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.
