Imaging poly(ADP-ribose) polymerase-1 (PARP1) in vivo with 18F-labeled brain penetrant positron emission tomography (PET) ligand

Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 holds potential therapeutic benefits for various pathologies. Despite the current FDA approval of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) ligand is crucial for disease biology and target occupancy studies, aiding the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its 18F-isotopologue ([18F]5). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographical, and in vivo PET imaging in non-human primates, demonstrates the capacity of [18F]5 for specific binding to PARP1 and successful penetration of the BBB. These findings position [18F]5 as a viable molecular imaging tool, poised to facilitate the exploration of physiopathological changes of PARP1 across various diseases.