A Program for Innovative PET Radioligand Development and Application - A Translational Toolbox for Treatments for Mental Health

项目总结/摘要 分子神经科学、遗传学和基础行为科学的进步极大地扩展了我们的研究领域。 知识和理解的病因和病理生理学的精神疾病，并确定新的 用于治疗开发的分子靶点。PET成像也同样得到了极大的发展， 为精神障碍的分子成像和治疗开发提供了关键的翻译工具。宠物 用靶特异性放射性配体进行成像在阐明分子靶中起着关键作用， 作为多巴胺、5-羟色胺、阿片样物质、GABA、谷氨酸、内源性大麻素和 乙酰胆碱系统，在抑郁症，精神分裂症和其他精神疾病的病理生理学。的 合适的放射性配体的可用性是探索PET成像在精神健康研究中的全部潜力的关键。 该更新申请的目标是推进开发，验证和 新型PET放射性配体在探测与精神健康有关的高优先级分子靶点中的应用 紊乱该计划建立在耶鲁PET中心在放射性配体开发方面的卓越能力之上， 临床评价我们采用分层开发策略：第1层-化学开发和体外测试; 第2层-非人灵长类动物体内评估;第3层-首次人体概念验证/确认研究; Tier 4 -用于研究精神疾病的机制。放射性配体进入发展 当有足够的理由表明推进放射性配体可以告知疾病时， 相关精神障碍的机制。该计划的外部科学小组和指导委员会 (NIMH项目负责人、行业和学术主题专家以及耶鲁大学的科学家）每年举行一次 会议提名新的目标和审查正在进行的数据，以优化放射性配体管道。放射性配体 在该方案下开发和生成的数据通过专门的网站、会议和信息中心传播。 报告和出版物，并与PET成像和心理健康研究界分享。 该计划通过NIMH计划官员参与决策，与NIMH的优先事项紧密结合- 使整个PET示踪剂开发和成像社区共同参与 奋进于验证新型放射性配体在精神健康研究中的重要分子靶点。初始 一个资金周期导致了多巴胺D1受体的新型激动剂示踪剂的验证，这是第一个在人类 检测组蛋白脱乙酰酶6（HDAC 6）和单酰基甘油脂肪酶（MAGL）的放射性示踪剂， 重要的是，GABA转运蛋白-1（GAT-1）的一流放射性示踪剂的开发，以及同类最佳的放射性示踪剂的开发， NMDA受体复合物的GluN 2B亚基的放射性示踪剂，我们建议将其翻译为第一个 在这个更新应用程序中的人的评价。下一个周期的成功将见证一流的验证， 用于人体GAT-1、GluN 2B和AMPA受体成像和定量的一流放射性示踪剂， 以及开发用于新靶点的新型放射性示踪剂，以通过PET成像推进心理健康研究。

Project Summary/Abstract Advances in molecular neuroscience, genetics, and basic behavioral science have vastly expanded our knowledge and understanding on the etiology and pathophysiology of mental illness, and identified new molecular targets for therapeutic development. PET imaging has similarly expanded dramatically and now provides critical translational tools for molecular imaging and therapeutic development in mental disorders. PET imaging with target-specific radioligands has played a critical role in the elucidation of molecular targets, such as receptors and transporters for the dopamine, serotonin, opioid, GABA, glutamate, endocannabinoid, and acetylcholine systems, in the pathophysiology of depression, schizophrenia, and other mental disorders. The availability of suitable radioligands is key to exploring the full potential of PET imaging in mental health research. The goal of this renewal application is to advance an innovative program in the development, validation, and application of novel PET radioligands to probe high priority molecular targets implicated in mental health disorders. This program builds on the Yale PET Center's outstanding capability in radioligand development and clinical evaluation. We use a tiered development strategy: Tier 1 - Chemistry development and in vitro testing; Tier 2 - In vivo assessment in non-human primates; Tier 3 – First-in-human proof of concept/validation studies; and Tier 4 - Application to investigate mechanisms of mental illnesses. Radioligands enter the development scheme at any tier when there is sufficient rationale that advancing the radioligand can inform disease mechanisms of relevant mental disorders. The program's External Scientific Panel and Steering Committee (NIMH program leaders, industry and academic subject-matter experts, and Yale scientists) hold annual meetings to nominate new targets and review ongoing data to optimize the radioligand pipeline. Radioligands developed and data generated under the program are disseminated via a dedicated website, conference presentations and publications, and shared with the PET imaging and mental health research community. This program aligns tightly with NIMH priorities by involvement of NIMH program officers in the decision- making process, and engages the entire PET tracer development and imaging community in the common endeavor to validate novel radioligands for molecular targets important in mental health research. The initial funding cycle resulted in the validation of a novel agonist tracer for the dopamine D1 receptor, the first-in-human testing of radiotracers for histone deacetylase 6 (HDAC6) and monoacylglycerol lipase (MAGL), and most significantly, the development of first-in-class radiotracers for the GABA transporter-1 (GAT-1), and best-in-class radiotracer for the GluN2B subunit of the NMDA receptor complex, which we propose to translate to first-in- human evaluation in this renewal application. Success in the next cycle will see validation of first-in-class and best-in-class radiotracers for imaging and quantification of GAT-1, GluN2B, and AMPA receptors in humans, and development of novel radiotracers for new targets to advance mental health research through PET imaging.