Synthesis and in vivo evaluation of [11C]PJ34, a potential radiotracer for imaging the role of PARP-1 in necrosis

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme of eukaryotic cells that has been implicated in response to DNA injury. PARP-1 detects single-strand DNA breaks induced by a variety of genotoxic insults. A hyperactivation of PARP-1 is believed to play a critical role in tissues undergoing cellular death by necrosis. Therefore, a radiotracer that could image PARP-1 levels with PET could provide a useful tool in measuring necrosis in a variety of pathological conditions. The phenanthridinone derivative, 2-(dimethylamino)-N-(5,6-dihydro-6-oxoplienanthridin-2-yl)acetamide (PJ34), has a high affinity for PARP-1 (IC50=20 nM) and is a suitable lead compound for PET radiotracer development. The synthesis of [C-11]PJ34 was accomplished by base-catalyzed reaction of the corresponding des-methyl precursor, N-(5,6-dihydro-6-oxophenanthridin-2-yl)-2-(methylamino)acetamide with [C-11]methyl iodide in DMF. The radiolabeling yield was 60% and the specific activity was similar to 2000 mCi/mu mol (decay corrected to E.O.B.). The total radiosynthesis time was approximately 50 min. Preliminary in vivo biodistribution studies in a rodent model of diabetes indicate that [C-11]PJ34 displays a high uptake in tissues where PARP-1 is hyperactivated. These data indicate that [C-11]PJ34 may be a useful radiotracer for imaging tissues undergoing cellular death via necrosis. (c) 2005 Elsevier Inc. All rights reserved.