Imaging poly(ADP-ribose) polymerase-1 (PARP1) in vivo with 18F-labeled brain penetrant positron emission tomography (PET) ligand
Xin Zhou, Jiahui Chen, Jimmy S. Patel, Wenqing Ran, Yinlong Li, Richard Van, Mostafa M.H. Ibrahim, Chunyu Zhao, Yabiao Gao, Jian Rong, Ahmad Chaudhary, Guocong Li, Junqi Hu, April T. Davenport, James B. Daunais, Yihan Shao, Chongzhao Ran, Thomas Collier, Ahmed Haider, David M. Schuster, Allan I. Levey, Lu Wang, Gabriel Corfas, Steven H. Liang
Abstract
Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies. Despite the increased use 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) radioligand is crucial for understanding disease biology and performing target occupancy studies, which may aid in 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 18 F-isotopologue ([ 18 F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographical, and in vivo PET imaging in non-human primates, demonstrates the capacity of [ 18 F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [ 18 F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes of PARP1 across various diseases.