Development of PET tracers for in vivo quantification of PDE10A

描述(由申请人提供)：该提案旨在开发一种特定的PET放射性示踪剂，用于体内定量磷酸二酯酶10A(PDE10A)。最近一项为期18个月的NIMH研究旨在评估针对精神分裂症的药物的抗精神病效果，结果显示，74%的患者因无效或无法忍受的副作用而停止服药。因此，迫切需要探索超越多巴胺D2受体阻断的新方法，这是所有现有抗精神病药物的主要作用模式。临床前生物学数据表明，抑制PDE10A活性可能是治疗精神分裂症和亨廷顿病(HD)等精神障碍的一种新的治疗方法。正电子发射断层成像(PET)是一种高灵敏度的非侵入性成像手段，可用于测量中枢神经系统中PDE10A的结合，从而提供有关其在活体受试者中的分子和细胞功能的定量信息。最近，一种特异性的PDE10A抑制剂MP-10衍生的两种PET配体在啮齿动物和非人类灵长类动物的脑中进行了评估。然而，识别一种能够穿透血脑屏障和高血浆蛋白结合力的放射性标记代谢物可能会阻碍该系列配体的临床应用。我们已经从三个不同的结构类别中确定了几个候选的PDE10A PET配体进行评估。候选化合物的选择以每个类别中类似的纳米分子亲和力/高选择性化合物的例子为指导，即：咪唑并[1，5-a]喹恶啉、辛诺林和咪唑并[1，5-a]吡啶并[3，2-e]吡嗪。将合成每个系列中具有代表性的候选化合物，并将进行初步的体外评估，以确认这些化合物与PDE10A的亲和力。然后，将对选定的候选进行放射合成和纯化。最多3个放射性配基将通过成年雄性大鼠的体外动物解剖研究进行评估，以初步确定血脑屏障的通透性和生物分布。这些候选药物(S)将通过NIMH精神活性药物筛选计划(PDSP)和磷酸二酯酶分析进行平行筛选，以确定其他大脑靶点的药理活性，以区分不同的PDE。基于这些结果，将确定临床研究的最佳候选者，并将其用于随后在狒狒体内对PDE10A的体内定量，作为灵长类动物的验证。用于体内可视化PDE10A的PET示踪剂的可用性将为研究与PDE10A的结合提供一个临床有用的工具，作为其在精神分裂症和HD的病理生理学中的作用的指示剂，并将有助于评估正在开发的用于治疗精神病和认知障碍的PDE10A靶向药物。因此，成功的示踪剂将既了解病理生理学，又促进PDE10A抑制剂在精神病和认知障碍中的发展。

DESCRIPTION (provided by applicant): 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.