Abstract 2463: 18F-Talazoparib: A novel potential PET imaging agent of PARP
Authors: Muzzioli Riccardo , Pisaneschi Federica , Rao Yi , Gammon Seth , Piwnica-Worms David 
Published: June 2022

Background: Poly-(ADP-ribose) polymerases (PARPs) are an enzyme family that catalyze the transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD+) to an acceptor protein. PARP family members play fundamental roles in single-strand DNA break (SSB) repair, cell signaling of DNA damage and inflammation, cell death, and cellular replication. Various PARP inhibitors have been developed and PARP1 inhibitors are currently used to treat subsets of breast and ovarian cancer patients. Of all the PARP inhibitors studied, Talazoparib (Pfizer), appears to be the most stable in pre-clinical and clinical studies, affords nanomolar affinity to PARP1, and demonstrates the highest affinity trapping of PARP on the DNA-protein complex. Imaging of PARP using a radiolabeled inhibitor has been proposed for patient selection, therapy dose optimization and validation of target engagement. Several PARP imaging agents have been developed and studied as possible tracers, by modifying the structure of an original PARP inhibitor to accommodate an imaging or therapeutic isotope. Herein we used a copper-mediated 18F-radio-fluorination strategy with a novel aryl boronic ester precursor to access 18F-Talazoparib (18F-TZ), a 18F-radiolabeled form of the structurally identical Talazoparib.

Methods: A novel boronic ester precursor was synthetized in six steps synthesis with an overall yield of 3.3% and characterized by NMR and mass spectrometry. Radiofluorination was performed using an automatic GE TracerLab system and analytical radioHPLC was used for tracer characterization and for stability analysis. A panel of tumor cell lines representing a variety of PARP expression levels (Hela, SUM149, SUM1315, MDA-MB-436, MDA-MB-231, PSN1, MiaPaca2, Jurkat) were tested for time-dependent uptake and specific binding, utilizing both 4 °C and excess cold TZ blocking.

Results: 18F-TZ was synthetized in 5.0±0.80% (n=20) radiochemical yield and a molar activity of 18.9-98.0 GBq/µmol by a copper-mediated radiofluorination of the corresponding pinacolic boronic ester, followed by purification via semi-preparative HPLC and reformulation in ethanol. 18F-TZ was obtained in &gt;99% radiochemical purity, displaying up to 4 hr shelf stability (25 °C and 4 °C) in PBS (10% EtOH). 18F-TZ was also stable in human plasma up to 4 hr at 37 °C. Both shelf and plasma stability tests showed a decrease of the radioHPLC peak consistent with decay half-life, but did not show the formation of secondary species. All cell lines selected for the in cellulo study showed uptake of radioactive 18F-TZ after 30 min of incubation at 37 °C. Cell uptake was blocked &gt;98% by excess cold TZ or incubation of cells at 4 °C.

Conclusion: 18F-Talazoparib was synthesized by copper-mediated radiofluorination from the corresponding pinacol ester and demonstrates both uptake and target specificity in PARP-expressing tumor cells.

Citation Format: Riccardo Muzzioli, Federica Pisaneschi, Yi Rao, Seth Gammon, David Piwnica-Worms. 18F-Talazoparib: A novel potential PET imaging agent of PARP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2463.