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Abstract: Introduction: The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [11C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET. Methods: A procedure was developed for labeling MP-10 with carbon-11. [11C]MP-10 was evaluated in vivo both in the pig and baboon brain. Results: Alkylation of the corresponding desmethyl compound with [11C]methyl iodide produced [11C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [11C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1–2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [11C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [11C]MP-10 were slower, reaching peak tissue concentrations at 30–60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [11C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution (V T) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential (BP ND) as the outcome measure of specific binding. Quantification of [11C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP ND estimates consistent with those obtained by the two-tissue compartment model. Conclusion: We demonstrated that [11C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the brain by PET. [Copyright &y& Elsevier]