Nucleoside based proliferation imaging markers

• US 7,928,210 B2
• Filed: 03/03/2008
• Issued: 04/19/2011
• Est. Priority Date: 03/01/2007
• Status: Expired due to Fees

• Current Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Original Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Inventors: Karimi, Farhad, Gangadharmath, Umesh, Padgett, Henry C., Duclos, Brian, Yeh, Robert M, Kolb, Hartmuth C., Mocharla, Vani P., Liang, Qianwa, Chen, Kai, Zhao, Tieming, Walsh, Joseph C.
• Primary Examiner(s): Lewis; Patrick T
• Application Number:
  US12/074,538
• Publication Number:
  US 20090016958A1
• Time in Patent Office: 1,142 Days
• Field of Search: None
• US Class Current: 536/23.1
• CPC Class Codes: A61K 51/0491 Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/067 with ribosyl as the saccharide radical
• CPC Class Codes: C07H 19/073 with 2-deoxyribosyl as the saccharide radical

Abstract

Disclosed herein are novel radiolabeled nucleosides and methods for detecting cellular proliferation in a mammal, the method comprising administrating an effective amount of a radiolabeled nucleoside; the method comprising: a) administering to the mammal a diagnostically effective amount of the nucleoside to the mammal; b) allowing the nucleoside to distribute into the effective tissue; and c) imaging the tissue, wherein an increase in binding of the compound to tissue compared to a normal control level of binding indicates that the mammal is suffering from a disease involving cellular proliferation.

Claims

1. A compound of the Formula 1:

2. The compound of claim 1, wherein:

Y is hydroxy;

R³ is —

X—

Z; and

R⁴ is CH₃.

3. The compound of claim 1 that is:

4. The compound of claim 2, wherein A is OH.

5. The compound of claim 1, wherein:

A is —

O—

X-halo, wherein X is —

CH₂CH₂—

;

Y is hydroxy;

R³ is H; and

R⁴ is CH₃—

.

6. The compound of claim 1, wherein R³ is selected from the group consisting of halo-C_1-4alkyl, perhaloC_1-4alkyl, halo-C_1-4alkyl-aryl, halo-C_1-4alkyl-heteroaryl-C_1-4alkyl, halo-C _1-6alkylOC(O)CH(C_1-5alkyl)-, C_1-5alkyl, C_3-6cycloalkyl, C_3-12cycloalkylC_1-5alkyl, C_6-14aryl, C_6-10arylC_1-4alkyl, heteroaryl, heteroarylC_1-3alkyl-heteroarylC _1-3alkyl-, (C_1-6alkyl)₂NC(O)CH(C_1-5alkyl)-.

7. The compound of claim 6, wherein R³ is halo-C_1-4alkyl.

8. The compound of claim 1, wherein at least one of the alkylenyl groups of X is branched.

10. The compound of claim 8, wherein A is H.

11. The compound of claim 8, wherein Y is Z or halo.

12. The compound of claim 10, wherein Y is selected from the group consisting of F and ¹⁸F.

13. The compound of claim 8, wherein R⁴ is CH₃.

14. The compound of claim 8, wherein R⁴ is C_2-5a1kyl, aryl, heteroaryl, halo-C _1-4alkyl, halo-C_1-4alkyl-heteroaryl-, halo-C_1-4alkyl-heteroarylC_1-4alkyl, halo-C_1-4alkyl-aryl-and halo-C_1-4alkyl-arylC_1-4alkyl.

15. The compound of claim 8, wherein Y is selected from the group consisting of halo-C_1-4alkyl-aryl, halo-C_1-4alkyl-heteroaryl, halo-C_1-4alkoxy, perhaloC_1-4-alkoxy, wherein at least one of the carbon atoms of halo-C_1-4alkyl-aryl, halo-C_1-4alkyl-heteroaryl, halo-C_1-4alkoxy, perhaloC_1-4-alkoxy is optionally substituted with hydroxyl.

16. The compound of claim 14, wherein Y is halo-C_1-4alkyl-heteroaryl.

17. The compound of claim 15, wherein the heteroaryl is a triazole.

18. The compound of claim 14, wherein R³ is H.

19. The compound of claim 10, wherein R³ is halo-C_1-4alkyl.

20. The compound of claim 10, wherein R³ is halo-C_1-4alkyl-heteroaryl-C_1-4alkyl.

21. The compound of claim 8, selected from the group consisting of:

23. The compound of claim 21, wherein A is H.

25. The compound of claim 23, wherein Y is OH.

27. The compound of claim 21, that is

29. The compound of claim 27, wherein Y is OH.

9. A compound of the Formula 1:

22. A compound of the Formula 1:

24. The compound of claim 22, wherein R³ is H.

26. The compound of claim 24, wherein R⁴ is halo-C_1-4alkyl-heteroaryl-.

28. A compound of the Formula 1:

30. The compound of claim 28, wherein R³ is CH₂—

CH₂-halo.

31. A compound of the Formula 1: