Radiosynthesis and Evaluation of Talazoparib and Its Derivatives as PARP-1-Targeting Agents

• Main Authors: Dong Zhou, Huaping Chen, Cedric Mpoy, Sadia Afrin, Buck E. Rogers, Joel R. Garbow, John A. Katzenellenbogen, Jinbin Xu
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: Biomedicines
• Subjects: PARP-1; Talazoparib; binding assay; biodistribution; targeted radiotherapy
• Online Access: https://www.mdpi.com/2227-9059/9/5/565

Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the target of several FDA-approved inhibitors. Several of these inhibitors have been radiolabeled for non-invasive imaging of PARP-1 expression or targeted radiotherapy of PARP-1 expressing tumors. In particular, derivatives of olaparib and rucaparib, which have reduced trapping potency by PARP-1 compared to talazoparib, have been radiolabeled for these purposes. Here, we report the first radiosynthesis of [¹⁸F]talazoparib and its in vitro and in vivo evaluation. Talazoparib (<b>3a″</b>) and its bromo- or iodo-derivatives were synthesized as racemic mixtures (<b>3a</b>, <b>3b</b> and <b>3c</b>), and these compounds exhibit high affinity to PARP-1 (<i>K</i>_i for talazoparib (<b>3a″</b>): 0.65 ± 0.07 nM; <b>3a</b>: 2.37 ± 0.56 nM; <b>3b</b>: 1.92 ± 0.41 nM; <b>3c</b>: 1.73 ± 0.43 nM; known PARP-1 inhibitor Olaparib: 1.87 ± 0.10 nM; non-PARP-1 compound Raclopride: >20,000 nM) in a competitive binding assay using a tritium-labeled PARP-1 radioligand [³H]WC-DZ for screening. [¹⁸F]Talazoparib (<b>3a″</b>) was radiosynthesized via a multiple-step procedure with good radiochemical and chiral purities (98%) and high molar activity (28 GBq/μmol). The preliminary biodistribution studies in the murine PC-3 tumor model showed that [¹⁸F]talazoparib had a good level of tumor uptake that persisted for over 8 h (3.78 ± 0.55 %ID/gram at 4 h and 4.52 ± 0.32 %ID/gram at 8 h). These studies show the potential for the bromo- and iodo- derivatives for PARP-1 targeted radiotherapy studies using therapeutic radionuclides.