Evaluation of the CNS penetration of a next generation PARP inhibitor, AZD9574, in cynomolgus monkey using positron emission tomography

Abstract The current clinically approved PARP inhibitors have limited subtype selectivity and are to some degree restricted in their ability to penetrate the central nervous system (CNS) due to efflux transporters, potentially limiting their efficacy in treating metastatic disease or primary tumors in the brain. The current study evaluated the potential of AZD9574, a next generation, PARP1 selective inhibitor/trapper, to penetrate the CNS in cynomolgus monkey, and its occupancy of the PARP1 enzyme, using positron emission tomography (PET). In vitro bidirectional efflux assay data suggested AZD9574 showed minimal substrate potential compared to the clinically approved PARP inhibitors. This was reflected in an increased ratio of unbound brain to unbound plasma concentration (Kpuu) in the rat of ~0.31. Therefore AZD9574 was taken forward into cynomolgus monkey PET studies. Firstly, the Kpuu was determined following dosing of [11C]AZD9574, co-administered with unlabeled drug to minimize the impact of specific binding. The high specific signal observed lead to the development of [11C]AZ3391, a PARP1 selective, CNS penetrant PET tracer, which was subsequently used to directly assess the PARP1 target engagement of AZD9574 in the brain. AZD9574 was found to show a Kpuu in cynomolgus monkeys of 0.79, close to unity with unbound plasma concentrations suggesting minimal CNS restriction. Furthermore, an i.v. infusion dose response study with AZD9574, conducted to examine its ability to block target occupancy by the PET tracer [11C]AZ3391, demonstrated a reduction in [11C]AZ3391 accumulation in whole brain. The resulting calculated occupancy of AZD9574 ranged from 17% for the lowest dose (0.003 mg/kg) to 95% for the highest dose tested (0.05 mg/kg). Comparable reduction in occupancy was seen for peripheral tissue, such as bone marrow, supporting the conclusion that AZD9574 shows minimal CNS restriction. These data show that AZD9574 is the first PARP inhibitor to reach the clinic which combines PARP1 selectivity, trapping and high CNS penetration in a single molecule and supports its development as a potential therapy for the treatment of metastatic disease and primary brain tumors. Citation Format: Andy Pike, Amber Balazs, Zsolt Cselényi, Sébastien L. Degorce, Avipsa Ghosh, Sudhir M. Hande, Jeffrey Johannes, Peter Johnström, Martin J. Packer, Magnus Schou, XiaoLan Zheng. Evaluation of the CNS penetration of a next generation PARP inhibitor, AZD9574, in cynomolgus monkey using positron emission tomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5076.