COX-2-targeted imaging agents

• US 20050002859A1
• Filed: 06/25/2004
• Published: 01/06/2005
• Est. Priority Date: 06/25/2003
• Status: Abandoned Application

• Current Assignee: Vanderbilt University
• Original Assignee: Vanderbilt University
• Inventors: Marnett, Lawrence J., Prudhomme, Daniel, Timofeevski, Sergei
• Application Number:
  US10/877,303
• Publication Number:
  US 20050002859A1
• Time in Patent Office: Days
• US Class Current: 424/1.110
• CPC Class Codes: A61K 49/0433 containing an organic halogenated X-ray contrast-enhancing agent
• CPC Class Codes: A61K 49/0438 Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/10 Organic compounds
• CPC Class Codes: A61K 51/04 Organic compounds
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/26 with an acyl radical attached to the ring nitrogen atom
• CPC Class Codes: C07D 209/28 1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The presently disclosed subject matter provides a method for synthesizing a radiological imaging agent by reacting a COX-2-selective ligand with a compound comprising a detectable group, wherein the COX-2-selective ligand is a derivative of a non-steroidal anti-inflammatory drug (NSAID) comprising an ester moiety or a secondary amide moiety. Also provided are compositions that are synthesized using the method, as well as methods of using the compositions of the presently disclosed subject matter.

Claims

1. A method for synthesizing a radiological imaging agent, the method comprising reacting a COX-2-selective ligand with a compound comprising a detectable group, wherein the COX-2-selective ligand is a derivative of a non-steroidal anti-inflammatory drug (NSAID) comprising an ester moiety or a secondary amide moiety.

2. The method of claim 1, wherein a carboxylic acid group of the NSAID has been derivatized to an ester or a secondary amine.

3. The method of claim 1, wherein the NSAID is selected from the group consisting of fenamic acids, indoles, phenylalkanoic acids, phenylacetic acids, pharmaceutically acceptable salts thereof, and combinations thereof.

4. The method of claim 1, wherein the NSAID is selected from the group consisting of aspirin, o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS), indomethacin, 6-methoxy-α

-methyl-2-naphthylacetic acid, meclofenamic acid, 5,8,11,14-eicosatetraynoic acid (ETYA), diclofenac, flufenamic acid, niflumic acid, mefenamic acid, sulindac, tolmetin, suprofen, ketorolac, flurbiprofen, ibuprofen, aceloferac, alcofenac, amfenac, benoxaprofen, bromfenac, carprofen, clidanac, diflunisal, efenamic acid, etodolic acid, fenbufen, fenclofenac, fenclorac, fenoprofen, fleclozic acid, indoprofen, isofezolac, ketoprofen, loxoprofen, meclofenamate, naproxen, orpanoxin, pirprofen, pranoprofen, tolfenamic acid, zaltoprofen, zomepirac, and pharmaceutically acceptable salts thereof, and combinations thereof.

5. The method of claim 4, wherein the NSAID is selected from the group consisting of aspirin, o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS), indomethacin, meclofenamic acid, 5,8,11,14-eicosatetraynoic acid (ETYA), ketorolac, and pharmaceutically acceptable salts thereof, and combinations thereof.

6. The method of claim 1, wherein the secondary amide derivative is selected from the group consisting of indomethacin-N-methyl amide, indomethacin-N-ethan-2-ol amide, indomethacin-N-octyl amide, indomethacin-N-nonyl amide, indomethacin-N-(2-methylbenzyl) amide, indomethacin-N-(4-methylbenzyl) amide, indomethacin-N-[(R)-α

,4-dimethylbenzyl]amide, indomethacin-N-((S)-α

,4-dimethylbenzyl)amide, indomethacin-N-(2-phenethyl)amide, indomethacin-N-(4-fluorophenyl)amide, indomethacin-N-(4-chlorophenyl)amide, indomethacin-N-(4-acetamidophenyl)amide, indomethacin-N-(4-methylmercapto)phenyl amide, indomethacin-N-(3-methylmercaptophenyl)amide, indomethacin-N-(4-methoxyphenyl)amide, indomethacin-N-(3-ethoxyphenyl)amide, indomethacin-N-(3,4,5-trimethoxyphenyl)amide, indomethacin-N-(3-pyridyl)amide, indomethacin-N-5-[(2-chloro)pyridyl]amide, indomethacin-N-5-[(1-ethyl)pyrazolo]amide, indomethacin-N-(3-chloropropyl)amide, indomethacin-N-methoxycarbonylmethyl amide, indomethacin-N-2-(2-L-methoxycarbonylethyl)amide, indomethacin-N-2-(2-D-methoxycarbonylethyl)amide, indomethacin-N-(4-methoxycarbonylbenzyl)amide, indomethacin-N-(4-methoxycarbonylmethylphenyl)amide, indomethacin-N-(2-pyrazinyl)amide, indomethacin-N-2-(4-methylthiazolyl)amide, indomethacin-N-(4-biphenyl)amide, and combinations thereof.

7. The method of claim 1, wherein the detectable group is selected from the group consisting of a halogen-containing moiety, a fluorescent moiety, a metal ion-chelating moiety, a dye, a radioisotope-containing moiety, and combinations thereof.

8. The method of claim 7, wherein the halogen-containing moiety comprises a chloride atom, a fluorine atom, an iodine atom, a bromine atom, or a radioactive isotope thereof.

9. The method of claim 1, wherein the radiological imaging agent comprises the following structure:

10. The method of claim 9, wherein the radiological imaging agent comprises the following structure:

11. The method of claim 10, wherein at least one of R7 and R8 comprises ¹⁸F.

12. The method of claim 10, wherein R7 is Cl, R2 has the following structure:

13. The method of claim 10, wherein R7 is Cl and R2 has the following structure:

14. The method of claim 10, wherein R7 is Cl and R2 has the following structure:

15. The method of claim 10, wherein R7 is Cl and R2 has the following structure:

16. The method of claim 15, further comprising a coordinated metal ion.

17. The method of claim 16, wherein the coordinated metal ion is selected from the group consisting of Gd³⁺, Eu³⁺, Fe³⁺, Mn²⁺, Yt³⁺, Dy³⁺, and Cr³⁺.

18. The method of claim 17, wherein the coordinated metal ion is Gd³⁺ or Eu³⁺.

19. The method of claim 10, wherein R7 is Cl and R2 has the following structure:

20. The method of claim 19, wherein X is ¹⁸F.

21. The method of claim 10, wherein R7 is Cl and R2 has the following structure:

22. The method of claim 21, wherein R8 is ¹⁸F.

23. The method of claim 10, wherein R7 is Cl and R2 has the following structure:

24. The method of claim 9, wherein the radiological imaging agent comprising the following structure:

25. The method of claim 24, wherein R9 is Br, n=2, and R2 is p-¹⁸F-benzene.

26. The method of claim 1, wherein the radiological imaging agent comprises the following structure:

27. The method of claim 26, wherein the fluorine atom is ¹⁸F.

28. The method of claim 1, wherein the radiological imaging agent comprises the following structure:

29. The method of claim 1, wherein the radiological imaging agent comprises the following structure:

30. The method of claim 29, wherein R10 has the following structure:

39. The method of claim 30, wherein the (NSAID) is selected from the group consisting of fenamic acids, indoles, phenylalkanoic acids, phenylacetic acids, pharmaceutically acceptable salts thereof, and combinations thereof.

31. A method for imaging a target tissue in a subject, the method comprising:

(a) administering to the subject a radiological imaging agent under conditions sufficient for binding the radiological imaging agent to the target tissue, wherein the radiological imaging agent comprises a derivative of a non-steroidal anti-inflammatory drug (NSAID) comprising an ester moiety or a secondary amide moiety and further comprises a detectable group; and

(b) detecting the detectable group in the target tissue.

32. The method of claim 31, wherein a carboxyl group of the non-steroidal anti-inflammatory drug has been derivatized to an ester or secondary amide.

33. The method of claim 31, wherein the target tissue is selected from the group consisting of an inflammatory lesion, a tumor, a pre-neoplastic lesion, a neoplastic cell, a pre-neoplastic cell, and a cancer cell.

34. The method of claim 33, wherein the pre-neoplastic lesion is selected from the group consisting of a colon polyp and Barrett'"'"'s esophagus.

35. The method of claim 33, wherein the tumor is selected from the group consisting of a primary tumor, a metastasized tumor, and a carcinoma.

36. The method of claim 31, wherein the subject is a mammal.

37. The method of claim 36, wherein the mammal is a human.

38. The method of claim 31, wherein the administering is via a route selected from the group consisting of peroral, intravenous, intraperitoneal, inhalation, and intratumoral.

40. The method of claim 31, wherein the NSAID is selected from the group consisting of aspirin, o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS), indomethacin, 6-methoxy-α

-methyl-2-naphthylacetic acid, meclofenamic acid, 5,8,11,14-eicosatetraynoic acid (ETYA), diclofenac, flufenamic acid, niflumic acid, mefenamic acid, sulindac, tolmetin, suprofen, ketorolac, flurbiprofen, ibuprofen, aceloferac, alcofenac, amfenac, benoxaprofen, bromfenac, carprofen, clidanac, diflunisal, efenamic acid, etodolic acid, fenbufen, fenclofenac, fenclorac, fenoprofen, fleclozic acid, indoprofen, isofezolac, ketoprofen, loxoprofen, meclofenamate, naproxen, orpanoxin, pirprofen, pranoprofen, tolfenamic acid, zaltoprofen, zomepirac, and pharmaceutically acceptable salts thereof, and combinations thereof.

41. The method of claim 40, wherein the NSAID is selected from the group consisting of aspirin, o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS), indomethacin, meclofenamic acid, 5,8,11,14-eicosatetraynoic acid (ETYA), ketorolac, and pharmaceutically acceptable salts thereof, and combinations thereof.

42. The method of claim 31, wherein the detectable group is selected from the group consisting of a halogen-containing moiety, a fluorescent moiety, a metal ion-chelating moiety, a dye, a radioisotope-containing moiety, and combinations thereof.

43. The method of claim 31, wherein the detecting is by positron emission tomography, near infrared luminescence, or monochromatic X-ray.

44. The method of claim 31, wherein the radiological imaging agent comprises the following structure:

45. The method of claim 44, wherein the radiological imaging agent comprises the following structure:

46. The method of claim 45, wherein at least one of R7 and R8 comprises ¹⁸F.

47. The method of claim 45, wherein R7 is Cl and R2 has the following structure:

48. The method of claim 45, wherein R7 is Cl and R2 has the following structure:

49. The method of claim 45, wherein R7 is Cl and R2 has the following structure:

50. The method of claim 45, wherein R7 is Cl and R2 has the following structure:

51. The method of claim 50, further comprising a coordinated metal ion.

52. The method of claim 51, wherein the coordinated metal ion is selected from the group consisting of Gd³⁺, Eu³⁺, Fe³⁺, Mn²⁺, Yt³+, Dy³⁺, and Cr³⁺.

53. The method of claim 52, wherein the coordinated metal ion is Gd³⁺ or Eu³⁺.

54. The method of claim 45, wherein R7 is Cl and R2 has the following structure:

55. The method of claim 54, wherein X is ¹⁸F.

56. The method of claim 45, wherein R7 is Cl and R2 has the following structure:

57. The method of claim 56, wherein R8 is ¹⁸F.

58. The method of claim 45, wherein R7 is Cl and R2 has the following structure:

59. The method of claim 44, wherein the radiological imaging agent comprising the following structure:

60. The method of claim 59, wherein R9 is Br, n=2, and R2 is p-¹⁸F-benzene.

61. The method of claim 31, wherein the radiological imaging agent comprises the following structure:

62. The method of claim 61, wherein the fluorine atom is ¹⁸F.

63. The method of claim 31, wherein the radiological imaging agent comprises the following structure:

64. The method of claim 31, wherein the radiological imaging agent comprises the following structure:

65. The method of claim 64, wherein R10 has the following structure:

66. A radiological imaging agent comprising a detectable group and a COX-2-selective ligand, wherein the ligand is a derivative of a non-steroidal anti-inflammatory drug (NSAID) comprising an ester moiety or a secondary amide moiety.

67. The radiological imaging agent of claim 66, wherein a carboxyl group of the non-steroidal anti-inflammatory drug has been derivatized to an ester or secondary amide.

68. The radiological imaging agent of claim 66, wherein the radiological imaging agent comprises the following structure:

69. The radiological imaging agent of claim 68, wherein the radiological imaging agent comprises the following structure:

70. The method of claim 69, wherein at least one of R7 and R8 comprises ¹⁸F.

71. The radiological imaging agent of claim 69, wherein R7 is Cl and R2 has the following structure:

72. The radiological imaging agent of claim 69, wherein R7 is Cl and R2 has the following structure:

73. The radiological imaging agent of claim 69, wherein R7 is Cl and R2 has the following structure:

74. The radiological imaging agent of claim 69, wherein R7 is Cl and R2 has the following structure:

75. The radiological imaging agent of claim 74, further comprising a coordinated metal ion.

76. The radiological imaging agent of claim 75, wherein the coordinated metal ion is selected from the group consisting of Gd³⁺, Eu³⁺, Fe³⁺, Mn²⁺, Yt³⁺, Dy³⁺, and Cr³⁺.

77. The radiological imaging agent of claim 76, wherein the coordinated metal ion is Gd³⁺ or Eu³⁺.

78. The radiological imaging agent of claim 69, wherein R7 is Cl and R2 has the following structure:

79. The radiological imaging agent of claim 78, wherein X is ¹⁸F.

80. The radiological imaging agent of claim 69, wherein R7 is Cl and R2 has the following structure:

81. The radiological imaging agent of claim 80, wherein R8 is ¹⁸F.

82. The radiological imaging agent of claim 69, wherein R7 is Cl and R2 has the following structure:

83. The radiological imaging agent of claim 68, wherein the radiological imaging agent comprising the following structure:

84. The radiological imaging agent of claim 83, wherein R9 is Br, n=2, and R2 is p-¹⁸F-benzene.

85. The radiological imaging agent of claim 66, wherein the radiological imaging agent comprises the following structure:

86. The radiological imaging agent of claim 85, wherein the fluorine atom is ¹⁸F.

87. The radiological imaging agent of claim 66, wherein the radiological imaging agent comprises the following structure:

88. The radiological imaging agent of claim 66, wherein the radiological imaging agent comprises the following structure:

89. The radiological imaging agent of claim 88, wherein R10 has the following structure:

90. The radiological imaging agent of claim 66, wherein the radiological imaging agent comprises the following structure:

91. The radiological imaging agent of claim 66, wherein the radiological imaging agent comprises the following structure:

92. A radiological imaging agent comprising a detectable group and an indomethacin derivative selected from the group consisting of:

93. The radiological imaging agent of claim 92, wherein one or more fluorine atoms present is ¹⁸F.