Some content of this application is unavailable at the moment.
If this situation persist, please contact us atFeedback&Contact
1. (WO2019008308) POLARISATION TRANSFER VIA A SECOND METAL COMPLEX
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

Claims

1. A method for the preparation of an imaging medium via transfer from a hyperpolarised singlet state that is not parahydrogen, said method comprising the steps of:

(i) preparing a system containing:

parahydrogen; a magnetisation transfer complex, with a molecular symmetry that allows the creation of a singlet state between spin pairs within it, said complex including a reversibly bound small molecule transference substrate;

applying a magnetic field such that hyperpolarisation is transferred into the transfer complex, including the reversibly bound small molecule transference substrate;

(ii) separately or simultaneously introducing a recipient complex capable of binding the small molecule transference substrate, said recipient complex including a recipient substrate, such that the recipient complex and recipient substrate, including the bound transference substrate, is hyperpolarised; and

(iii) providing an imaging medium by:

(a) separating the hyperpolarised recipient complex;

(b) separating the hyperpolarised recipient substrate; or

(c) separating the transference substrate.

2. A method according to claim 1 wherein the hyperpolarisation is achieved by SABRE.

3. A method according to claims 1 or 2 wherein the small molecule transference substrate is characterised by a long lifetime in a low magnetic field.

4. A method according to any one of the preceding claims wherein the small molecule transference substrate has a singlet state lifetime that will be 20 seconds or more.

5. A method according to claim 2 wherein the method includes the use of a SABRE hyperpolarisation transfer catalyst.

6. A method according to claim 5 wherein a SABRE hyperpolarisation transfer catalyst is placed in the aqueous phase.

7. A method according to any one of the preceding claims wherein parahydrogen (p-H2) gas is added to the system whilst agitating the system.

8. A method according to claim 7 wherein ultrasound is used to agitate the system.

9. A method according to any one of the preceding claims wherein the recipient metal complex contains appropriate 2H, CI or O labels to maximise the relaxation times of the nuclei spins that are to be hyperpolarised.

10. A method according to any one of the preceding claims wherein the small molecule transference substrate contains appropriate 13C or 15N labelling to maximise the proportion of the substrate that can be created in a hyperpolarised NMR visible form in conjunction with appropriate 2H, O or CI labelling to extend their magnetic state lifetimes.

11. A method according to any one of the preceding claims wherein the selected small molecule transference substrate contains spin pairs of appropriate ¾ I3C, 31P, 15N, 9Si or 19F labels to enable the formation of long-live states (singlet states) between the corresponding spin pairs (e.g. 1H, 13C, 31P, 15N, 29Si or 19F) within a molecular scaffold that contains appropriate 2H or CI labelling to extend their lifetime.

12. A method according to any one of the preceding claims wherein the small molecule transference substrate contains spin pairs that are homo-nuclear.

13. A method according to any one of the preceding claims wherein the small molecule transference substrate contains spin pairs that are selected from 'Η/Ή and 13C/13C.

14. A method according to any one of claim 1 to 11 wherein the small molecule transference substrate contains spin pairs that are hetero-nuclear.

15. A method according to claim 14 wherein the small molecule transference substrate contains spin pairs that are selected from 'U C, 'H l9F and 'H/15N.

16. A method according to any one of the preceding claims wherein the hyperpolarisation is transferred into the small molecule transference substrate in an optimised magnetic field from parahydrogen to create a strongly hyperpolarised response that is subsequently converted into a singlet state across the spin-pair through radio frequency excitation.

17. A method according to claim 16 wherein the magnetic field is an ultra-low magnetic field.

18. A method according to claim 17 wherein the ultra-low magnetic field is <1 G (<10 T).

19. A method according to claim 6 wherein the magnetisation transfer catalyst is provided with at least one suitable ligation site enabling it to interact with one or more small molecule transference substrates.

20. A method according to claim 19 wherein the magnetisation transfer catalyst comprises an iridium based catalyst.

21. A method according to claim 20 wherein the magnetisation transfer catalyst comprises [IrCl(COD)IMes] and analogues thereof.

22. A method according to any one of the preceding claims wherein magnetisation transfer complex includes iridium with at least one N-heterocyclic carbene (NHC) ligand.

23. A method according to any one of the preceding claims wherein the N- heterocyclic carbene (NHC) ligand is selected from:

41

24. A method according to any one of the preceding claims wherein the small molecule transference substrate comprises at least one suitable ligation site to interact with the magnetisation transfer complex.

25. A method according to any one of the preceding claims wherein the small molecule transference substrate is selected from one or more of pyridine (py), pyridazine (pdz), methyl-pyridazine (methyl-pdz), i¾-nicotinate (nic) and Cl2-i¾-15N2-pyridazine.

26. A method according to any one of the preceding claims wherein the recipient complex is a recipient metal complex.

27. A method according to any one of the preceding claims wherein the recipient metal complex and the recipient substrate are present at point (i) of the method, i.e. complex bound to the small molecule transference substrate

28. A method according to any one of the preceding claims wherein a biphasic element is introduced in order to enable the hyperpolarisation transfer process to be completed in a single vessel.

29. A method according to claim 28 wherein the biphasic element comprises preparing a fluid containing two separate components, where one is in water and the second an immiscible co-solvent.

30. A method according to claims 28 or 29 wherein the ratio of phases is selected to maximise the degree of recipient hyperpolarisation and/ or to maximise the speed of phase separation.

31. A method according to any one claims 28 to 30 wherein an aqueous solvent mixture combination is used to maximise the relaxation time of the hyperpolarised recipient complex in this solution by employing D20.

32. A method according to any one of claims 28 to 31 wherein an aqueous solvent mixture combination is used to maximise the relaxation time of the hyperpolarised recipient complex in this solution by employing a D20 ¾0 mixture of suitable proportions

33. A method according to any one of claims 28 to 32 wherein an aqueous solvent mixture combination is used to maximise the relaxation time of the hyperpolarised recipient complex in this solution by adding a further co-solvent to an appropriate aqueous phase.

34. A method according to any one of claims 28 to 33 wherein one or more solvent phase-separation promoter(s), e.g. NaCl or Na02CCH3 or NaOH or NaHC03 or Na2C03 or ethanol is added.

35. A method according to any one of the preceding claims wherein the hyperpolarised small molecule transference substrate and the recipient substrate, are each capable of binding reversibly to the recipient complex.

36. A method according to claim 26 wherein the recipient metal complex comprises a transition metal complex.

37. A method according to claim 36 wherein the transition metal complex comprises a metal atom selected from the group consisting of Ru, Rh, Ir, W, Pd and Pt.

38. A method according to any one of the preceding claims wherein the recipient complex comprises one or more Iigands in addition to the ligand comprising the hyperpolarisable nucleus.

39. A method according to claim 38 wherein the one or more additional ligands comprises organic or inorganic ligands which are mono-, bi- or multidentate in nature.

40. A method according to claim 39 wherein the one or more additional ligands comprises an NHC ligand.

41. A method according to claim 40 wherein the recipient complex comprises one or more phosphine ligands in addition to the ligand to be hyperpolarized.

42. A method according to any one of the preceding claims wherein the recipient complex is attached to a solid support.

43. A method according to any one of the preceding claims wherein the recipient complex contains spin pairs of appropriate Ή, 13C, 31P, ,5N, 29Si or 19F labels to enable the formation of long-live states (singlet states) between the corresponding spin pairs (e.g. ¾ 13C, 31P, 15N, 29Si or 19F) within a molecular scaffold that contains appropriate 2H or CI labelling to extend their lifetime.

44. A method according to any one of the preceding claims wherein the recipient complex contains spin pairs that are homo-nuclear.

45. A method according to claim 44 wherein the recipient complex contains spin pairs that are selected from Ή/Ή and 13C/13C.

46. A method according to any one of claims 1 to 43 wherein the recipient complex contains spin pairs that are hetero-nuclear.

47. A method according to claim 47 wherein the recipient complex contains spin pairs that are selected from Ή/13ϋ, Ή/1^ and Ή/,5Ν.

48. A method according to any one of the preceding claims wherein the recipient substrate contains at least one ligating group, such as O, N, S, P, or C to enable binding to the recipient metal complex.

49. A method according to any one of the preceding claims wherein the recipient substrate is selected from the group consisting of nicotinamide, nicotine, pyrazine, 5-methyl pyrimidine, acetate, pyruvate, ethoxide, hydroxide, oxalate or gluconate, sugars like glucose or fructose, urea, amides, amino acids like glutamate, glycine, cysteine or aspartate, GABA (γ-aminobutyric acid), nucleotides, vitamins like ascorbic acid, serotonin, penicillin derivatives and sulfonamides.

50. A method according to claim 49 wherein the recipient substrate is pyruvate.

51. A method according to any one of claims 1 to 49 wherein the recipient substrate is selected from the group consisting of intermediates in normal metabolic cycles such as the citric acid cycle like fumaric acid and pyruvic acid.

52. A method according to any one of claims 1 to 48 wherein the recipient complex is replaced by a molecular agent with a three dimensional structure.

53. A method according to claim 52 wherein the molecular agent with a three dimensional structure is selected from the group consisting of a protein, an en2yme, a polysaccharide, DNA and RNA.

54. A method according to any one of the preceding claims wherein the method includes the use of an in-line probe, e.g. a UV probe, to establish that the catalyst concentration is sufficiently low for in vivo injection.

55. A method according to claim 33 wherein a catalyst deactivator is added to facilitate catalyst transfer to a non-aqueous component.

56. A method according to claim 55 wherein a catalyst deactivator is a chelating ligand.

57. A method of producing a hyperpolarised target substrate imaging medium, said method comprising the steps of:

(i) preparing a system containing a magnetisation transfer complex, said complex including a reversibly bound small molecule transference substrate;

(ii) adding H2 or parahydrogen (/?-¾) gas to the system;

(iii) applying a magnetic field such that hyperpolarisation is transferred into the transfer complex, including the reversibly bound small molecule transference substrate;

(iv) separately or simultaneously introducing a recipient complex capable of binding the small molecule transference substrate, said recipient complex including a recipient substrate, such that the recipient complex and recipient substrate, including the bound transference substrate, is hyperpolarised; and

(v) separating the hyperpolarised recipient complex; the hyperpolarised recipient substrate; or the separating the transference substrate to provide a hyperpolarised target substrate imaging medium.

58. A pharmaceutically acceptable formulation comprising a solution of a hyperpolarised recipient substrate for use as an imaging medium, wherein said hyperpolarised recipient substrate is prepared by transfer from a hyperpolarised singlet state that is not parahydrogen, said method comprising the steps of:

(i) preparing a system containing:

parahydrogen; a magnetisation transfer complex, with a molecular symmetry that allows the creation of a singlet state between spin pairs within it, said complex including a reversibly bound small molecule transference substrate;

applying a magnetic field such that hyperpolarisation is transferred into the transfer complex, including the reversibly bound small molecule transference substrate;

(ii) separately or simultaneously introducing a recipient complex capable of binding the small molecule transference substrate, said recipient complex including a recipient substrate, such that the recipient complex and recipient substrate, including the bound transference substrate, is hyperpolarised.

59. A pharmaceutically acceptable formulation according to claim 58 wherein the substrate is selected from the group consisting of nicotinamide, nicotine, pyrazine, 5-methyl pyrimidine, acetate, pyruvate, ethoxide, hydroxide, oxalate or gluconate,

sugars like glucose or fructose, urea, amides, amino acids like glutamate, glycine, cysteine or aspartate, GABA (γ-aminobutyric acid), nucleotides, vitamins like ascorbic acid, serotonin, penicillin derivatives and sulfonamides.

60. A pharmaceutically acceptable formulation according to claim 59 wherein the substrate is pyruvate.

61. A pharmaceutically acceptable formulation according to claim 58 wherein the substrate is an intermediate in normal metabolic cycles such as the citric acid cycle, like fumaric acid and pyruvic acid.

62. A pharmaceutically acceptable formulation according to claim 58 wherein the pharmaceutically acceptable formulation comprises a solution of a hyperpolarised recipient substrate in a saline solution of a hyperpolarised substrate for use as an imaging medium.

63. An imaging medium for in vivo magnetic resonance (MR) detection comprising a hyperpolarised recipient substrate wherein said hyperpolarised recipient substrate is prepared by transfer from a hyperpolarised singlet state that is not parahydrogen, said method comprising the steps of:

(i) preparing a system containing:

parahydrogen; a magnetisation transfer complex, with a molecular symmetry that allows the creation of a singlet state between spin pairs within it, said complex including a reversibly bound small molecule transference substrate;

applying a magnetic field such that hyperpolarisation is transferred into the transfer complex, including the reversibly bound small molecule transference substrate;

(ii) separately or simultaneously introducing a recipient complex capable of binding the small molecule transference substrate, said recipient complex including a recipient substrate, such that the recipient complex and recipient substrate, including the bound transference substrate, is hyperpolarised.

64. A method, formulation or imaging medium as described herein with reference to the accompanying examples and figures.