Labeled macrophage scavenger receptor antagonists for imaging atherosclerosis and vulnerable plaque

• US 6,974,567 B2
• Filed: 08/14/2003
• Issued: 12/13/2005
• Est. Priority Date: 02/23/2001
• Status: Expired due to Fees

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Inventors: Liu, Shuang, Edwards, David Scott
• Primary Examiner(s): Jones, Dameron L.
• Application Number:
  US10/641,688
• Publication Number:
  US 20040057900A1
• Time in Patent Office: 852 Days
• Field of Search: 424/1.11, 424/1.65, 424/9.1, 424/9.4, 424/9.42, 424/9.44, 424/9.45, 424/9.451, 424/9.455, 424/1.81, 424/1.85, 424/1.89, 206/223, 206/569, 206/570, 534/7, 534 10- 16
• US Class Current: 424/9.4
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds

Abstract

Detectably labeled macrophage scavenger receptor antagonists useful for the diagnosis and monitoring of various cardiovascular diseases including but not limited to atherosclerosis, vulnerable plaque, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.

Claims

1. A compound of the following formula:

M-(BM)_n

wherein

M is a radionuclide that is a positron emitter;

n is an integer from 1to 10; and

BM is an SR-A antagonist of formula;

wherein

R¹ is independently selected from;

H, R¹-benzamido, R¹-benzylether, R¹-benzylamino, amino, fluoralkyl, halo, cyano, nitro, aryloxyl, haloaryl, aryl, alkoxy, an 1,2-benzo;

or R¹ represents a fused ring forming naphthalene moiety with the six membered aryl ring it substitutes;

R² is a direct bond to M; and

m is an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein said radionuclide is ¹⁸F or ¹¹C.

3. The compound of claim 2 wherein said radionuclide is ¹⁸F.

8. A method to diagnose a cardiovascular disease in a patient comprising administering to the patient in need of such diagnosis an effective amount of a compound of claim 1 and detecting the presence of the compound.

9. The method of claim 8 wherein the cardiovascular disease is selected from:

atherosclerosis, vulnerable plaque, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.

10. A method to diagnose a cardiovascular disease in a patient comprising administering to the patient in need of such diagnosis an effective amount of a compound of claim 3 and detecting the presence of the compound.

11. The method of claim 10 wherein the cardiovascular disease is selected from:

atherosclerosis, vulnerable plaque, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.

12. A method to monitor a cardiovascular disease in a patient comprising administering to the patient in need of such monitoring an effective amount of a compound of claim 1 and detecting the presence of the compound.

13. The method of claim 12 wherein the cardiovascular disease is selected from:

atherosclerosis, vulnerable plaque, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.

14. A method to monitor a cardiovascular disease in a patient comprising administering to the patient in need of such monitoring an effective amount of a compound of claim 3 and detecting the presence of the compound.

15. The method of claim 14 wherein the cardiovascular disease is selected from:

atherosclerosis, vulnerable plaque, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.

16. A method to monitor the progression of an atherosclerotic lesion in a patient comprising administering to the patient in need of such monitoring an effective amount of a compound of claim 1 and detecting the presence of the compound.

17. A method to detect vulnerable plaque comprising administering to the patient in need of such detection a compound of claim 1 and detecting the presence of the compound.

18. A method to monitor the progression of an atherosclerotic lesion in a patient comprising administering to the patient in need of such monitoring an effective amount of a compound of claim 3 and detecting the presence of the compound.

19. A method to detect vulnerable plaque comprising administering to the patient in need of such detection a compound of claim 3 and detecting the presence of the compound.

20. The method of claim 8 wherein the detection comprises positron emission tomography.

21. The method of claim 10 wherein the detection comprises positron emission tomography.

36. A pharmaceutical composition comprising a predetermined quantity of a compound of claim 1, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier or diluent.

37. The pharmaceutical composition of claim 36 further comprising an effective amount of a stabilizer.

38. The pharmaceutical composition of claim 37 wherein the stabilizer is selected from the group:

ascorbic acid, benzyl alcohol, gentisic acid or a metal salt thereof, p-aminobenzoic acid or a salt thereof, cysteamine, 5-amino-2-hydroxybenzoic acid or a metal salt thereof;

nicotinic acid or a metal salt thereof, nicotinamide, a polyhydroxylated aromatic compound, an aromatic amine, and a hydroxylated aromatic amine.

39. A pharmaceutical composition comprising a predetermined quantity of a compound of claim 3, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier or diluent.

40. The pharmaceutical composition of claim 39 further comprising an effective amount of a stabilizer.

41. The pharmaceutical composition of claim 40 wherein the stabilizer is selected from the group:

ascorbic acid, benzyl alcohol, gentisic acid or a metal salt thereof, p-aminobenzoic acid or a salt thereof, cysteamine, 5-amino-2-hydroxybenzoic acid or a metal salt thereof, nicotinic acid or a metal salt thereof, nicotinamide, a polyhydroxylated aromatic compound, an aromatic amine, and a hydroxylated aromatic amine.

48. A kit comprising a sealed vial comprising a predetermined quantity of a compound of claim 1 or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier or diluent.

49. The kit of claim 48 further comprising at least one of a reducing agent, a bulking agent, or a weak transfer ligand.

50. A kit comprising a sealed vial comprising a predetermined quantity of a compound of claim 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

51. The kit of claim 50 further comprising at least one of a reducing agent, a bulking agent, or a weak transfer ligand.

56. A kit comprising (a) a first vial comprising a predetermined quantity of a compound of claim 1, or a pharmaceutically acceptable salt thereof;

and (b) a second vial comprising a pharmaceutically acceptable carrier or diluent.

57. The kit of claim 56 further comprising at least one of a reducing agent, a bulking agent, or a weak transfer ligand.

58. A kit comprising (a) a first vial comprising a predetermined quantity of a compound of claim 3, or a pharmaceutically acceptable salt thereof;

and (b) a second vial comprising a pharmaceutically acceptable carrier or diluent.

59. The kit of claim 58 further comprising at least one of a reducing agent, a bulking agent, or a weak transfer ligand.

4. A compound of the following formula:

M-(BM)_n

wherein,

M is radionuclide that is a positron emitter;

n is an integer from 1 to 10; and

BM is an SR-A antagonist of formula;

wherein

R¹ is independently selected from;

H, R¹-benzamido, R¹-benzylether, R¹-benzylamino, amino, fluoralkyl, halo, cyano, nitro, aryloxyl, haloaryl, aryl, alkoxy, an 1,2-benzo;

or R represents a fused ring forming naphthalene moiety with the six membered aryl ring it substitutes;

R² is a direct bond to M;

m is an integer from 1 to 4;

M′

is a metal ion selected from Fe(III, Os(III), Co(III), Ni(II), Cu(II), Mn(IJ), o Al(III);

M″

is a metal-containing moiety selected from;

V═

O, MO═

O, Re═

O, or Tc═

O;

d

L is a coligand selected from;

trialkylphosphine, triarylphosphine, triarylyalkylphosphine, pyridine or pyridine analog with appropriate substituent on the pyridine ring;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 wherein:

M′

is a metal ion selected from Fe(III, Os(III), Co(III), Ni(II), or Cu(II); and

M″

is a metal-containing moiety selected from;

V═

O, Mo═

O, or Re═

O.

6. The compound of claim 5 wherein said radionuclide is ¹⁸F or ¹¹C.

7. The compound of claim 6 wherein said radionuclide is ¹⁸F.

22. A method to diagnose a cardiovascular disease in a patient comprising administering the patient in need of such diagnosis an effective amount of a compound of claim 4 and detecting the presence of the compound.

23. The method of claim 22 wherein the cardiovascular disease is selected from:

atherosclerosis, vulnerable plaque, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.

24. A method to diagnose a cardiovascular disease in a patient comprising administering the patient in need of such diagnosis an effective amount of a compound of claim 7 and detecting the presence of the compound.

25. The method of claim 24 wherein the cardiovascular disease is selected from:

atherosclerosis, vulnerable plaque, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.

26. A method to monitor a cardiovascular disease in a patient comprising administering to the patient in need of such monitoring an effective amount of a compound of claim 4 and detecting the presence of the compound.

27. The method of claim 26 wherein the cardiovascular disease is selected from:

atherosclerosis, vulnerable plaque, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.

28. A method to monitor a cardiovascular disease in a patient comprising administering to the patient in need of such monitoring an effective amount of a compound of claim 7 and detecting the presence of the compound.

29. The method of claim 28 wherein the cardiovascular disease is selected from:

atherosclerosis, vulnerable plaque, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.

30. A method to monitor the progression of an atherosclerotic lesion in a patient comprising administering to the patient in need of such monitoring an effective amount of a compound of claim 4 and detecting the presence of the compound.

31. A method to monitor the progression of an atherosclerotic lesion in a patient comprising administering to the patient in need of such monitoring an effective amount of a compound of claim 7 and detecting the presence of the compound.

32. A method to detect vulnerable plaque comprising administering to the patient in need of such detection a compound of claim 4 and detecting the presence of the compound.

33. A method to detect vulnerable, plaque comprising administering to the patient in need of such detection a compound of claim 7 and detecting the presence of the compound.

34. The method of claim 22 wherein the detection comprises positron emission tomography.

35. The method of claim 24 wherein the detection comprises positron emission tomography.

42. A pharmaceutical composition comprising a predetermined quantity of a compound of claim 4 or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier or diluent.

43. The pharmaceutical composition of claim 42 further comprising an effective amount of a stabilizer.

44. The pharmaceutical composition of claim 43 wherein the stabilizer is selected from the group:

ascorbic acid, benzyl alcohol, gentisic acid or a metal salt thereof, p-aminobenzoic acid or a salt thereof, cysteamine, 5-amino-2-hydroxybenzoic acid or a metal salt thereof, nicotinic acid or a metal salt thereof, nicotinamide, a polyhydroxylated aromatic compound, an aromatic amine, and a hydroxylated aromatic amine.

45. A pharmaceutical composition comprising a predetermined quantity of a compound of claim 7, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier or diluent.

46. The pharmaceutical composition of claim 45 further comprising an effective amount of a stabilizer.

47. The pharmaceutical composition of claim 46 wherein the stabilizer is selected from the group:

ascorbic acid, benzyl alcohol, gentisic acid or a metal salt thereof, p-aminobenzoic acid or a salt thereof, cysteamine, 5-amino-2-hydroxybenzoic acid or a metal salt thereof, nicotinic acid or a metal salt thereof, nicotinamide, a polyhydroxylated aromatic compound, an aromatic amine, and a hydroxylated aromatic amine.

52. A kit comprising a sealed vial comprising a predetermined quantity of a compound of claim 4 or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier or diluent.

53. The kit of claim 52 further comprising at least one of a reducing agent, a bulking agent, or a weak transfer ligand.

54. A kit comprising a sealed vial comprising a predetermined quantity of a compound of claim 7 or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier or diluent.

55. The kit of claim 54 further comprising at least one of a reducing agent, a bulking agent, or a weak transfer ligand.

60. A kit comprising (a) a first vial comprising a predetermined quantity of a compound of claim 4, or a pharmaceutically acceptable salt thereof;

and (b) a second vial comprising a pharmaceutically acceptable carrier or diluent.

61. The kit of claim 60 further comprising at least one of a reducing agent, a bulking agent, or a weak transfer ligand.

62. A kit comprising (a) a first vial comprising a predetermined quantity of a compound of claim 7, or a pharmaceutically acceptable salt thereof;

and (b) a second vial comprising a pharmaceutically acceptable carrier or diluent.

63. The kit of claim 62 further comprising at least one of a reducing agent, a bulking agent, or a weak transfer ligand.