Development of PET tracers for in vivo quantification of PDE10A

开发用于 PDE10A 体内定量的 PET 示踪剂

• 批准号: 8413211
• 负责人: MAJO VATTOLY JOSEPH
• 金额: $ 23.04万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-20 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413211
• 关键词: Adult; Adverse effects; Affinity; Animals; Antipsychotic Agents; Area; Binding; Binding Sites; Biodistribution; Biological; Biological Assay; Biological Sciences; Blood - brain barrier anatomy; Brain; Brain imaging; Categories; Cell physiology; Cerebellum; Clinical; Clinical Research; Cognition Disorders; Corpus striatum structure; Cyclic AMP; Data; Development; Disease; Dissection; Dopamine; Dopamine D2 Receptor; Drug Targeting; Effectiveness; Enzymes; Evaluation; Functional disorder; Glutamates; Goals; High Pressure Liquid Chromatography; Human; Huntington Disease; Hydrolysis; Image; Imagery; In Vitro; Inhibitory Concentration 50; Kinetics; Life; Ligand Binding; Ligands; Literature; Measures; Methods; Modeling; Molecular; National Institute of Mental Health; Neurotransmitters; Outcome; Papaverine; Papio; Patients; Permeability; Pharmaceutical Preparations; Plasma Proteins; Positron-Emission Tomography; Preclinical Drug Evaluation; Primates; Protein Binding; Psychotic Disorders; Psychotropic Drugs; Pyrazines; Quinoxalines; Radiolabeled; Rattus; Reproducibility; Research; Research Design; Rodent; Role; Scanning; Scheme; Schizophrenia; Series; Specificity; Structure; Testing; Time; Tissues; Tracer; Validation; base; candidate selection; caudate nucleus; design; flexibility; imaging modality; imaging probe; in vivo; inhibitor/antagonist; male; nonhuman primate; novel strategies; novel therapeutic intervention; phosphoric diester hydrolase; pre-clinical; programs; putamen; radioligand; radiotracer; receptor; tool; uptake

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.

描述（由申请方提供）：该提案旨在开发一种特异性PET放射性示踪剂，用于磷酸二酯酶10A（PDE 10A）的体内定量。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疗效，结果显示，74%的患者因无效或无法忍受的副作用而停药。因此，迫切需要探索超越多巴胺D2受体阻滞的新方法，多巴胺D2受体阻滞是所有现有抗精神病药的主要作用模式。临床前生物学数据表明，抑制PDE 10 A活性可能是治疗精神分裂症和亨廷顿病（HD）等疾病中精神病的新治疗方法。正电子发射断层扫描（PET）成像是一种高灵敏度的非侵入性成像方式，可用于测量CNS中的PDE 10A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，在啮齿动物和非人灵长类动物脑中评价了来自MP-10（一种特异性PDE 10A抑制剂）的两种PET配体。然而，能够穿透血脑屏障和高血浆蛋白结合的放射性标记的代谢物的鉴定可能会阻碍配体在该系列中的临床应用。我们已经从三种不同的结构类别中确定了几种候选物作为PDE 10A PET配体进行评价。候选物的选择由每一类别中的类似纳摩尔亲和力/高选择性化合物的实例指导，即：咪唑并[1，5-a]喹喔啉、噌啉和咪唑并[1，5-a]吡啶并[3，2-e]吡嗪。将合成每个系列的代表性候选物，并进行初步体外评价，以确认这些化合物对PDE 10A的亲和力。然后将进行选定候选物的放射合成和纯化。将通过成年雄性大鼠的离体动物解剖研究评价最多3种放射性配体，以初步测定血脑屏障通透性和生物分布。将通过NIMH精神活性药物筛选计划（PDSP）和磷酸二酯酶测定法在细胞中筛选这些候选药物对其他脑靶点的药理学活性，以区分不同PDE。根据结果，将确定临床研究的最佳候选物，并用于狒狒中PDE 10A的后续体内定量，作为灵长类动物中的验证。用于PDE 10A体内可视化的PET示踪剂的可用性将为研究与PDE 10A的结合提供临床有用的工具，作为其在精神分裂症和HD的病理生理学中的作用的指标，并且还将有助于评估正在开发的用于治疗精神病和认知障碍的PDE 10A靶向药物。因此，成功的示踪剂将告知病理生理学并促进精神病和认知障碍中PDE 10A抑制剂的开发。