Imaging agents and methods of imaging NAALADase or PSMA

• US 20040054190A1
• Filed: 01/10/2003
• Published: 03/18/2004
• Est. Priority Date: 01/10/2002
• Status: Active Grant

• Current Assignee: Georgetown University, Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Zhang, Jiazhong, Pomper, Martin Gilbert, Kozikowski, Alan P., Musachio, John L.
• Granted Patent: US 7,408,079 B2
• Time in Patent Office: Days
• US Class Current: 548/253
• CPC Class Codes: A61B 6/508 for non-human patients
• CPC Class Codes: A61K 49/0032 Methine dyes, e.g. cyanine dyes
• CPC Class Codes: A61K 49/0052 Small organic molecules oligomers, polymers, dendrimers A61K49/0054
• CPC Class Codes: A61K 51/0402 carboxylic acid carriers, fatty acids amino acids A61K51/0406
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 323/59 with acylated amino groups bound to the carbon skeleton
• CPC Class Codes: C07F 11/005 compounds without a metal-carbon linkage
• CPC Class Codes: C12Q 1/37 involving peptidase or proteinase
• CPC Class Codes: G01N 2333/705 Assays involving receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: G01N 33/5005 involving human or animal cells immunoassay G01N33/56966; immunoassays of protozoa G01N33/56905; protozoa in screening assays C12Q1/025
• CPC Class Codes: G01N 33/60 involving radioactive labelled substances
• CPC Class Codes: G01N 33/62 involving urea
• CPC Class Codes: G01N 33/689 related to pregnancy or the gonads

Abstract

The present invention relates to compounds particularly asymmetric urea compounds which are labeled with one or more radioisotopes and which are suitable for imaging or therapeutic treatment of tissues, organs, or tumors which express NAALADase and/or PSMA. In another embodiment, the invention relates to methods of imaging tissues, organs, or tumors using radiolabeled compounds of the invention, particularly tissues, organs, or tumors which express NAALADase and/or PSMA to which the compounds of the invention have an affinity.

Claims

1. A compound according to Formula I

2. The compound of claim 1, wherein the R group comprises at least one radioactive isotope or fluorescent dye.

3. The compound of claim 1, wherein the R group comprises one or more positron emitting radioactive isotopes.

4. The compound of claim 1, wherein the R group comprises one or more isotopes selected from ¹¹C, ¹⁸F, ⁹⁹Tc, ¹²³I or any combination thereof.

5. The compound of claim 1, wherein the compound is according to Formula Ia:

6. The compound of claim 1, wherein the compound is according to Formula II

7. The compound of claim 6, wherein R¹ comprises one or more fluorescent dyes, radioisotopes selected from ¹¹C, ¹⁸F, ⁹⁹Tc, ¹²³I, or any combination thereof.

8. The compound of claim 6, wherein R¹ is selected from the group consisting of ¹¹C-methyl, optionally substituted C_1-6alkyl, optionally substituted C_7-12aralkyl, optionally substituted C_6-12aryl, each of which may be substituted with one or more ¹¹C-methyl groups, ¹⁸F, ⁹⁹Tc, ¹²³I, ¹²⁵I, ¹³¹I, or a combination thereof.

9. The compound of claim 8, wherein R¹ is ¹¹C-methyl, C_1-6alkyl substituted with one or more ¹⁸F, or benzyl substituted with one or more ¹⁸F.

10. The compound of claim 6, wherein R¹ comprises one or more radioisotope suitable for use in radiation therapy.

11. The compound of claim 1, wherein the compound is according to Formula III:

12. The compound of claim 11, wherein the compound is according to Formula IV:

13. The compound of claim 11, wherein Ar comprises one or more positron emitting isotopes of ¹¹C, ¹⁸F, ⁹⁹Tc, ¹²³I or any combination thereof.

14. The compound of claim 12, wherein R² is selected from the group consisting of ¹¹C-methyl, ¹¹C-methoxy, optionally substituted C_1-6alkyl, optionally substituted C_7-12aralkyl, optionally substituted C_6-12aryl, each of which may be substituted with one or more ¹¹C-methyl groups, ¹⁸F, ⁹⁹Tc, ¹²³I, ¹²⁵I, ¹³¹I, or a combination thereof.

15. The compound of claim 12, wherein R² is phenyl substituted with one or more groups selected from hydroxy, ¹¹C-methoxy, ¹¹C-methyl, ¹⁸F, ¹²³I, benzoyloxy which may be substituted with one or more fluoro groups, or a combination thereof.

16. A compound of claim 1 which has a binding affinity to NAALADase or PSMA of less than about 10 μ

M.

17. A compound of claim 1 which has a binding affinity to NAALADase or PSMA of less than about 1 μ

M.

18. A compound of claim 1 which has a binding affinity to NAALADase or PSMA of less than about 100 nM.

19. A compound of claim 1 which has a binding affinity to NAALADase or PSMA of less than about 10 nM.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or salt of claim 1.

21. A package comprising a pharmaceutical composition of claim 20 in a container and further comprising indicia comprising at least one of:

instructions for using the composition to image cells or tissues expressing at least one of NAALADase or PSMA, or instructions for using the composition to image glutamatergic neurotransmission in a patient suffering from a stress-related disorder, or instructions for using the composition to image prostate cancer.

38. The compound of claim 1, wherein the compound is according to Formula V:

39. The compound of claim 38, wherein the compound is according to Formula VI:

40. The compound of claim 38, wherein Ar comprises one or more positron emitting isotopes of ¹¹C, ¹⁸F, ⁹⁹Tc, ¹²³I, or any combination thereof.

41. The compound of claim 39, wherein R² is selected from the group consisting of ¹¹C-methyl, ¹¹C-methoxy, optionally substituted C_1-6alkyl, optionally substituted C_7-12aralkyl, optionally substituted C_6-12aryl, each of which may be substituted with one or more ¹¹C-methyl groups, ¹⁸F, ⁹⁹Tc, ¹²³I, ¹²⁵I, ¹³¹I, or a combination thereof.

42. The compound of claim 39, wherein R² is phenyl substituted with one or more groups selected from hydroxy, ¹¹C-methoxy, ¹¹C-methyl, ¹⁸F, ¹²³I, benzoyloxy which may be substituted with one or more fluoro groups, or a combination thereof.

43. The compound of claim 1, wherein the compound is according to Formula VII:

44. The compound of claim 43, wherein the compound is according to Formula VIII:

45. The compound of claim 12, wherein the compound is according to Formula IX:

46. The compound of claim 45, wherein R³ is FITC, a derivative thereof, carbocyanine, or a derivative thereof.

47. The compound of claim 1, wherein the compound is selected from the group consisting of:

2-[3-(1-Carboxy-3-¹¹C-methylsulfanyl-propyl)-ureido]-pentanedioic acid,

2-[3-(1-Methoxycarbonyl-3-¹¹C-methylsulfanyl-propyl)-ureido]-pentanedioic acid,

2-[3-(1-Carboxy-2-¹¹C-methylsulfanyl-ethyl)-ureido]-4-(1H-tetrazol-5-yl)-butyric acid,

2-{3-[Carboxy-(4-¹¹C-methoxy-phenyl)-methyl]-ureido}-pentanedioic acid,

2-{3-[Carboxy-(4-fluoro-phenyl)-methyl]-ureido}-pentanedioic acid,

2-{3-[Carboxy-(3-fluoro-phenyl)-methyl]-ureido}-pentanedioic acid,

2-{3-[Carboxy-(2-fluoro-phenyl)-methyl]-ureido}-pentanedioic acid,

2-[3-(1-Carboxy-4-fluoro-butyl)-ureido]-pentanedioic acid,

2-[3-(1-Carboxy-4-fluoro-3-methyl-butyl)-ureido]-pentanedioic acid,

2-{3-[1-Carboxy-2-(2-fluoro-benzylsulfanyl)-ethyl]-ureido}-pentanedioic acid,

2-{3-[1-Carboxy-2-(3-fluoro-benzylsulfanyl)-ethyl]-ureido}-pentanedioic acid,

2-{3-[1-Carboxy-2-(4-fluoro-benzylsulfanyl)-ethyl]-ureido}-pentanedioic acid,

2-{3-[1-Carboxy-2-(2-fluoro-ethylsulfanyl)-ethyl]-ureido}-pentanedioic acid,

2-(3-{1-Carboxy-2-[4-(2-fluoro-benzoyloxy)-phenyl]-ethyl}-ureido)-pentanedioic acid,

2-(3-{1-Carboxy-2-[4-(3-fluoro-benzoyloxy)-phenyl]-ethyl}-ureido)-pentanedioic acid,

2-(3-{1-Carboxy-2-[4-(4-fluoro-benzoyloxy)-phenyl]-ethyl}-ureido)-pentanedioic acid,

2-(3-{1-Carboxy-2-[4-(4-fluoromethyl-benzoyloxy)-phenyl]-ethyl}-ureido)-pentanedioic acid,

2-[3-(1-Carboxy-2-{4-[4-(4-fluoro-butyl)-benzoyloxy]-phenyl}-ethyl)-ureido]-pentanedioic acid,

2-(3-{1-Carboxy-2-[4-(4-fluoro-benzyloxy)-phenyl]-ethyl}-ureido)-pentanedioic acid,

2-{3-[1-Carboxy-2-(4-hydroxy-3-iodo-phenyl)-ethyl]-ureido}-pentanedioic acid,

2-{3-[1-Carboxy-2-(4-fluoro-phenyl)-ethyl]-ureido}-pentanedioic acid,

2-{3-[1-Carboxy-2-(3-fluoro-phenyl)-ethyl]-ureido}-pentanedioic acid,

2-{3-[1-Carboxy-2-(2-fluoro-phenyl)-ethyl]-ureido}-pentanedioic acid,

2-{3-[1-Carboxy-2-(4-iodo-phenyl)-ethyl]-ureido}-pentanedioic acid,

2-{3-[1-Carboxy-2-(3-iodo-phenyl)-ethyl]-ureido}-pentanedioic acid, and

2-{3-[1-Carboxy-2-(2-iodo -phenyl)-ethyl]-ureido}-pentanedioic acid.

22. An imaging method comprising the steps of:

providing a radiolabeled compound according to the formula;

wherein

R is selected from the group consisting of fluoroalkyl, aryl, benzyl, thiol, and alkylthiol, each of which is optionally substituted with an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkanoyl, or optionally substituted aralky, optionally substituted alkoxy, optionally substituted aralkyloxy, or optionally substituted phenoxy;

Q is hydrogen, optionally substituted alkyl, optionally substituted benzyl or optionally substituted phenyl; and

Z is Q or a tetrazole;

or a pharmaceutically acceptable salt thereof;

contacting cells or tissues with the radiolabeled compound; and

making a radiographic image.

23. The method of claim 22, wherein the imaging method is suitable for use in imaging glutamateric neurotransmission.

24. The method of claim 22, wherein the imaging method is suitable for use in imaging presynaptic glutamatergic neurotransmission.

25. The method of claim 22, wherein the imaging method is suitable for imaging of cancer which expresses at least one of NAALADase or PSMA.

26. The method of claim 22, wherein the imaging method is suitable for imaging of prostate cancer.

27. The method of claim 26, wherein the imaging method is suitable for imaging prostate cancer including metastases.

28. The method of claim 22, wherein the imaging method is suitable for imaging angiogenesis.

29. The method of claim 28, wherein the angiogenesis is associated with tumors, collagen vascular disease, cancer, stroke, vascular malformations, retinopathy, and normal tissue development.

30. The method of claim 22, wherein the radiolabeled compound exhibits a target to non-target ratio of at least about 5:

1.

31. The method of claim 22, wherein the radiolabeled compound is stable in vivo.

32. The method of claim 22, wherein the radiolabeled compound substantially localizes to a site or sites expressing at least one of NAALADase or PSMA, within about 120 minutes after administration.

33. The method of claim 22, wherein the radiolabeled compound substantially localizes to a site or sites expressing at least one of NAALADase or PSMA, within about 60 minutes after administration.

34. The method of claim 22, wherein the radiolabeled compound substantially localizes to a site or sites expressing at least one of NAALADase or PSMA, within about 30 minutes after administration.

35. The method of claim 22, wherein the radiolabeled compound is detected by a gamma camera, positron emission tomography (PET) or single photon emission tomography (SPECT).

36. The method of claim 22, wherein the subject is a human, rat, mouse, cat, dog, horse, sheep, cow, monkey, avian, or amphibian.

37. A compound which is 2-[3-(1-Carboxy-2-¹¹C-methylsulfanyl-ethyl)-ureido]-pentanedioic acid.