DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

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.

Fully Automated, High-Dose Radiosynthesis of [18F]PARPi

“…The identification of responders versus non-responders using a non-invasive technique, such as positron emission tomography (PET), is a valuable approach to patient stratification. Therefore, several PET imaging tracers targeting PARP have been developed for this purpose [ 7 , 8 , 9 , 10 ].…”

“…Additionally, performing the procedure on a synthetic platform ensures reproducibility, and often results in shorter production time [ 13 ]. Finally, a limiting manual intervention reduces the risk of microbiological contamination; human operators are the most likely source of contamination in a GMP laboratory [ 7 , 14 ].…”

Positron emission tomography imaging sheds new light on hypoxia and antitumor therapies

“…The 17‐member family of poly(ADP‐ribose)polymerase (PARP) proteins play an essential role in several DNA damage repair pathways, especially PARP1 142 . A series of PARP1‐targeted PET tracers have been investigated in both preclinical and clinical studies, in which most focus on the evaluation of PARP‐targeted therapy and radiotherapy 143 . Wilson et al.…”

“…A2ARs‐targeted PET agents can help reveal the underlying mechanisms. There are two types of A2Ars‐targeted PET agents, including xanthine‐ and triazolopyrimidine‐based tracers, some of which have been applied in humans, such as 11 C‐TMSX, 11 C‐SCH442416, 11 C‐preladenant, 11 C‐KW6002, and 18 F‐MNI‐444 143 . However, most studies focused on A2ARs in the brain and explored tracer distribution in neurological disorders.…”

“…142 A series of PARP1-targeted PET tracers have been investigated in both preclinical and clinical studies, in which most focus on the evaluation of PARP-targeted therapy and radiotherapy. 143 Wilson et al designed a PARP1targeted probe 18 F-olaparib and demonstrated that radiation may well increase PARP1 expression and 18 F-olaparib uptake in tumors, and the radioactive uptake correlated linearly with PARP1 expression 125 (Figure 3A). Based on these data, PARP-targeted PET agents offer a potent toolbox to investigate the mechanism of hypoxia and chemo-or radiotherapy resistance.…”