LAUSR

Simple Summary In parallel to the successful clinical implementation of PARP1/2 inhibitors as anti-cancer drugs, which interfere with the DNA repair machinery, these small molecule agents have also gained attention as vehicles for molecular imaging and radiotherapy. In this review article, we summarize the development and preclinical evaluation of radioactively-labelled PARP inhibitors for positron emission tomography (PET) for many applications, such as selecting patients for PARP inhibitor treatment, response prediction or monitoring, and diagnosis of tumors. We report on early clinical studies that show safety and feasibility of PARP-imaging in humans. In addition, we summarize the latest developments in the field of PARP-targeted radiotherapy, where PARP inhibitors are studied as vehicles to deposit highly cytotoxic radioisotopes in close proximity to the DNA of tumor cells. Lastly, we look at synthetic strategies for PARP-targeted imaging and therapy agents that are compatible with large scale production and clinical translation. Abstract Since it was discovered that many tumor types are vulnerable to inhibition of the DNA repair machinery, research towards efficient and selective inhibitors has accelerated. Amongst other enzymes, poly(ADP-ribose)-polymerase 1 (PARP1) was identified as a key player in this process, which resulted in the development of selective PARP inhibitors (PARPi) as anti-cancer drugs. Most small molecule PARPi’s exhibit high affinity for both PARP1 and PARP2. PARPi are under clinical investigation for mono- and combination therapy in several cancer types and five PARPi are now clinically approved. In parallel, radiolabeled PARPi have emerged for non-invasive imaging of PARP1 expression. PARP imaging agents have been suggested as companion diagnostics, patient selection, and treatment monitoring tools to improve the outcome of PARPi therapy, but also as stand-alone diagnostics. We give a comprehensive overview over the preclinical development of PARP imaging agents, which are mostly based on the PARPi olaparib, rucaparib, and recently also talazoparib. We also report on the current status of clinical translation, which involves a growing number of early phase trials. Additionally, this work provides an insight into promising approaches of PARP-targeted radiotherapy based on Auger and α-emitting isotopes. Furthermore, the review covers synthetic strategies for PARP-targeted imaging and therapy agents that are compatible with large scale production and clinical translation.