[¹⁸F]-Labeled PARP-1 PET Imaging of PSMA Targeted Alpha Particle Radiotherapy Response

Introduction: The growing interest and clinical translation of alpha particle (α) therapies brings with it new challenges to assess target cell engagement and to monitor therapeutic effect. Noninvasive imaging has great potential to guide α-treatment and to harness the potential of these agents in the complex environment of disseminated disease. Poly(ADP) ribose polymerase 1 (PARP-1) is among the most abundantly expressed DNA repair enzymes with key roles in multiple repair pathways - such as those induced by irradiation. In the current study, we evaluate whether a third-generation PARP1-specific radiotracer, [¹⁸F]-PARPZ (previously as [¹⁸F]WC-DZ-F) PET imaging is able to monitor the response of [²²⁵Ac]-PSMA-617 on castrate resistant prostate cancer xenografts.

Methods: [¹⁸F]PARPZ and [²²⁵Ac]-PSMA-617 were prepared based on the published protocols. When BRCA1 null castrate resistant prostate cancer (22Rv1) xenografts were ready for treatment, 11 KBq (300 nCi) of [²²⁵Ac]-PSMA-617 was administrated via injection into the retro-orbital sinus. [¹⁸F]PARPZ PET imaging (approximately 7.4 MBq (200 µCi) of [¹⁸F]PARPZ per mouse) was performed on 22Rv1 xenografts at day 1 and 6 of [²²⁵Ac]-PSMA-617 post-injection. After PET imaging, 22Rv1 tumor tissue were collected for further ex-vivo autoradiography, and the sectioned tissue slides were fixed for histological staining of PARP-1.

Results: Both [¹⁸F]-PARPZ and [²²⁵Ac]-PSMA-617 were obtained with the radiochemical purity of greater than 97%. There was no notable differences in [¹⁸F]-PARPZ distribution between the control and treated groups in all normal organs and in 22Rv1 tumor (4.79 ± 1.59 vs 4.21 ± 1.16, P = 0.05) at day 1 of [²²⁵Ac]-PSMA-617 administration. However, [¹⁸F]-PARPZ PET imaging was able to distinguish treated from control (saline) xenografts by uptake (5.76 ± 0.84 (control) vs 7.33 ± 0.99 (treated), P = 0.04) at day 6 of [²²⁵Ac]-PSMA-617 treatment. The treated group showed a significant increased tracer accumulation between day 1 and day 6 (P = 0.0021). Kinetic analysis of tracer accumulation also suggested that the localization of the agent to sites of increased PARP-1 expression was a consequence of DNA damage response.

Conclusions: [¹⁸F]-PARPZ PET imaging is able to measure significant increases in PARP imaging tracer localization to targeted α -therapy treated tumors in a model system of prostate cancer. Thus, [¹⁸F]-PARPZ lays the ground-work for the initiation of clinical investigation of DNA damage response imaging in patients treated with both approved (Radium-223 dichloride) and investigational alpha particle radiotherapy. Acknowledgements: This work was supported by R01-CA201035, R01-CA229893 and U24-CA209837. We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital for supporting the Small Animal Cancer Imaging shared resource, which in part provided imaging services. The Siteman Cancer Center is funded by NCI Cancer Center Support Grant #P30 CA091842.

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