Radiolabeled Tracers for Poly (ADP-RIBOSE) Polymerase-1 (PARP-1), Methods and Uses Therefor

Abstract

Disclosed are PARP-1 inhibitors, which can be 18 F-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.

What is claimed is: 
     
         1 - 19 . (canceled) 
     
     
         20 . A method for inhibiting a Poly (ADP-ribose) polymerase-1 (PARP-1) enzyme comprising contacting the PARP-1 enzyme with a compound or pharmaceutically acceptable salt thereof of structure 
       
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 20 , wherein the PARP-1 enzyme is contacted with the compound at a concentration of at least 6.3 nanomolar (nM). 
     
     
         22 . The method of  claim 20 , wherein the PARP-1 enzyme is in a subject having cancer or inflammation. 
     
     
         23 . The method of  claim 22 , wherein the subject is a human. 
     
     
         24 . The method of  claim 22 , wherein the subject is a cat, dog, mouse, guinea pig, rabbit, rat, horse, a sheep, a cow, or a goat. 
     
     
         25 . The method of  claim 22 , wherein the PARP-1 enzyme in the subject is contacted by administering the compound or pharmaceutically acceptable salt thereof to the subject. 
     
     
         26 . A method of synthesizing a compound or pharmaceutically acceptable salt thereof of structure 
       
         
           
           
               
               
           
         
         comprising reacting a mesylate precursor compound of structure 
       
       
         
           
           
               
               
           
         
         wherein Ms is a mesylate group, with [ 18 F]fluoride in a nucleophilic substitution reaction. 
       
     
     
         27 . The method of  claim 26 , wherein [ 18 F]KF and K 2 CO 3 , are reacted with the mesylate precursor compound. 
     
     
         28 . The method of  claim 26 , further comprising purifying the compound by high performance liquid chromatography. 
     
     
         29 . The method of  claim 26 , wherein the compound or pharmaceutically acceptable salt thereof is obtained at a specific activity of 5500 to 18000 mCi/μmol. 
     
     
         30 . A method of synthesizing a compound or pharmaceutically acceptable salt thereof of structure 
       
         
           
           
               
               
           
         
         comprising reacting a precursor compound of structure 
       
       
         
           
           
               
               
           
         
         wherein R is 
       
       
         
           
           
               
               
           
         
       
       and wherein   is a bond,
 with 2-[ 18 F]fluoroethyl azide in a Cu(I) catalyzed click reaction. 
 
     
     
         31 . The method of  claim 30 , further comprising purifying the compound by high performance liquid chromatography.