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

项目摘要/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 对精神疾病的病因学和病理生理学的知识和理解，并确定了新的 治疗发展的分子靶点。宠物成像也同样戏剧性地扩大了，现在 为精神疾病的分子成像和治疗开发提供关键的翻译工具。宠物 靶点特异性放射性配基的成像在阐明分子靶点方面发挥了关键作用，如 作为多巴胺、5-羟色胺、阿片、GABA、谷氨酸、内源性大麻素的受体和转运体 乙酰胆碱系统，在抑郁症、精神分裂症和其他精神障碍的病理生理学中。这个 合适的放射性配基的可用性是探索PET成像在精神健康研究中的全部潜力的关键。 此续订申请的目标是在开发、验证和 新型PET放射性配基在探索与心理健康相关的高优先级分子靶点中的应用 精神错乱。该计划建立在耶鲁PET中心在放射性配体开发和 临床评价。我们采用分级开发策略：第一级--化学开发和体外测试； 第2级--非人类灵长类的活体评估；第3级--首次人类概念验证/验证研究； 和Tier 4-用于研究精神疾病机制的应用程序。放射性配体进入发展阶段 当有足够的理由认为推进放射性配基可以告知疾病时，任何级别的方案 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项目领导人、行业和学术主题专家以及耶鲁大学科学家)举行年度 会议提名新的目标并审查正在进行的数据，以优化放射性配基管道。放射性配体 根据该方案开发的数据和产生的数据通过一个专门的网站、会议 演示文稿和出版物，并与PET成像和心理健康研究社区共享。 该计划通过让NIMH计划官员参与决策，与NIMH的优先事项紧密结合- 制造过程，并参与整个PET示踪剂开发和成像社区的共同 努力为精神健康研究中重要的分子靶标验证新的放射性配基。首字母 资金循环导致了一种新的多巴胺D1受体激动剂示踪剂的验证，这是人类第一次 组蛋白脱乙酰基酶6(HDAC6)和单酰基甘油脂肪酶(MAGL)的放射性示踪剂测试，以及MOST 值得注意的是，针对GABA转运体-1(GAT-1)的一流放射性示踪剂的开发，以及一流的 NMDA受体复合体GluN2B亚单位的放射性示踪剂，我们建议将其翻译为First in-in-First-in- 此续订申请中的人工评估。在下一个周期的成功将看到一流的和 用于人体GAT-1、GluN2B和AMPA受体成像和定量的同类最佳放射性示踪剂， 以及开发用于新靶点的新型放射性示踪剂，以通过PET成像推进精神健康研究。

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.