[¹⁸F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

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.

Using the Cu-mediated ¹⁸F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the ¹⁸F-labelled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [¹⁸F]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.

[¹⁸F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9 % ± 3 % and 3 % ± 1 % activity yields non-decay corrected). [¹⁸F]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 [¹⁸F]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461.

Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents.