Nitro-imidazole hypoxia imaging agents

• US 7,807,394 B2
• Filed: 04/04/2008
• Issued: 10/05/2010
• Est. Priority Date: 04/05/2007
• Status: Expired due to Fees

• Current Assignee: Siemens Molecular Imaging Incorporated (Siemens AG)
• Original Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Inventors: Gao, Zhiyong, Kolb, Hartmuth C., Gangadharmath, Umesh B., Liang, Qianwa, Collier, Thomas Lee, Duclos, Brian A., Padgett, Henry Clifton, Zhao, Tieming, Walsh, Joseph C., Karimi, Farhad, Kasi, Dhanalakshmi
• Primary Examiner(s): CHUNG, SUSANNAH LEE
• Application Number:
  US12/098,390
• Publication Number:
  US 20090010846A1
• Time in Patent Office: 914 Days
• Field of Search: 548/300.1, 435/7.23, 436/63
• US Class Current: 435/7.23
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 59/002 Heterocyclic compounds
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to novel radioactively labeled bioreducible tracers of Formula I useful for detecting hypoxic tumors or ischemic tissue in vivo. In one embodiment, the tracers consist of a 2-nitroimidazole moiety, a triazole, metabolically stable linker with pharmacokinetics enhancing substituents, and a radioisotope. The preferred in vivo imaging modality is positron emission tomography.

Claims

1. A compound consisting of the formula I:

2. The compound of claim 1, wherein X is a (C₁-C₄)alkylenyl group optionally substituted with 1, 2 or 3 hydroxyl groups or 1, 2 or 3 —

NH₂ or —

NH(C₁-C₄)alkyl group.

3. The compound of claim 2, wherein X is selected from the group consisting of —

CH₂—

, —

CH₂—

CH₂—

, —

CH₂—

CH₂—

CH₂—

, —

CH₂—

CH₂—

CH₂—

CH₂—

, —

CH₂—

CH(OH)—

, —

CH(OH)—

CH₂—

, —

CH(OH)—

CH₂—

CH₂—

, —

CH₂—

CH(OH)—

CH₂—

, —

CH₂—

CH₂—

CH(OH)— and

—

CH₂—

CH(OH)—

CH(OH)—

CH₂—

.

4. The compound of claim 1, wherein A comprises ¹¹C.

5. The compound of claim 1 consisting of the formula II or III

7. The compound of any one of claims 1-6, wherein Z is an (C₁-C₄)alkylenyl group optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of hydroxyl, thiol, amino, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, thio(C₁-C₄)alkyl and halo.

8. The compound of claim 7, wherein Z is selected from the group consisting of —

CH₂—

, —

CH₂—

CH₂—

, —

CH₂—

CH₂—

CH₂—

, —

CH₂—

CH₂—

CH₂—

CH₂—

, —

CH₂—

CH(OH)—

, —

CH(OH)—

CH₂—

, —

CH(OH)—

CH₂—

CH₂—

, —

CH(CH₂OH)—

CH₂—

, —

CH₂—

CH(OH)—

CH₂—

, —

CH₂—

CH₂—

CH(OH)— and

—

CH₂—

CH(OH)—

CH(OH)—

CH₂—

.

9. The compound of any one of claims 1-8, wherein A is ¹⁸F or ¹¹C-Me.

10. The compound of claim 9, wherein A is ¹⁸F.

11. The compound of claim 10 consisting of the formula:

16. The compound of claim 1 selected from the group consisting of:

6. A compound consisting of the formula IIb:

12. A compound consisting of the formula IV:

13. The compound of claim 12, wherein X is (C₁-C₅)alkylenyl, unsubstituted or substituted with 1 or 2 X¹.

14. A compound consisting of the formula V:

15. The compound of claim 14 consisting of the formula