Synthesis and Characterization of Radio-Halogenated Talazoparib Analogues for Imaging and Radioligand Therapy

Talazoparib (TZ) is a potent poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor that uniquely traps PARP complexes at sites of single-strand DNA damage thereby offering opportunities for targeted radioligand therapy. Radiolabeled halogenated TZ derivatives were synthesized using boronic ester precursors to enable incorporation of diagnostic and therapeutic radionuclides: ¹⁸F for PET imaging, ⁷⁷Br for Auger electron radiotherapy, and ²¹¹At for targeted alpha radiotherapy. Copper-mediated radio-halogenation afforded racemic ¹⁸F-TZ, ⁷⁷Br-TZ, and ²¹¹At-TZ in sufficient radiochemical yields (4.3 ± 2.6%, n = 33; 29.0 ± 12.0%, n = 4; 3.6 ± 3.8%, n = 9, respectively), ∼99% radiochemical purity and proven stability under formulation conditions. Molecular dynamics simulations of halo-TZ derivatives predicted an inverse relationship between halogen size and PARP1 binding affinity. Indeed, cell uptake of radio-halogenated TZ analogues indicated selective uptake in a panel of cell types that correlated with PARP1 levels but was inversely related to the atomic radii of the halogen series. Despite modest specific activity and specific uptake, ⁷⁷Br-TZ showed significant cytotoxicity. Further investigation of ¹⁸F-TZ with ⁷⁷Br-TZ as a radiotheranostic pair will be facilitated by the synthetic schemes herein.