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（由适用提供）：本提案的目的是制定一项放射性配体开发计划，以发现，测试和应用创新的PET放射线，以探测精神疾病实施的高优先级分子靶标。该计划将基于分子神经影像学现有的放射性发展实验室和临床计划，以创建有效选择和测试放射线的强大过程。我们建议利用一个分层 具有第1级化学发展和体外测试的放射性物体开发和应用策略，第2层 - 非人类隐私，第3层元素的获取和人类概念和验证研究证明以及4-应用于测试动作机制，评估脑渗透机构，概念和验证研究的证明。根据现有数据的不同，如果有足够的理由来推进放射线，则可以在任何层中进入开发计划，这将为相关的心理健康疾病机制提供信息。目的是在资金允许的情况下同时在不同的层面上开发多个放射线。 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放射线管道。在特定目标1-3中，我们建议开发针对D1多巴胺受体，GABA Transporter和PDE2A的放射性弹药器，并与Pharmaceutical同事合作，既是用于精神健康障碍的放射性疾病开发的关键目标的典范，也可以证明为Innoverative Pet radiolioligand radioligant radioligand Inspractionaligation Programe的概念证明。通过拟议的PET成像程序获得的协议，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标的大脑分布，检查和区分靶标亚型，研究靶标在心理健康障碍中的表达，并证明靶标占用率以确定潜在的治疗化合物的最佳治疗剂量的机会。全面的放射性发展开发计划旨在与制药行业，生物技术和学者合作，以识别并有效地评估与最终加速心理健康疾病治疗发展相关的分子靶标。开发来证明目标参与的工具是评估可以探索病理生物学和/或为精神健康疾病提供新颖疗法的化合物的关键步骤。