Radiolabeled tracers for poly (ADP-ribose) polymerase-1 (PARP-1), methods and uses therefor

• US 9,993,570 B2
• Filed: 07/05/2016
• Issued: 06/12/2018
• Est. Priority Date: 01/05/2014
• Status: Active Grant

• Current Assignee: Washington University In St Louis
• Original Assignee: Washington University In St Louis
• Inventors: Mach, Robert, Chu, Wenhua, Zhou, Dong, Michel, Loren, Chen, Delphine
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): Donohue, Sean R
• Application Number:
  US15/201,765
• Publication Number:
  US 20160339124A1
• Time in Patent Office: 707 Days
• Field of Search: 424 189
• CPC Class Codes: A61B 6/037 Emission tomography
• CPC Class Codes: A61K 51/0468 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 235/18 with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Disclosed are PARP-1 inhibitors, which can be ¹⁸F-labeled for use as tracers in positron emission tomographic (PET) imaging. Further disclosed are methods of synthesis. Of the compounds synthesized, 2-[p-(2-Fluoroethoxy)phenyl]-1.3.10-triazatricyclo[6.4.1.0^4,13]trideca-2,4(13),5,7-tetraen-9-one (12) had the highest inhibition potency for PARP-1 (IC₅₀=6.3 nM). Synthesis of [¹⁸F]-12 is disclosed under conventional conditions in high specific activity with 40-50% decay-corrected yield. MicroPET imaging using [¹⁸F]-12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [¹⁸F]-12 in a tumor. Binding, can be blocked by olaparib. The compounds have utility for tumor imaging.

Claims

1. A compound or pharmaceutically acceptable salt thereof of structure

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the fluorine designated F is an ¹⁸F fluorine.

3. A method of imaging a tissue in a subject, comprising:

administering to a subject a compound or pharmaceutically acceptable salt thereof of structure

4. The method of imaging a tissue in a subject according to claim 3, wherein the tissue is a tumor tissue.

5. The method of imaging a tissue in a subject according to claim 3, wherein the tissue is an inflamed tissue.