Technetium-depyridine complexes, and methods of use thereof

• US 20030235843A1
• Filed: 03/11/2003
• Published: 12/25/2003
• Est. Priority Date: 03/11/2002
• Status: Active Grant

• Current Assignee: Molecular Insight Pharmaceuticals Incorporated (Lantheus Holdings, Inc.)
• Original Assignee: Biostream, Inc.
• Inventors: Maresca, Kevin P., Babich, John W.
• Granted Patent: US 7,381,399 B2
• Time in Patent Office: Days
• US Class Current: 435/6.12
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07F 13/005 Compounds without a metal-carbon linkage

Abstract

One aspect of the invention relates to novel complexes of technetium (Tc) with various heteroaromatic ligands, e.g., pyridyl and imidazolyl ligands, and their use in radiopharmaceuticals for a variety of clinical diagnostic and therapeutic applications. Another aspect of the invention relates to novel pyridyl ligands that form a portion of the aforementioned complexes. Methods for the preparation of the technetium complexes are also described. Another aspect of the invention relates to novel pyridyl ligands based on derivatized lysine, alanine and bis-amino acids for conjugation to small peptides by solid phase synthetic methods. Additionally, the invention relates to methods for imaging regions of a mammal using the complexes of the invention.

Claims

1. A compound represented by A:

2. The compound of claim 1, wherein said compound is complexed with a radionuclide.

3. The compound of claim 1, wherein said compound is complexed with a radionuclide, wherein said radionuclide is technetium or rhenium.

4. The compound of claim 1, wherein m is 1.

5. The compound of claim 1, wherein n is 1.

6. The compound of claim 1, wherein m is 1;

and n is 1.

7. The compound of claim 1, wherein R′

is absent.

8. The compound of claim 1, wherein R″

is absent.

9. The compound of claim 1, wherein R′

is absent; and

R″

is absent.

10. The compound of claim 1, wherein m is 1;

n is 1;

R′

is absent; and

R″

is absent.

11. The compound of claim 1, wherein R is —

(CH₂)_d—

R₈₀.

12. The compound of claim 1, wherein m is 1;

n is 1;

R′

is absent;

R″

is absent; and

R is —

(CH₂)_d—

R₈₀.

13. The compound of claim 1, wherein m is 1;

n is 1;

R′

is absent;

R″

is absent; and

R is —

(CH₂)_d—

R₈₀;

wherein said compound is complexed with a radionuclide.

14. The compound of claim 1, wherein m is 1;

n is 1;

R′

is absent;

R″

is absent; and

R is —

(CH₂)_d—

R₈₀;

wherein said compound is complexed with a radionuclide, wherein said radionuclide is technetium or rhenium.

15. The compound of claim 1, wherein R is an amino acid radical.

16. The compound of claim 1, wherein R is an amino acid radical;

m is 1; and

n is 1.

17. The compound of claim 1, wherein R is an amino acid radical;

m is 1;

n is 1;

R′

is absent; and

R″

is absent.

18. The compound of claim 1, wherein R is an amino acid radical;

m is 1;

n is 1;

R′

is absent; and

R″

is absent;

wherein said compound is complexed with a radionuclide.

19. The compound of claim 1, wherein R is an amino acid radical;

m is 1;

n is 1;

R′

is absent; and

R″

is absent;

wherein said compound is complexed with a radionuclide, wherein said radionuclide is technetium or rhenium.

20. The compound of claim 1, wherein the amino acid radical is —

CH₂CH₂CH₂CH₂CH(NH₂)CO₂H.

21. The compound of claim 1, wherein the amino acid radical is —

CH(CO₂H)CH₂CH₂CH₂CH₂NH₂.

22. The compound of claim 1, wherein the amino acid radical is —

CH₂CH₂CO₂H.

23. The compound of claim 1, wherein the amino acid radical is —

CH(CO₂H)(CH₂)_xCH(NH₂)CO₂H, wherein x is an integer from 3 to 9 inclusively.

53. A formulation, comprising a compound according to any of claims 1-52;

and a pharmaceutically acceptable excipient.

54. A method of imaging a region in a patient, comprising the steps of:

administering to a patient a diagnostically effective amount of a compound of claim 2, 3, 13, 14, 18, 19, 25, 26, 36, 37, 41, 42, 48, or 49; and

obtaining an image of said region of said patient.

55. The method of claim 54, wherein said region of said patient is the head or thorax.

56. A method of preparing a peptide conjugate incorporating a compound of claim 15, 38, or 47, wherein the peptide conjugate is prepared using solid phase synthetic techniques.

24. A compound represented by B:

25. The compound of claim 24, wherein said compound is complexed with a radionuclide.

26. The compound of claim 24, wherein said compound is complexed with a radionuclide, wherein said radionuclide is technetium or rhenium.

27. The compound of claim 24, wherein Z is carboxylate.

28. The compound of claim 24, wherein m is 1.

29. The compound of claim 24, wherein n is 1.

30. The compound of claim 24, wherein m is 1;

and n is 1.

31. The compound of claim 24, wherein Z is carboxylate;

m is 1; and

n is 1.

32. The compound of claim 24, wherein R′

is absent.

33. The compound of claim 24, wherein Z is carboxylate;

m is 1;

n is 1; and

R′

is absent.

34. The compound of claim 24, wherein R is —

(CH₂)_d—

R₈₀.

35. The compound of claim 24, wherein Z is carboxylate;

m is 1;

n is 1;

R′

is absent; and

R is —

(CH₂)_d—

R₈₀.

36. The compound of claim 24, wherein Z is carboxylate;

m is 1;

n is 1;

R′

is absent; and

R is —

(CH₂)_d—

R₈₀;

wherein said compound is complexed with a radionuclide.

37. The compound of claim 24, wherein Z is carboxylate;

m is 1;

n is 1;

R′

is absent; and

R is —

(CH₂)_d—

R₈₀;

wherein said compound is complexed with a radionuclide, wherein said radionuclide is technetium or rhenium.

38. The compound of claim 24, wherein R is an amino acid radical.

39. The compound of claim 24, wherein R is an amino acid radical;

m is 1; and

n is 1.

40. The compound of claim 24, wherein R is an amino acid radical;

m is 1;

n is 1; and

R′

is absent.

41. The compound of claim 24, wherein R is an amino acid radical;

m is 1;

n is 1; and

R′

is absent;

wherein said compound is complexed with a radionuclide.

42. The compound of claim 24, wherein R is an amino acid radical;

m is 1;

n is 1; and

R′

is absent;

wherein said compound is complexed with a radionuclide, wherein said radionuclide is technetium or rhenium.

43. The compound of claim 24, wherein the amino acid radical is —

CH₂CH₂CH₂CH₂CH(NH₂)CO₂H.

44. The compound of claim 24, wherein the amino acid radical is —

CH(CO₂H)CH₂CH₂CH₂CH₂NH₂.

45. The compound of claim 24, wherein the amino acid radical is —

CH₂CH₂CO₂H.

46. The compound of claim 24, wherein the amino acid radical is —

CH(CO₂H)(CH₂)_xCH(NH₂)CO₂H, wherein x is an integer from 3 to 9 inclusively.

47. A compound represented by C:

48. The compound of claim 47, wherein said compound is complexed with a radionuclide.

49. The compound of claim 47, wherein said compound is complexed with a radionuclide, wherein said radionuclide is technetium or rhenium.

50. The compound of claim 47, wherein L is methylenecarboxylate;

and L′

is alkyl.

51. The compound of claim 47, wherein L is 2-methylenepyridyl;

and L′

is alkyl.

52. The compound of claim 47, wherein L is alkyl;

and L′

is 2-methylene pyridyl.