Preclinical evaluation of [18F]MA3: a CB2 receptor agonist radiotracer for PET

Background and Purpose: Non-invasive in vivo imaging of cannabinoid CB receptors using PET is pursued to study neuroinflammation. The purpose of this study is to evaluate the in vivo binding specificity of [F]MA3, a CB receptor agonist, in a rat model with local overexpression of human (h) CB receptors. Methods: [F]MA3 was produced with good radiochemical yield and radiochemical purity. The radiotracer was evaluated in rats with local overexpression of hCB receptors and in a healthy non-human primate using PET. Key Results: Ex vivo autoradiography demonstrated CB-specific binding of [F]MA3 in rat hCB receptor vector injected striatum. In a PET study, increased tracer binding in the hCB receptor vector-injected striatum compared to the contralateral control vector-injected striatum was observed. Binding in hCB receptor vector-injected striatum was blocked with a structurally non-related CB receptor inverse agonist, and a displacement study confirmed the reversibility of tracer binding. This study identified the utility of mutated inactive vector model for evaluation of CB receptor agonist PET tracers. [F]MA3 PET scans in the non-human primate showed good uptake and fast washout from brain, but no CB receptor-specific binding was observed. Conclusion and Implications: Evaluation of [F]MA3 in a rat model with local overexpression of hCB receptors showed CB receptor-specific and reversible tracer binding. [F]MA3 showed good brain uptake and subsequent washout in a healthy non-human primate, but no specific binding was observed. Further clinical evaluation of [F]MA3 in patients with neuroinflammation is warranted.