Evaluation of [18F]JHU94620-d8 for imaging brain cannabinoid type 2 receptors in rodents and non-human primates

1Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA (Email: xxx) 2Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research Site Leipzig, 04318 Leipzig, Germany *Authors contributed equally to this work. Background Positron emission tomography (PET) imaging of cannabinoid receptor type 2 (CB2R) has been challenging because selective and metabolically stable PET tracers have thus far been unavailable. Here, we describe [18F]JHU94620-d8, a deuterated isotopologue of [18F]JHU94620, which was purposely designed to image CB2R with improved metabolic stability in rodents and non-human primates. Methods [18F]JHU94620-d8 was radiolabeled from its bromobutane-d8 precursor by reacting with [18F]F–K2.2.2. in CH3CN at 80°C for 15 minutes. PET imaging was performed in 6 male Sprague Dawley rats and a rhesus macaques after intravenous injection of [18F]JHU94620-d8 at high molar activity and radiochemical purity under baseline and blocked conditions. Cold parent (1.5 mg/kg) was used as a blocking agent. The efflux transporter substrate potential of the tracer was also assessed in mice with dual P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP) transporter knockout. Ex vivo experiments were performed in rats (n=3) to check for brain parent and radiometabolite concentrations at 30 min post-radioligand injection. Tracer uptake was also evaluated in a rat model of inflammation induced by lipopolysaccharide (LPS) (50 µg in 5µL) injected into the right striatum at Days 1, 9, and 15 post-LPS injection (n=6). Results In rats under baseline and blocked conditions, [18F]JHU94620-d8 displayed rapid uptake and quick washout. No blocking effect was observed with cold parent. In monkeys, peak brain uptake was higher in blocked versus baseline conditions (4.8 vs. 3.4 standardized uptake value (SUV)), and both condi