Total-body PET of two approved PARP inhibitors: [18F]Olaparib and [11C]Niraparib in Non-Human Primates

The development of total-body positron emission tomography (TB-PET) has enabled the evaluation of the in vivo biodistribution of radiopharmaceuticals in both brain and peripheral organs in real-time simultaneously. Poly(adenosine diphosphate ribose) polymerase−1 (PARP-1) is a protein implicated in DNA damage repair. PARP-1 is often overexpressed in ovarian and breast cancers. Several PARP-inhibitors have been developed and deployed as anti-cancer therapeutics such as Niraparib ( Zejula , GSK) and Olaparib ( Lynparza , AstraZeneca & Merck). Radiolabeling of PARP-inhibitors offers a means to evaluate their target engagement in the whole subject. This has the potential to monitor the cancer treatment outcome and disease progression beyond breast and ovarian cancers, especially when they have metastasized. In this study, we introduced a novel method to radiolabel Niraparib with carbon-11. We also evaluated its in vivo biodistribution and compared with [ 18 F]Olaparib. Here, we report a novel method of radiosynthesis for [ 11 C]Niraparib. In addition, we compared its biodistribution with [ 18 F]Olaparib in a rhesus macaque model. Even though both compounds were developed as PARP-1 inhibitors, the TB-PET results showed differences in tracer uptake and distribution, consistent with their distinct chemical structures and physicochemical properties. [ 11 C]Niraparib demonstrated higher uptake than [ 18 F]Olaparib in the central nervous system (CNS), specifically the caudate (Fold-change = 2.22; P value = 0.001), cerebellum (Fold-change = 1.75; P value = 0.0231), occipital (Fold-change = 1.88; P value = 0.0205), putamen (Fold-change = 2.59; P value = 0.0048), and thalamus (Fold-change = 2.19; P value = 0.0280). [ 11 C]Niraparib and [18F]Olaparib also demonstrated different biodistribution in the body. Specifically, [ 18 F]Olaparib demonstrated significantly higher uptake in the spleen (Fold-change = 1.64; P value = 0.0115). Our findings demonstrate the utility of TB-PET for evaluating the biodistribution of radiolabeled PARP-1 inhibitors in brain and peripheral organs. The instrument also affords high sensitivity, allowing the tracer distribution analysis with low amount of radioactive tracer injection. Consistent with prior preclinical reports, [ 11 C]Niraparib exhibited higher brain uptake than [ 18 F]Olaparib, TB-PET additionally enabled simultaneous quantification of this difference alongside peripheral organ biodistribution in the same subjects. These imaging findings support further investigation of Niraparib’s potential as a CNS-penetrant PARP inhibitor candidate.