In Vitro and In Vivo Characterization of Alpha-Synuclein PET Radiotracers

α-突触核蛋白 PET 放射性示踪剂的体外和体内表征

• 批准号: 10241512
• 负责人: ROBERT H MACH
• 金额: $ 104.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-24 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241512
• 关键词: Affinity; Alzheimer' s Disease; Amyloid beta-Protein; Ataxia; Autonomic Dysfunction; Autopsy; Autoradiography; Binding; Binding Sites; Biodistribution; Biological Assay; Brain; Cells; Clinical; Clinical Research; Communication; Cryoelectron Microscopy; Cytoplasmic Inclusion; Data; Dementia with Lewy Bodies; Deposition; Development; Disease; Disease Progression; Genes; Goals; Human; Image; Imaging ligands; In Vitro; Individual; Kinetics; Label; Laboratories; Lead; Levodopa; Lewy Bodies; Lewy neurites; Ligands; Macaca; Measures; Movement Disorders; Multiple System Atrophy; Mutation; National Institute of Neurological Disorders and Stroke; Neocortex; Nerve Degeneration; Neurons; Parkinson Disease; Parkinson' s Dementia; Parkinsonian Disorders; Pathogenesis; Pathologic; Pharmaceutical Chemistry; Positron-Emission Tomography; Process; Property; Proteins; Radiochemistry; Rattus; Recombinants; Research; Rodent; Role; Sampling; Series; Structure; Structure-Activity Relationship; Teleconferences; Therapeutic; Time; Tissues; Tracer; Validation; abeta accumulation; alpha synuclein; base; cerebral atrophy; density; diagnostic accuracy; human tissue; imaging agent; imaging study; improved; in silico; in vivo; meetings; member; microPET; mouse model; nonhuman primate; prevent; programs; progression marker; protein TDP-43; protein structure; radioligand; radiotracer; screening; synucleinopathy; targeted biomarker; tau Proteins; tau aggregation; tissue preparation; uptake

PROJECT 1: Development of Alpha Synuclein PET Radioligands for Imaging Synucleinopathies The goal of Project 1 is to conduct a series of in vitro binding studies, in vivo brain uptake and PET imaging studies in the process of evaluating radiotracers for imaging aggregated alpha synuclein (Asyn) in the synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). The compounds evaluated in this project will be identified via in silico ultrahigh throughput screening and traditional structure-activity relationship (SAR) studies conducted in the Medicinal Chemistry and Radiochemistry (MCRC) Core. The in vitro binding assays described in this project will consist of three different types: 1) screening of “in silico hits” in Asyn fibrils using radioligands for the different binding sites with the goal of identifying “fibril confirmed hits”; 2) in vitro binding assays of the fibril confirmed hits to identify new lead compounds having an affinity for ASyn in PD and MSA tissue of <50 nM; and, 3) indirect and direct binding assays of compounds developed as part of the SAR studies in the MCRC Core targeting or more of the binding sites in Asyn fibrils. Compounds having a high affinity for Asyn and good selectivity versus other proteinopathies (Abeta, tau and TDP43) will be advanced to a series of in vitro autoradiography and in vivo studies as a means of identifying a suitable candidate(s) for translational imaging studies in humans. Another function of Project 1 is to cross-validate potential PET radiotracers having a high affinity for 4R tau developed by the MCRC Core and evaluated in Project 2. The successful accomplishment of the research objectives of this U19 Center will require the frequent communication between the members of the MCRC Core, Project 1 and Project 2. This will be accomplished by through the series of bi-weekly teleconference calls and meetings of the Center Steering Committee, External Liaison Committee, and NINDS program staff as outlined in the administrative Core. The ultimate goal of the research described in Project 1 is to identify radiotracers for the different synucleinopathies that will be conducted in translational imaging studies described in the Clinical Core.

项目1：用于成像突触核病的α-突触核蛋白PET放射性配基的开发 项目1的目标是进行一系列体外结合研究、活体脑摄取和PET成像 放射性示踪剂成像聚集型α-突触核蛋白(Asyn)的研究 并核病，包括帕金森氏病(PD)、路易体痴呆(DLB)和多发性 系统萎缩(MSA)。本项目中评估的化合物将通过硅胶超高电子显微镜进行鉴定。 药物通量筛选和传统构效关系(SAR)研究 化学和放射化学(MCRC)核心。本项目中描述的体外结合试验将包括 三种不同的类型：1)使用不同结合的放射性配基筛选异步化纤维中的“In silo Hits” 2)对原纤维进行体外结合分析以确定确认的命中 在PD和MSA组织中鉴定与ASyn有亲和力的新先导化合物，以及，3)间接和 作为MCRC核心目标或更多目标的SAR研究的一部分而开发的化合物的直接结合分析 Asyn纤维中的结合位点。与其他化合物相比，具有高亲和力和良好选择性的化合物 蛋白质病(Abeta、tau和TDP43)将发展为一系列体外放射自显影和体内放射成像。 研究是确定合适的人类翻译成像研究候选者(S)的一种手段。另一个 项目1的功能是交叉验证潜在的对4R tau具有高亲和力的PET放射性示踪剂 MCRC的核心，并在项目2中进行了评估。圆满实现了本项目的研究目标 U19中心将需要MCRC核心、项目1和成员之间的频繁沟通 项目2.这将通过以下方式完成：每两周举行一系列电话会议和会议 中心指导委员会、外部联络委员会和NINDS计划工作人员 管理核心。项目1中描述的研究的最终目标是确定放射性示踪剂 将在临床核心中描述的转译成像研究中进行的不同的联核性疾病。