Radiolabeled tracers for poly (adp-ribose) polymerase-1 (parp-1), methods and uses therefor

Patent metadata

Field	Value
Publication number	US-2016339124-A1
Application number	US-201615201765-A
Country	US
Kind code	A1
Filing date	Jul 5, 2016
Priority date	Jan 5, 2014
Publication date	Nov 24, 2016
Grant date	—

Abstract

Disclosed arc PARP-1 inhibitors, which can be 18 P-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 (IC 50 =6.3 nM). Synthesis of [ 18 F]-12 is disclosed under conventional conditions in high specific activity with 40-50% decay-corrected yield, MicroPET imaging using [ 18 F]-12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [ 18 F]-12 in a tumor. Binding, can be blocked by olaparib. The compounds have utility for tumor imaging.

First claim

What is claimed is:

1 . A compound or pharmaceutically acceptable salt thereof of structure

wherein R is selected from the group consisting of

whereby

is a bond.

2 . A compound or pharmaceutically acceptable salt thereof in accordance with claim 1 , wherein R is

3 . A compound or pharmaceutically acceptable salt thereof in accordance with claim 2 , wherein the F is an 18 F.

4 . A compound or pharmaceutically acceptable salt thereof in accordance with claim 1 , wherein R is

5 . A compound, or pharmaceutically acceptable salt thereof in accordance with claim 1 , wherein R is

6 . A compound or pharmaceutically acceptable salt thereof in accordance with claim 5 , wherein the F is an 18 F.

7 . A compound or pharmaceutically acceptable salt thereof of structure

wherein R is selected from the group consisting of

whereby

is a bond.

8 . A compound or pharmaceutically acceptable salt thereof in accordance with claim 7 , wherein R is

9 . A compound or pharmaceutically acceptable salt thereof in accordance with claim 8 , wherein the F is an 18 F.

10 . A compound or pharmaceutically acceptable salt thereof in accordance with claim 7 , wherein R is

11 . A compound or pharmaceutically acceptable salt thereof in accordance with claim 7 , wherein R is

12 . A compound or pharmaceutically acceptable salt thereof in accordance with claim 11 , wherein the F is an 18 F.

13 . A method of imaging a tissue in a subject, comprising:
administering to a subject a compound or pharmaceutically acceptable salt thereof selected from the group consisting of

wherein R is selected from the group consisting of

whereby

is a bond; and
subjecting the subject to PET scanning, wherein the compound comprises a positron-emitting radionuclide.

14 . A method of imaging a tissue in a subject in accordance with claim 13 , wherein the tissue is a tumor tissue.

15 . A method of imaging a tissue in a subject in accordance with claim 14 , wherein the compound is

16 . A method of imaging a tissue in a subject in accordance with claim 13 , wherein the tissue is an inflamed tissue.

17 . A method of imaging a tissue in a subject in accordance with claim 16 , wherein the compound is

18 . A method of imaging a tissue in a subject in accordance with claim 13 , wherein the compound is

and R is selected from the group consisting

whereby

is a bond.

19 . A method of imaging a tissue in a subject in accordance with claim 13 , wherein the compound is

and R is selected from the group consisting of

whereby

is a bond.

Assignees

• Univ Washington

Inventors

• Mach Robert
• Chu Wenhua
• Zhou Dong
• Michel Loren
• Chen Delphine

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title