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

创新 PET 放射性配体开发和应用计划 - 心理健康治疗的转化工具箱

• 批准号: 9767859
• 负责人: Richard E. Carson
• 金额: $ 125.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767859
• 关键词: Binding; Biotechnology; Brain; Characteristics; Chemistry; Clinical; Collaborations; Data; Data Management Resources; Development; Disease; Dopamine D1 Receptor; Dose; Drug Industry; Enzymes; Exhibits; Failure; Funding; GABA transporter; Goals; Grant; Human; In Vitro; Industry; Leadership; Ligands; Measures; Mental Health; Mental disorders; Molecular; Molecular Mechanisms of Action; Molecular Target; Penetrance; Pharmacologic Substance; Positron-Emission Tomography; Process; Program Development; Protocols documentation; Radiolabeled; Resource Allocation; Risk; Role; Scheme; Schizophrenia; Scientist; Testing; Therapeutic; Toxicology; Tracer; United States National Institutes of Health; Validation; Work; autism spectrum disorder; design; drug candidate; imaging program; in vitro testing; in vivo; innovation; laboratory development; lead optimization; meetings; mental development; neuroimaging; nonhuman primate; novel; novel therapeutics; online resource; phosphoric diester hydrolase; programs; public health relevance; public-private partnership; radioligand; radiotracer; success; therapeutic development; tool; uptake; validation studies; web site

 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.

 描述（由申请人提供）：该提案的目的是开发一个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有关的高优先级分子靶标。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的基础上。和临床计划，以创建有效选择和测试放射性配体的稳健流程。 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 - 非人类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 - 测试机制的应用根据现有数据，如果有足够的理由表明放射性配体的进步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。我们的目标是在资金允许的情况下在不同级别同时开发多种放射性配体，我们将为每个开发级别实施先验的进行/不进行决策规则，因为我们认识到任何放射性配体在第 1 层失败的风险最大，并且成功的可能性增加。 a 配体从第 1 级进展到第 4 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体目标、审查持续数据并管理资源分配，以优化配体在具体目标 1-3 中，我们建议与制药同事合作开发针对 D1 多巴胺受体、GABA 转运蛋白和 PDE2a 的放射性示踪剂，既作为精神健康障碍的放射性配体开发的关键目标的例子，又作为创新 PET 放射性配体开发合作计划战略的概念 通过拟议的 PET 成像计划获得的协议、IND 和数据将通过 MNI 网站和现有在线资源提供。 (SNIDD) PET 成像提供了确定分子靶标的大脑分布、检查和区分靶标亚型、研究靶标在精神健康障碍中的表达以及证明靶标占据以确定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，识别和有效评估相关的分子靶点，最终加速精神健康疾病的治疗开发。开发工具来证明靶点参与是至关重要的。评估的步骤可以探索病理学和/或为精神健康障碍提供新疗法的化合物。