Details

Autor(en) / Beteiligte

• Zhou, Dong
• Chen, Huaping
• Mpoy, Cedric
• Afrin, Sadia
• Rogers, Buck E
• Garbow, Joel R
• Katzenellenbogen, John A
• Xu, Jinbin

Titel

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

Ist Teil von

• Biomedicines, 2021-05, Vol.9 (5), p.565

Ort / Verlag

Switzerland: MDPI AG

Erscheinungsjahr

2021

Link zum Volltext

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• 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 [ F]talazoparib and its in vitro and in vivo evaluation. Talazoparib ( ) and its bromo- or iodo-derivatives were synthesized as racemic mixtures ( , and ), and these compounds exhibit high affinity to PARP-1 ( for talazoparib ( ): 0.65 ± 0.07 nM; : 2.37 ± 0.56 nM; : 1.92 ± 0.41 nM; : 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 [ H]WC-DZ for screening. [ F]Talazoparib ( ) 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 [ F]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.