A Program for Innovative PET Radioligand Development and Application - atranslational toolbox for treatments for Mental Health

 描述（由申请人提供）：本提案旨在开发一项放射性配体开发计划，以发现、测试和应用创新的PET放射性配体来探测与精神疾病相关的高优先级分子靶点。该计划将建立在分子神经成像现有的放射性配体开发实验室和临床计划，以创建一个强大的过程，有效地选择和测试放射性配体。我们建议使用分层 放射性配体开发和应用策略，包括第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-IND获取和人类概念验证和验证研究，以及第4层-应用于测试作用机制，评估脑转移率和候选药物的靶向占用率。根据现有数据，如果有足够的理由认为推进放射性配体将告知相关的精神健康疾病机制，则放射性配体可以进入任何级别的开发计划。目标是在资金允许的情况下同时开发不同层次的多种放射性配体。我们将为每个开发层级实施先验的通过/不通过决策规则，认识到任何放射性配体的失败风险在第1层最大，并且配体从第1层进展到第4层的成功可能性增加。由NIH领导层、MNI科学家以及行业和学术主题专家组成的计划指导委员会将提名放射性配体目标，审查正在进行的数据，并管理资源分配，以优化计划放射性配体管道。在具体目标1-3中，我们建议与制药同事合作开发靶向D1多巴胺受体、GABA转运蛋白和PDE 2a的放射性示踪剂，作为精神健康疾病放射性配体开发的关键靶点示例，并作为创新PET放射性配体开发合作计划策略的概念验证。通过拟议的PET成像程序获取的方案、IND和数据将通过MNI网站和现有在线资源（SNIDD）提供。PET成像提供了确定分子靶标的脑分布、检查和区分靶标亚型、研究精神健康障碍中靶标的表达以及证明靶标占据以确定潜在治疗化合物的最佳治疗剂量的机会。全面的放射性配体开发计划旨在与制药行业，生物技术和学术界合作，以识别和有效评估与最终加速精神健康疾病治疗开发相关的分子靶标。开发工具来证明目标接合是评估可能探测病理生物学和/或为精神健康障碍提供新疗法的化合物的关键步骤。

 DESCRIPTION (provided by applicant): The purpose of this proposal is to develop a radioligand development program to discover, test and apply innovative PET radioligands to probe high priority molecular targets implicated in mental illness. This program will build on Molecular Neuroimaging's existing radioligand development laboratory and clinical program to create a robust process to effectively select and test radioligands. We propose to utilize a tiered radioligand development and application strategy with Tier 1 - Chemistry development and in vitro testing, Tier 2 - In vivo assessment in non-human primates, Tier 3-IND acquisition and human proof of concept and validation studies, and Tier 4 - Application to test mechanisms of action, assess brain penetrance, and target occupancy of drug candidates. Depending on the existing data, radioligands may enter the development scheme at any tier if there is sufficient rationale that advancing the radioligand will inform relevant mental health disease mechanisms. The goal is to simultaneously develop multiple radioligands at different tiers as funding allows. We will implement a priori go/no-go decision rules for each development tier recognizing that the risk of failure for any radioligand is greatest at Tier 1 and likelihood of success increases a the ligand progresses from Tier 1 to Tier 4. The program Steering Committee consisting of NIH leadership, MNI scientists, and industry and academic subject-matter experts will nominate radioligand targets, review ongoing data, and manage resource allocation to optimize the program radioligand pipeline. In specific aims 1-3, we propose to develop radiotracers targeting the D1 dopamine receptor, GABA transporter, and PDE2a in collaboration with pharmaceutical colleagues both as examples of key targets for radioligand development for mental health disorders and as a proof of concept for the strategy for a collaborative program for innovative PET radioligand development. The protocols, INDs and data acquired through the proposed PET imaging program will be made available through the MNI website and an existing online resource (SNIDD). PET imaging provides the opportunity to determine the brain distribution of the molecular target, to examine and distinguish target subtypes, to investigate the expression of the target in mental health disorders, and to demonstrate the target occupancy to determine an optimal therapeutic dose of potential therapeutic compounds. The comprehensive radioligand development program is designed to work collaboratively with the pharmaceutical industry, biotech and academics to identify and efficiently assess molecular targets relevant to ultimately accelerate therapeutic development for mental health diseases. Developing tools to demonstrate target engagement is a crucial step in assessing compounds that may probe the pathobiology and/or provide novel therapies for mental health disorders.