Purpose Poly(ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1-3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP3 and to investigate its potential for PARP targeting in vivo . Procedures Using the Cu-mediated 18 F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the 18 F-labeled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [ 18 F]AZD2461 in vitro was assessed in a range of pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP expression, and in vivo in xenograft-bearing mice. Blocking experiments were performed with both olaparib and AZD2461. Results [ 18 F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9% ± 3% and 3% ± 1% Activity yields non-decay corrected). [ 18 F]AZD2461 was taken up in vivo in PARP1-expressing tumours and the highest uptake was observed for PSN-1 cells (7.34 ± 1.16%ID/g). In vitro blocking experiments showed a lesser ability of olaparib to reduce [ 18 F]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461. Conclusion Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents.
Molecular Imaging and Biology