The proposal aims to develop a specific PET radiotracer for in vivo quantification of the enzyme phosphodiesterase 10A (PDE10A). A recent 18-month NIMH study designed to evaluate antipsychotic effectiveness of drugs targeting schizophrenia revealed that 74% of patients discontinued their medication due to inefficacy or intolerable side effects. Thus, there is an urgent need for exploring novel approaches beyond dopamine D2 receptor blockade, which is the primary mode of action of all existing antipsychotics. Preclinical biological data suggest that inhibition of PDE10A activity could be a novel therapeutic approach for the treatment of psychosis in disorders such as schizophrenia and Huntington's disease (HD). Positron emission tomography (PET) imaging is a highly sensitive non-invasive imaging modality that can be utilized to measure PDE10A binding in CNS and thus provide quantitative information regarding its molecular and cellular function in living subjects. Recently two PET ligands derived from MP-10, a specific PDE10A inhibitor, were evaluated in rodent and non-human primate brain. However identification of a radiolabeled metabolite capable of penetrating the blood-brain barrier and high plasma protein binding may hamper the clinical utility of ligands in this series. We have identified several candidates from three distinct structure classes for evaluation as PDE10A PET ligands. The selection of the candidates is guided by the examples of analogous nanomolar affinity/high selectivity compounds in each of the categories namely: imidazo[1,5-a]quinoxaline, cinnoline and imidazo[1,5-a]pyrido[3,2-e]pyrazine. Representative candidates from each of the series will be synthesized and a preliminary in vitro evaluation will be carried out to confirm the affinity of these compounds for PDE10A. The radiosynthesis and purification of select candidates will then be performed. A maximum of 3 radioligands will be evaluated by ex vivo animal dissection studies in adult male rats for the initial determination of blood-brain barrier permeability and biodistribution. These candidate(s) will be screened in paralell for pharmacological activity at other brain targets by the NIMH Psychoactive Drug Screning Program (PDSP) and from phosphodiesterase assays to differentiate between different PDEs. Based on the results, an optimal candidate for clinical studies will be identified and used for subsequent in vivo quantification of PDE10A in baboon as a validation in primate. The availability of a PET tracer for in vivo visualization of PDE10A would provide a clinically useful tool for studying binding to PDE10A as an indicator of its role in the pathophysiology of schizophrenia and HD and would also assist in evaluating PDE10A-targeted drugs that are being developed for the treatment of psychosis and cognitive disorders. Thus, the successful tracer will both inform about pathophysiology and facilitate development of PDE10A inhibitors in psychosis and cognitive disorders. PUBLIC HEALTH RELEVANCE: The proposal aims to develop a specific PET radiotracer for in vivo quantification of the enzyme phosphodiesterase 10A (PDE10A). Preclinical biological data suggest that inhibition of PDE10A activity could be a novel therapeutic approach for the treatment of psychosis in disorders such as schizophrenia and Huntington's disease. The successful development of a PET tracer would both inform about pathophysiology and facilitate development and evaluation of PDE10A inhibitors in psychosis and cognitive disorders.