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

 描述(由申请人提供)：本提案的目的是开发一个放射性配基开发计划，以发现、测试和应用创新的PET放射性配基，以探测与精神疾病有关的高优先级分子靶标。该计划将建立在分子神经成像公司现有的放射配基开发实验室和临床计划的基础上，以创建一个有效选择和测试放射性配基的可靠过程。我们建议使用分层的 放射配基的开发和应用战略，包括第1级-化学开发和体外测试，第2级-在非人类灵长类动物中的体内评估，第3级-Ind获取和人类概念验证和验证研究，以及第4级-应用于测试作用机制，评估脑穿透性，以及候选药物的靶标占有率。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，放射性配体可能会在任何级别进入发展计划。其目标是在资金允许的情况下，在不同级别同时开发多个放射性配体。我们将为每个开发阶段实施先验的通过/不通过决策规则，认识到任何放射性配基的失败风险在第一级最大，成功的可能性增加，配基从第一级进展到第四级。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基目标，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基管道。在具体的目标1-3中，我们建议与医药同行合作，开发针对多巴胺D1受体、GABA转运体和PDE2a的放射性示踪剂，作为治疗精神健康障碍的放射配基开发的关键靶点的例子，并作为创新PET放射性配基开发的合作计划战略的概念证明。通过拟议的PET成像计划获得的方案、IND和数据将通过MNI网站和现有的在线资源(SNIDD)提供。PET成像提供了确定分子靶点的脑分布、检查和区分靶点亚型、调查靶点在精神健康障碍中的表达以及显示靶点占有率以确定潜在治疗化合物的最佳治疗剂量的机会。全面的放射性配基开发计划旨在与制药业、生物技术和学术界合作，确定并有效评估与最终加快心理健康疾病治疗开发相关的分子靶点。开发工具来展示靶向参与是评估可能探测病理生物学和/或为心理健康障碍提供新疗法的化合物的关键一步。

 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.