2H, ArH); 7.38-7.27 (m, 3H, ArH); 6.96-6.91

(m, IH, ArH); 6.89-6.82 (m, 2H, ArH); 6.77-6.71 (m, IH, ArH); 5.26 (d, IH, J=5.5Hz, CHOAr); 4.13-3.97 (m, 4H); 3.77-3.68 (m, IH); 2.98-2.80 (m, 4H); 1.44 (t, 3H, J=7.5Hz, CH3). NMR 13C (MeOH-d4); 5=150.9 (C); 148.7 (C); 138.6 (C); 129.3 (CHAr); 128.6 (CHAr); 123.5 (CHAr); 121.9 (CHAr); 118.9 (CHAi-); 115.5 (CHAr); 83.4 (CHO); 78.8 (CHOAr); 67.0 (CH2O); 65.7 (CH2O); 46.8 (NCH2CH2); 45.1 (NCH2CH); 15.3 (CH3).

(S)-tert-butyl 2-((S)-hydroxy(3-iodophenyl)methyl)morpholine-4-carboxylate (24b)
Compound 24b was obtained based on the exemplary synthesis of compound 24a.

NMR 1H (CDCl3), δ=1.41 (s, 9H, 3CH3); 2.71 (bs, IH); 2.95 (td, IH, J=I 1.5, 2.4Hz); 3.20 (bs, IH); 3.44 (t, IH, J=7.6Hz); 3.54 (td, IH, J=I 1.5, 2.8Hz); 3.63 (bs, IH); 3.82 (d, IH, J=15.2Hz); 3.95 (dd, IH, J=I 1.5, 2.0Hz); 4.47 (d, IH, J=6.8Hz); 7.09 (t, IH, J=8.0Hz, CHAr); 7.30 (d, IH, J=8.0Hz, CHAr); 7.65 (d, IH, J=8.0Hz, CHAr); 7.74 (s, IH, CHAr). NMR 13C (CDCl3), δ=28.3 (3C, 3CH3); 43.4 (bs, 1C, CH2); 44.1 (bs, 1C, CH2); 66.4 (1C, CH2); 74.1 (bs, 1C, CH); 78.9 (1C, CH); 80.2 (1C, Cq); 94.5 (1C, Cq); 126.2 (1C, CHAr); 130.2 (1C, CHAr); 135.7 (1C, CHAr); 137.3 (1C, CHAr); 141.9 (1C, Cq); 154.6 (1C, Cq, C=O).

(S)-tert-bu1yl 2-((R)-hydroxy(3-iodophenyl)methyl)morpholine-4-cai;boxylate (25b)
Compound 25b was obtained based on the exemplary synthesis of compound 25a.
NMR 1H (CDCl3), δ=1.41 (s, 9H, 3CH3); 2.77-2.89 (m, 3H); 3.51 (td, 2H, J=I 1.5, 2.7Hz); 3.80-3.85 (m, 2H); 3.88 (dd, IH, J=I 1.5, 2.7Hz); 4.73 (d, IH, J=4.3Hz); 7.08 (t, IH, J=8.0Hz, CHAr); 7.32 (d, IH, J=8.0Hz, CHAr); 7.62 (d, IH, J=8.0Hz, CHAr); 7.72 (s, IH, CHAr). NMR 13C (CDCl3), δ=28.2(3C, 3CH3); 43.0 (bs, 1C, CH2); 43.8 (bs, 1C, CH2); 66.7 (bs, 3C, 3CH2); 73.6 (1C, CH); 78.3 (1C, CH); 80.2 (1C, Cq); 94.4 (1C, Cq); 125.7 (1C, CHAr); 130.1 (1C, CHAr); 135.4 (1C, CHAr); 136.9 (1C, CHAr); 142.2 (1C, Cq); 154.8 (1C, Cq, C=O).

(S)-tert-butyl 2-((R)-hydroxy(5-iodotniophen-2-yl)methyl)moφholine--4—carboxylate (24c)

Compound 24c was obtained based on the exemplary synthesis of compound 24a.
NMR 1H (CDCl3), δ=l .33 (s, 9H, 3CH3); 2.66 (bs, IH); 2.82-2.87 (m, IH); 3.26 (bs,

IH); 3.36-3.40 (m, IH); 3.44 (td, IH, J=I LO, 2.5Hz); 3.65-3.75 (m, 2H); 3.85 (dd, IH, J=I LO,

2.0Hz); 4.68 (d, IH, J=6.0Hz); 6.59 (d, IH, J=4.0Hz, CHAr); 7.00 (d, IH, J=4.0Hz, CHAr).

NMR 13C (CDCl3), δ=28.3 (3C, CH3); 43.9 (bs, 1C, CH2); 44.2 (bs, 1C, CH2); 66.4 (1C, CH2);

70.7 (1C, CH); 76.9 (1C, Cq); 78.5 (1C, CH); 80.2 (1C, Cq); 126.9 (1C, CHAr); 136.3 (1C, CHAr); 154.6 (1C, Cq, C=O).

(S)-tert-butyl 2-((S)-hydroxy(5-iodothiophen-2-yl)methyl)moφholine-4-carboxylate (25c)
Compound 25c was obtained based on the exemplary synthesis of compound 25a.
NMR 1H (CDCl3), δ=1.33 (s, 9H, 3CH3); 2.59-2.66 (m, IH); 2,78 (bs, IH); 3.28 (bs, IH); 3.42 (td, IH, J=9.2, 2.0Hz); 3.46-3.48 (m, IH); 3.72 (bs, IH); 3.81 (dd, IH, J=9.2, 2.0Hz); 3.85 (bs, IH); 4.78 (d, IH, J=3.6Hz); 6.59 (d, IH, J=2.8Hz, CHAr); 7.00 (d, IH, J=2.8Hz, CHAr). NMR 13C (CDCl3), δ=28.4 (3C, CH3); 43.7 (1C, CH2); 44.7 (bs, 1C, CH2); 66.6 (1C, CH2); 70.7 (1C, CH); 73.6 (1C, Cq); 78.1 (1C, CH); 80.3 (1C, Cq); 128.8 (1C, CHAr); 136.3 (1C, CHAr); 149.7 (1C, Cq); 154.8 (1C, Cq, C=O).

(S)-tert-butyl 2-((S)-(2-hydroxyphenoxy)(phenyl)methyl)morpholine-4-carboxylate (29b)
Compound 29b was obtained based on the exemplary synthesis of compound 29a.
NMR 1H (CDCl3), δ=1.41 (s, 9H, 3CH3); 2.58 (bs, IH); 3.01 (t, IH, J=I lHz); 3.53 (bs, IH); 3.74 (td, IH, J=12, 3Hz); 3.91 (bs, 2H); 4.13 (dd, IH, J=12, 3Hz); 4.51 (d, IH, J=8.5Hz); 6.52-6.54 (m, IH, CHAr); 6.58-6.61 (m, IH, CHAr); 6.96-6.98 (m, 2H, CHAr); 7.34-7.42 (m, 5H, CHAr); 7.75 (bs, IH). NMR 13C (CDCl3), 5=28.3 (3C, 3CH3); 43.7 (bs, 1C, CH2); 44.1 (bs, 1C, CH2); 66.8 (1C, CH2); 78.5 (1C, CH); 80.3 (1C, Cq); 87.5 (bs, 1C, CH); 116.1 (1C, CHAr); 119.6 (1C, CHAr); 121.0 (1C, CHAr); 125.1 (1C, CHAr); 127.5 (2C, CHAr); 128.9 (1C, CHAr); 129.1 (1C, CHAr); 136.8 (1C, Cq); 145.9 (1C, Cq); 149.1 (1C, Cq); 154.5 (1C, Cq).

(S)-tert-butyl 2-((S)-(2-iodophenoxy)(phenyl)methyl)morpholme-4-carboxylate (29c)
Compound 29c was obtained based on the exemplary synthesis of compound 29a.
NMR 1H (CDCl3), δ=1.44 (s, 9H, 3CH3); 2.74 (dd, IH, J=13.1, 10.8Hz); 2.86 (bs, IH); 3.58 (t, IH, J=2Hz); 3.88-3.95 (m, 4H); 5.28 (s, IH); 6.61-6.65 (m, 2H, CHAr); 7.10 (t, IH, 1=7, 1.6Hz, CHAr); 7.29-7.40 (m, 5H, CHAr); 5.74 (d, IH, J=7Hz, CHAr). NMR 13C (CDCl3), 5=28.4 (3C, CH3); 42.9 (bs, 1C, CH2); 44.3 (bs, 1C, CH2); 80.0 (1C, Cq); 80.5 (bs, 1C, CH); 81.6 (bs, 1C, CH); 87.5 (bs, 1C, Cq); 113.7 (1C, CHAr); 122.8 (1C, CHAr); 127.3 (2C, CHAr); 128.4 (1C, CHAr); 128.5 (1C, CHAr); 129.5 (1C, CHAr); 136.0 (1C, Cq); 139.5 (2C, CHAr); 154.8 (1C, Cq); 156.0 (1C, Cq).

(S)-tert-butyl 2-((S)-(2-ethoxyphenoxy)(3-iodophenyl)methyl)morpholine-4— carboxylate (29d)
Compound 29d was obtained based on the exemplary synthesis of compound 29a.
NMR 1H (CDCl3), 5=1.46 (s, 12H, 4CH3); 2.90-2.95 (m, 2H); 3.65 (td, IH, J=I 1.6, 2.5Hz); 3.76-3.96 (m, 3H);"4.05-4.15 (m, 3H); 5.11 (d, IH, J=4.8Hz); 6.73-6.92 (m, 4H, 4CHAr); 7.05 (t, IH, J=8.0Hz, CHAr); 7.39 (d, IH, J=7.6Hz, CHAr); 7.61 (d, IH, J=7.6Hz, CHAr); 7.81 (s, IH, CHAr). NMR 13C (CDCl3), 5=15.0 (1C, CH3); 28.3 (3C, CH3); 43.9 (bs, 1C, CH2); 44.5 (bs, 1C, CH2); 64.3 (1C, CH2); 66.7 (1C, CH2); 77.7 (1C, CH); 80.0 (1C, Cq); 81.6 (1C, CH); 94.2 (1C, Cq); 113.8 (1C, CHAi-); 118.9 (1C, CHAr); 120.7 (1C, CHAr); 123.0 (1C, CHAr); 126.7 (1C, CHAr); 129.9 (1C, CHAr); 136.1 (1C, CHAr); 137.1 (1C, CHAr);
140.2 (1C, Cq); 147.3 (1C, Cq); 150.1 (1C, Cq); 154.7 (1C, Cq, C=O).

(S)-tert-butyl 2-((S)-(2H!trifluoromethyl)phenoxy)(3-iodophenyl)metriyl)morpholine-^l-carboxylate (29e)
Compound 29e was obtained based on the exemplary synthesis of compound 29a.
NMR 1H (CDCl3), δ=1.47 (s, 9H, 3CH3); 2.68-2.92 (m, 2H); 3.54 (m, IH); 3.81-3.85 (m, 2H); 3.90 (dd, IH, J=I 1.5, 2.5Hz); 3.99^.05 (m, IH); 5.28-5.29 (m, IH); 6.73 (d, IH, J=8.5Hz, CHAr); 6.95 (d, IH, J=8.5Hz, CHAr); 7.06 (t, IH, J=7.5Hz, CHAr); 7.29-7.37 (m, 2H, CHAr); 7.59-7.63 (m. 2H, CHAr); 7.73 (s, IH, CHAr). NMR 13C (CDCl3), δ=28.3 (3C, 3CH3); 43.0 (bs, 1C, CH2); 44.5 (bs, 1C, CH2); 66.9 (1C, CH2); 76.5 (1C, CH); 78.7 (1C, CH); 80.6 (1C, Cq); 94.4 (1C, Cq); 113.7 (1C, CHAr); 117.2 (1C, CHAr); 119.4 (1C, Cq); 119.6 (1C, CHAr); 120.6 (1C, CHAr); 123.0 (1C, Cq); 126.4 (1C, CHAr); 133.2 (1C, CHAr); 136.0 (1C, CHAr); 137.5 (1C, CHAr); 154.7 (1C, Cq); 155.0 (1C, Cq).

(S)-tert-butyl 2-((S)-(o-tolyloxy)(3-iodoρhenyl)methyl)morpholine-4-carboxylate (29r)
Compound 29f was obtained based on the exemplary synthesis of compound 29a.
NMR 1H (CDCl3), δ=1.39 (s, 9H, 3CH3); 2.28 (s, 3H, CH3); 2.66 (bs, IH); 2,82 (bs, IH); 3.46 (td, IH, J=ILO, 2.0Hz); 3.74-3.87 (m, 4H); 5.07 (d, IH, J=4.5Hz); 6.53 (d, IH, J=8.5Hz, CHAr); 6.75 (t, IH, J=7.5Hz, CHAr); 6.92 (t, IH, J=7.5Hz, CHAr); 6.99 (d, IH, J=7.5Hz, CHAr); 7.06 (d, IH, J=8.5Hz, CHAr); 7.27 (d, IH, J=7.5Hz, CHAr); 7.55 (d, IH, J=7.5Hz, CHAr); 7.67 (s, IH, CHAr). NMR 13C (CDCl3), δ=16.5 (1C, CH3); 28.4 (3C, 3CH3); 43.2 (bs, 1C, CH2); 44.0 (bs, 1C, CH2); 66.8 (1C, CH2); 77.5 (1C, CH); 79.1 (1C, CH); 80.1 (1C, Cq); 94.4 (1C, Cq); 112.9 (1C, CHAr); 121.1 (1C, CHAr); 126.3 (1C, CHAr); 126.7 (1C, CHAr); 127.3 (1C, Cq); 130.1 (1C, CHAr); 130.9 (1C, CHAr); 135.8 (1C, CHAr); 137.2 (1C, CHAr); 139.8 (1C, Cq); 154.7 (1C, Cq); 155.6 (1C, Cq).

(S)-tert-butyl 2-((R)-(2-methoxyphenoxy)(5-iodothiophen-2-yl)methyl)morpholme-4-carboxylate (29g)
Compound 29g was obtained based on the exemplary synthesis of compound 29a.
NMR 1H (CDCl3), δ=1.47 (s, 9H, 3CH3); 2.98-3.03 (m, 2H); 3.53-3.58 (m, IH); 3.81-3.83 (m, 2H); 3.85 (s, 3H, CH3); 3.94 (dd, IH, J=IO, 2.5Hz); 4.04 (d, IH, J=IOHz); 5.39 (d, IH, J=4.5Hz); 6.63-6.66 (m, IH, CHAr); 6.75-6.78 (m, IH, CHAr); 6.82 (t, IH, J=7.0Hz, CHAr);

6.87-6.89 (m, IH, CHAr); 6.97 (t, IH, J=7.0Hz, CHAi-); 7.05 (s, IH, CHAr). NMR 13C
(CDCl3), δ=28.4 (3C5 CH3); 40.0 (bs, 1C, CH2); 42.1 (bs, 1C, CH2); 55.9 (1C, CH3); 66.9 (1C, CH2); 76.9 (1C, Cq); 77.7 (1C, CH); 78.3 (1C, CH); 80.1 (1C, Cq); 112.4 (1C, CHAr); 119.8 (1C, CHAr); 120.7 (1C, CHAr); 123.6 (1C, CHAr); 128.4 (1C, CHAr); 136.0 (1C, CHAr); 146.3 (1C, Cq); 152.1 (1C, Cq); 154.8 (1C, Cq).

(S)-tert-butyl 2-((R)-(ch-tolyloxy)(5-iodothiophen-2-yl)methyl)morpholine-4-carboxylate

(29h)
Compound 29h was obtained based on the exemplary synthesis of compound 29a.
NMR 1B (CDCl3), δ=l .45 (s, 9H, 3CH3); 2.28 (s, 3H, CH3); 2.79 (bs, IH); 2.94 (bs, IH);

3.58 (t, IH, J=IOHz); 3.81-3.97 (m, 4H); 5.44 (s, IH); 6.70-6.83 (m, 3H, CHAr); 7.03-7.13 (m,

3H, CHAr). NMR 13C (CDCl3), δ=16.5 (1C, CH3); 28.4 (3C, 3CH3); 43.2 (bs, 1C, CH2); 44.1

(bs, 1C, CH2); 66.8 (1C, CH2); 74.2 (1C, Cq); 76.7 (1C, CH); 77.3 (1C, CH); 80.2 (1C, Cq);

113.2 (1C, CHAr); 121.6 (1C, CHAr); 125.9 (1C, Cq); 126.7 (1C, CHAr); 127.7 (1C, CHAr); 130.9 (1C, Cq); 131.0 (1C, CHAr); 136.4 (1C, CHAr); 146.2 (1C, Cq); 154.8 (1C, Cq); 155.5

(1C, Cq).

(S)-tert-butyl 2-((R)-(2-(2-fluoroethoxy)phenoxy)(5-iodothiophen-2-yl)methyl)morpholine-4-carboxylate (29i)
Compound 29i was obtained based on the exemplary synthesis of compound 29a.
NMR 1H (CDCl3), 5=1.43 (s, 9H, 3CH3); 2.83-2.98 (m, 2H); 3.53-3.59 (m, IH); 3.70-3.88 (m, 3H); 3.95-3.98 (m, IH); 4.23 (t, IH, J=4.4Hz); 4.30 (t, IH, J=4.4Hz); 4.70-4.73 (m, IH); 4.82-4.85 (m, IH); 5.19 (d, IH, J=5.6Hz); 6.77-6.90 (m, 4H, CHAr); 1,21-134 (m, 3H, CHAr); 7.40-7.42 (m, 2H, CHAr). NMR 13C (CDCl3), δ=28.3 (3C, CH3); 42.9 (bs, 1C, CH2); 44.6 (bs, 1C, CH2); 66.6 (1C, CH2); 68.9 (d, J=21Hz, CH2); 78.1 (bs, 1C, CH); 79.9 (1C, Cq); 82.1 (d, J=82Hz, CH2); 115.6 (1C, CHAr); 118.6 (1C, CHAr); 122.1 (1C, CHAr); 122.4 (1C, CHAr); 127.4 (4C, CHAr); 128.3 (1C, CHAr); 128.4 (1C, CHAr); 137.3 (1C, Cq); 148.2 (1C, Cq); 149.4 (1C, Cq); 154.7 (1C, Cq).

(S>-2-((S)-(2-iodophenoxy)(phenyl)methyl)morphoHne (30b)
Compound 30b was obtained based on the exemplary synthesis of compound 30a.
NMR 1H (CD3OD), δ=1.69 (bs, IH, NH); 2.51 (t, IH, J-Il5OHz); 2.66-2.75 (m, 3H); 3.57 (td, IH, J=ILO5 3.1Hz); 3.85-3.89 (m, 2H); 5.13 (d, IH, J=5.7Hz); 6.52 (td, IH, J=7.7, 1.5Hz, CHAr); 6.56 (dd, IH, J=8.2, 1.0Hz, CHAr); 7.00 (td, IH, J=8.2, 1.0Hz, CHAr); 7.16-7.20 (m, IH, CHAr); 7.22-7.25 (m, 2H, CHAr); 7.28-7.30 (m, 2H, CHAr); 7.64 (dd, IH, J=7.7, 1.5Hz, CHAr). NMR 13C (CDCl3), δ=44.7 (1C, CH2); 46.1 (1C, CH2); 67.3 (1C, CH2); 77.8 (1C, CH); 80.9 (1C, CH); 86.3 (1C, Cq); 112.8 (1C, CHAr); 121.5 (1C, CHAr); 126.2 (2C, CHAr); 127.1 (1C, CHAr); 127.3 (2C, CHAr); 128.0 (1C, CHAr); 135.5 (1C, Cq); 138.3 (1C, CHAr); 155.3 (1C, Cq).

(S)-2-((R)-(2-methoxyphenoxy)(5-iodothiophen-2-yl)methyl)morpholme (30c)
Compound 30c was obtained based on the exemplary synthesis of compound 30a.
NMR 1H (CD3OD), 5=2.42-2.46 (m, IH); 2.56-2.59 (m, IH); 2.74-2.78 (m, 2H); 3.60- 3.64 (m, IH); 3.78 (s, 3H, CH3); 3.87-3.92 (m, 2H); 4.02 (d, IH, J=5.2Hz); 6.47 (dd, IH, J=4, IHz, CHAr); 6.68-6.74 (m, 3H, CHAr); 6.80 (d, IH, J=2Hz, CHAr); 7.00 (d, IH, J=4Hz).
NMR 13C (CD3OD), δ=45.7 (1C, CH2); 49.8 (1C, CH2); 56.4 (1C, CH3); 68.1 (1C, CH2); 72.9 (1C, Cq); 79.8 (1C, CH); 80.2 (1C, CH); 113.2 (1C, CHAr); 116.3 (1C, CHAr); 122.1 (1C, CHAr); 128.3 (1C, CHAr); 132.8 (1C, CHAr); 137.0 (1C, CHAr); 146.8 (1C, Cq); 149.1 (1C, Cq); 153.3 (1C, Cq).

(S)-2-((R)-(o-tolyloxy)(5-iodothiophen-2-yl)methyl)morpholine (30d)
Compound 3Od was obtained based on the exemplary synthesis of compound 30a.
NMR 1H (CD3OD), 8=2.13 (s, 3H, CH3); 2.37 (dd, IH, J=I 2, 10Hz); 2.51 (dd, IH, J=12,

1.5Hz); 2.72-2.75 (m, 2H); 3.28-3.30 (m, IH); 3.56-3.61 (m, IH); 3.81-3.95 (m, 3H); 6.42 (dd, IH, J=4, IHz, CHAr); 6.67 (d, IH, J=8Hz, CHAr); 6.85-6.87 (m, 2H, CHAr); 6.93 (d, IH, J=2Hz, CHAr); 6.98 (d, IH, J=4Hz, CHAr). NMR 13C (CD3OD), 8=16.7 (1C, CH3); 46.3 (1C, CH2); 50.6 (1C, CH2); 68.8 (1C, CH2); 73.1 (1C, Cq); 80.2 (1C, CH); 81.0 (1C, CH); 116.1 (1C, CHAr); 126.3 (1C, CHAr); 128.1 (1C, CHAr); 128.6 (1C, CHAr); 132.1 (1C, CHAr); 132.6 (1C, Cq); 137.3 (1C, CHAr); 154.2 (1C, Cq); 156.2 (1C, Cq).

(S)-2-((S)-(2-(2-fluoroethoxy)phenoxy)(phenyl)methyl)morpholme (30e)
Compound 3Oe was obtained based on the exemplary synthesis of compound 30a.
NMR 1H (CD3OD), 5=2.54-2.61 (m, 2H); 2.70-2.73 (m, 2H); 3.56-3.60 (m, IH); 3.86- 3.90 (m, 2H); 4.17-4.25 (m, 2H); 4.66 (t, J=4.0Hz); 4.76 (t, J=4.0Hz); 5.20 (d, IH, J=5.4Hz); 6.71-6.74 (m, IH, CHAr); 6.79-6.82 (m, 2H, CHAr); 6.89-6.90 (m, IH, CHAr); 7.22-7.29 (m, 3H, CHAr); 7.37-7.39 (m, 2H, CHAr). NMR 13C (CD3OD), 5=45.9 (1C, CH2); 47.6 (1C, CH2); 68.3 (1C, CH2); 70.2 (d, J=19Hz); 80.0 (1C, CH); 83.3 (d, J=168Hz); 83.7 (1C, CH); 116.6 (1C, CHAr); 118.8 (1C, CHAr); 122.9 (1C, CHAr); 123.2 (1C, CHAi-); 128.6 (2C, CHAr); 129.2 (1C, CHAr); 129.3 (2C, CHAr); 138.8 (1C, Cq); 149.3 (1C, Cq); 150.5 (1C, Cq).

EXAMPLE V
Synthesis V



PPh3/DIAD/THF

For a person of ordinary skill in the art, the exemplary synthesis of compound 30 from compounds 11a and 1 Ib, respectively, are generally related to that for compound 30a.

(S)-2-((S)-(2-ethoxyphenoxy)(phenyl)methyl)morpholine (30a), from 11a
To a suspension of NaH (60% oil dispersion, 59mg, 1.46mmol, 1.5eq, washed once with hexane) in ImI DMF was added dropwise 11 a (277mg, 0.979mmol, 1 eq) in 3ml DMF at RT under nitrogen atmosphere. After Ih, tricarbonylchromium complex 27a (405mg, 1.46mmol, 1.5eq) in 3ml DMF was added to the mixture. The mixture was stirred for 2h at RT and then cooled at O0C before addition of a solution of I2 (1.49g, 5.87mmol, 6eq) in 5ml THF over 30min. The mixture was stirred for 30min at RT, then 40ml of 10% (w/v) Na2S2O3 solution was added thereto. The mixture was extracted three times with EtOAc. The extracts were combined and washed twice with 30ml H2O. The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash
chromatography on silica gel with EtOAc/hexane (15:85) to provide (S)-2-((S)-(2- ethoxyphenoxy)(phenyl)methyl)-4— benzylmorpholine as a colorless oil (386mg, 95%). The material was dissolved in 5ml OfCH2Cl2 and 1Pr2NEt (831 μl, 5eq) and 1-chloroethylchloro-formate (521ml, 5eq) were successively added thereto. The resulting solution was refluxed for 4h. The solvent was evaporated in vacuum and portioned between H2O/ AcOEt. The organic phases were washed with H2O and dried over Na2SO4. Evaporation and chromatography (SiO2, CH2Cl2/Me0H 9/1) of the residue provided 30a as a white solid in 88% yield.

(S)-2-((S)-(2-ethoxyphenoxy)(phenyl)methyl)morpholine (30a), from l ib
To a mixture of alcohol lib (342mg, 1.21mmol, leq), triphenylphosphine (637mg, 2.43mmol, 2eq) and 2-ethoxyρhenol (28a) (0.31ml, 2.43mmol, 2eq) in 7ml THF at 0°C was added diisopropyl azodicarboxylate (0.47ml, 2.43mmol, 2eq). The mixture was allowed to reach RT and stirred for 24h. The crude was concentrated under reduced pressure and purified by flash chromatography on silica gel with EtOAc/hexane (15:85) to provide (S)-2-((S)-(2— ethoxyphenoxy)(phenyl) methyl)-4-benzylmorpholine as a colorless oil (267mg, 53%). The material was dissolved in 5ml of CH2Cl2 and 1Pr2NEt (831 μl, 5eq) and 1-chloroethylchloro-formate (521ml, 5eq) were successively added thereto. The resulting solution was refluxed for 4h. The solvent was evaporated in vacuum and portioned between H2O/AcOEt. The organic phases were washed with H2O and dried over Na2SO4. Evaporation and chromatography (SiO2, CH2Cl2ZMeOH 9/1) of the residue provided 30a as a white solid in 88% yield.
NMR 1H (CDCl3), 5=7.47-7.43 (m, 2H, ArH); 7.38-7.27 (m, 3H, ArH); 6.96-6.91 (m,

IH3 ArH); 6.89-6.82 (m, 2H, ArH); 6.77-6.71 (m, IH, ArH); 5.26 (d, IH, J=5.5Hz, CHOAr); 4.13-3.97 (m, 4H); 3.77-3.68 (m, IH); 2.98-2.80 (m, 4H); 1.44 (t, 3H, J=7.5Hz, CH3). NMR 13C (MeOH, 125MHz), δ=150.9 (C); 148.7 (C); 138.6 (C); 129.3 (CHAr); 128.6 (CHAr); 123.5 (CHAr); 121.9 (CHAi-); 118.9 (CHAr); 115.5 (CHAr); 83.4 (CHO); 78.8 (CHOAr); 67.0 (CH2O); 65.7 (CH2O); 46.8 (NCH2CH2); 45.1 (NCH2CH); 15.3 (CH3).

EXAMPLE VI
Synthesis VI

An exemplary composition of the invention can comprise a radiotracer in physiological saline. Without limitation, a composition may comprise a sterile, pyrogen-free solution of no-carrier-added 2(S)-[(S)-(2-[123I]iodophenoxy)(phenyl)methyl]morpholine radiotracer in physiological saline. For example, synthesis VI can also be used to prepare a radiotracer of the invention from those compounds provided by any one of the syntheses herein and combinations thereof. Moreover, the compounds provided by any one of syntheses herein can be modified to comprise a detectable marker by adaptation of conventional techniques known to a person of ordinary skill in the art. Exemplary conventional techniques can include those related to radioiodination. In one embodiment, radioiodination can be adapted to introduce a detectable marker to those compounds provided by any one of syntheses herein and combinations thereof. For example, a radiotracer can be prepared by reacting an N-Boc— protected trimethylstannyl precursor with Na[ 3I] in the presence of an oxidizing agent, for example, peracetic acid, followed by HPLC isolation and deprotection of the 123I-labeled intermediate in synthesis VI. The resulting radiolabeled product can be purified by means of HPLC and appropriately formulated.
To a shipping vial with dry Na[123I]ITNaOH are added, in the following order, 50% aqueous MeOH, 0.8M H3PO4 in the amount sufficient to neutralize the NaOH plus extra 1 Oμl, a solution of N-Boc-protected trimethylstannyl precursor (lOOμg, 0.19μmol) in 50μl of MeOH and 50μL of 6.4% aqueous peracetic acid freshly prepared by a 5-fold dilution of 32%
CH3C(O)OOH. The total volume of added reagents can be 320μl. After standing for about 14-16min at room temperature, the mixture in the vial can be quenched by the addition of 1 OOμl of a 100mg/ml solution OfNa2S2O5 in saturated aqueous NaHCO3. Optionally, the vial headspace can be flushed with 60ml of air into a charcoal filter. The vial can also be emptied and rinsed with 0.3-0.4ml of 85% aqueous MeCN. The rinse can also be combined with the quenched mixture and the resultant liquid injected onto a reverse-phase HPLC column. The column (Cl 8, lOμ, 4.6 x 250mm) can be eluted with a mixture of acetonitrile and water (85:15 v/v) at a flow rate of about l.Oml/min.

The fraction eluting at the retention time of the authentic N-Boc-protected
trimethylstannyl precursor can be collected into a 50ml flask containing ImI of trifluoroacetic acid (deprotecting agent). The solvent can also be removed on a rotary evaporator at about 45-50°C under reduced pressure/argon gas flow. The dry residue in the flask may then be treated with 4ml of a CF3COOH-CH2Cl2 (50:50 v/v) mixture for 5-7min at room temperature to ensure the complete removal of the protecting Boc-group. The contents of the flask can be evaporated to dryness (rotary evaporator, 45-5O0C, reduced pressure/argon gas flow), reconstituted in a total of 0.4-0.5ml of 60% aqueous MeCN and injected onto a reverse-phase HPLC column for final purification.
The column (Cl 8, 1 Oμ, 4.6 x 250mm) can be eluted with a mixture of acetonitrile, water and triethylamine (60:40:0.2 v/v/v) at a flow rate of about 1.Oml/min. The fraction eluting can be collected into a 50ml flask containing 50μl of 34mM L-ascorbic acid (stabilizer). The solvent may be removed on a rotary evaporator at about 45-50°C under reduced pressure/argon gas flow. The dry residue in the flask can be dissolved in 800μl of 50% ethanol and the resulting solution may be filtered through a 0.2μm sterilizing filter into an empty sterile vial. The formulation can be finalized by the addition of about 6-8ml of sterile 0.9% NaCl for injection through the same filter. Quality control testing can include visual inspection, determination of specific concentration, identity and radiochemical purity (by HPLC), pH, pyrogenicity and sterility (by compendial tests). Such testing may occur before administration to a subject or prior thereto. The preparation of the radiotracer can also be accomplished using a kit of the invention.

EXAMPLE VII
Synthesis VII


29b 31 32



33

(SHert-butyl 2-((S)-(2-((E)-3-(tributylstaniiyl)allyloxy)plienoxy)(phenyl)methyl)morpholine —4- carboxylate (31)
In dry acetone was dissolved compound 29a (107mg, leq), (E)-3-(tributylstannyl)allyl 4-methylbenzenesulfonate (263mg, 2eq) and K2CO3 (72mg, 2eq). The resulting mixture was stirred at 55°C for 18h before evaporation of the solvent. The residue was then purified by chromatography (SiO2, Hexane/AcOEt/Et3N 90/10/0.1), providing 31 as a colorless paste in 97% yield. m/z=715 (m + 1).

(S)-tert-butyl 2-((S)-(2-((E)-3-iodoallyloxy)phenoxy)(phenyl)methyl)morpholine-4-carboxylate (32)
To a solution of 31 (139mg, leq) in 4ml OfCHCl3 was added iodine (52mg, 1.05eq) dissolved in 2ml of CHCl3. The resulting mixture was stirred at RT for Ih, hydrolyzed with a saturated solution OfNa2S2O3 (5ml), subjected to CH2Cl2 extraction (3 x 5ml) and the organic phase was dried over Na2SO4. Evaporation and chromatography (SiO2, Hexane/AcOEt 85/15) provided 32 as a colorless oil. m/z=552 (m + 1).

(S)-2-((S)-(2-((E)-3-iodoallyloxy)phenoxy)(ρhenyl)methyl)morpholme (33)
To a solution of 32 (94mg, 1 eq) in 5ml of CH2Cl2 was added dropwise and at 0°C 0.5ml of TFA. The resulting mixture was stirred at RT for Ih before being hydrolyzed with 10ml of IN NaOH. Extraction with CH2Cl2 (3 x 5ml), drying of the organic phase, removal of the solvent and chromatography (SiO2, CHCl3/MeOH 85/15) provided compound 33 as a colorless oil in 97% yield.

EXAMPLE VIII
Synthesis VIII


An exemplary composition of the invention can comprise a radiotracer in physiological saline. Without limitation, a composition may comprise a sterile, pyrogen-free solution of no— carrier-added (S)-2-((S)-(2-((E)-3-[123I]iodoallyloxy)phenoxy)(phenyl)methyl)morpholine radiotracer in physiological saline. For example, synthesis VIII can also be used to prepare a radiotracer of the invention from those compounds provided by any one of syntheses herein and combinations thereof. Moreover, the compounds provided by any one of syntheses herein can be modified to comprise a detectable marker by adaptation of conventional techniques known to a person of ordinary skill in the art. Exemplary conventional techniques can include those related to radioiodination. In one embodiment, radioiodination can be adapted to introduce a detectable marker to those compounds provided by any one of syntheses herein and
combinations thereof. For example, a radiotracer can be prepared by reacting an N-Boc-protected trimethylstannyl precursor with Na[123I] in the presence of an oxidizing agent, for example, peracetic acid, followed by HPLC isolation and deprotection of the 123I-labeled intermediate in synthesis VII. The resulting radiolabeled product can be purified by means of HPLC and appropriately formulated.
To a shipping vial with dry Na[ 123I] 1/NaOH are added, in the following order, 50% aqueous MeOH, 0.8M H3PO4 in the amount sufficient to neutralize the NaOH plus extra lOμl, a solution of N-Boc-protected trimethylstannyl precursor (lOOμg, 0.19μmol) in 50μl of MeOH and 50μL of 6.4% aqueous peracetic acid freshly prepared by a 5-fold dilution of 32%
CH3C(O)OOH. The total volume of added reagents can be 320μl. After standing for about 14-lόmin at room temperature, the mixture in the vial can be quenched by the addition of lOOμl of a lOOmg/ml solution OfNa2S2O5 in saturated aqueous NaHCO3. Optionally, the vial headspace can be flushed with 60ml of air into a charcoal filter. The vial can also be emptied and rinsed with 0.3-0.4ml of 85% aqueous MeCN. The rinse can also be combined with the quenched mixture and the resultant liquid injected onto a reverse-phase HPLC column. The column (Cl 8, 1 Oμ, 4.6 x 250mm) can be eluted with a mixture of acetonitrile and water (85:15 v/v) at a flow rate of about l.Oml/min.
The fraction eluting at the retention time of the authentic N— Boc-protected.
trimethylstannyl precursor can be collected into a 50ml flask containing ImI of trifluoroacetic acid (deprotecting agent). The solvent can also be removed on a rotary evaporator at about 45-50°C under reduced pressure/argon gas flow. The dry residue in the flask may then be treated with 4ml of a CF3COOH-CH2Cl2 (50:50 v/v) mixture for 5-7min at room temperature to ensure the complete removal of the protecting Boc-group. The contents of the flask can be evaporated to dryness (rotary evaporator, 45-50°C, reduced pressure/argon gas flow), reconstituted in a total of 0.4-0.5ml of 60% aqueous MeCN and injected onto a reverse-phase HPLC column for final purification.
The column (Cl 8, lOμ, 4.6 x 250mm) can be eluted with a mixture of acetonitrile, water and triethylamine (60:40:0.2 v/v/v) at a flow rate of about 1.Oml/min. The fraction eluting can be collected into a 50ml flask containing 50μl of 34mM L— ascorbic acid (stabilizer). The solvent may be removed on a rotary evaporator at about 45-50°C under reduced pressure/argon gas flow. The dry residue in the flask can be dissolved in 800μl of 50% ethanol and the resulting solution maybe filtered through a 0.2μm sterilizing filter into an empty sterile vial. The formulation can be finalized by the addition of about 6-8ml of sterile 0.9% NaCl for injection through the same filter. Quality control testing can include visual inspection, determination of specific concentration, identity and radiochemical purity (by HPLC), pH, pyrogenicity and sterility (by compendial tests). Such testing may occur before administration to a subject or prior thereto. The preparation of the radiotracer can also be accomplished using a kit of the invention.

EXAMPLE IX
Table 3 provides binding affinities for compounds 30b, 33, 30c and 3Od evaluated by its competition against several conventional radioligands selective for SERT, DAT and NET membranes of cell lines transfected to express human genes for these transporter proteins. The conventional radioligands include [3H]citalopram for SERT (blank=10μM citalopram), [3H]WIN35428 for DAT (blank=10μM WIN35428) and [3H]nisoxetine for NET (blank=10 μM desipramine). Potencies as an inhibitory constant (Ki) ± SE in nanomolar (nM) are based on at least three separate determinations.

Table 3
Compound of SERT DAT NET NET versus NET versus the invention DAT SERT
30b > 1,00OnM 410 ± 91nM 0.84 ± 0.12nM 490 > 1,000
33 > 1,00OnM > 1,00OnM 8.7 > 1,000 > 1,000
30c 14InM 21OnM 79.6nM 2.6 1.77

30d 31% at l0μM 186nM 71.9nM 2.6 —

EXAMPLE X
A series of in vivo SPECT imaging evaluations were conducted involving bolus plus continuous infusion of a 2(S)-[(S)-(2-[123I]iodophenoxy)(phenyl)methyl]morpholine radiotracer of the invention in an ovariectomized female baboon. Moreover, a series of five in vivo SPECT imaging evaluations were performed in two baboons with the 2(S)-[(S)-(2—
[! I]iodophenoxy)(phenyl)methyl]morpholine radiotracer evaluating regional brain uptake and washout of activity. These evaluations were conducted on a brain dedicated annular ring SPECT device (CERASPECT). The subjects were induced with ketamine and maintained under isofiurane anesthesia for the duration of in vivo imaging. Body temperature, vital signs and fluid status were monitored over the course of the evaluations.
The subjects were positioned in the SPECT tomograph prior to radiotracer injection. Dynamic SPECT acquisitions were then initiated concomitant with the bolus injection of the radiotracer. Images were reconstructed with filtered back projection and attenuation was corrected using an empirically derived μ assuming uniform attenuation. Images within each dynamic set were also aligned in SPM and volumes of interest derived in MEDX. Activity was decay corrected to the time of the radiotracer injection.
Figure 1 shows regional brain time— activity data in a subject following a radiotracer injection of 6.15mCi and serial dynamic SPECT acquisitions. Consistent with the distribution of NET in the brain, the locus coeruleus (brainstem) and thalamus (dien) demonstrated the highest uptake of the radiotracer. Additionally, Figure 2 shows transaxial SPECT brain slices in a subject from baseline radiotracer evaluations (upper in vivo image panel) and following intravenous pretreatment with a conventional agent for NET abnormalities, lmg/kg dosage, lOmin before the radiotracer injection (lower in vivo image panel). Figure 3 also shows regional brain analysis of time— activity data in a subject receiving a bolus injection of the radiotracer and repeated SPECT evaluations following pretreatment with the conventional agent at a dosage of lmg/kg.
Figure 4 shows bolus plus constant infusion evaluation with the radiotracer in a subject. The radiotracer was administered at a ratio of 1 :3 and resulted in flat time-activity data across different brain regions. Each of the bolus injection SPECT evaluations with the radiotracer demonstrated satisfactory brain uptake and blockade with pretreatment using the conventional agent, which was consistent with specific NET binding.
While the present invention has been described herein in conjunction with a preferred embodiment, a person with ordinary skill in the art, after reading the foregoing specification, can effect changes, substitutions of equivalents and other types of alterations to that set forth herein. Each embodiment described above can also have included or incorporated therewith such variations as disclosed in regard to any or all of the other embodiments. Thus, it is intended that protection granted by Letters Patent hereon be limited in breadth and scope only by definitions contained in the appended claims and any equivalents thereof.