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：用于成像膜病变的α综合蛋白PET放射线的开发 项目1的目的是进行一系列体外结合研究，体内脑吸收和宠物成像 在评估放射性示例的过程中，用于成像聚集的α突触核蛋白（ASYN） 综合症，包括帕金森氏病（PD），痴呆症，有路易尸体（DLB）和多个 系统萎缩（MSA）。该项目中评估的化合物将通过Silico Ultrahigh中的 在药用中进行的吞吐量筛查和传统的结构活性关系（SAR）研究 化学和放射化学（MCRC）核心。该项目中描述的体外结合测定法将组成 在三种不同类型的类型中：1）使用放射性配体进行不同结合的ASYN原纤维中的“中击中” 旨在识别“原纤维确认的命中”的站点； 2）原纤维的体外结合刺激证实了对 鉴定在PD和MSA组织中对ASYN具有亲和力的新铅化合物； 3）间接和 作为MCRC核心靶向或更多的SAR研究的一部分而开发的化合物的直接结合断言 Asyn原纤维中的结合位点。对Asyn具有高亲和力的化合物与其他选择性 蛋白质病（Abeta，Tau和TDP43）将被提高到一系列体外自显影术和体内 研究是确定适合人类翻译成像研究的合适候选者的手段。其他 项目1的功能是对具有高亲和力对4R TAU的高亲和力进行交叉验证的潜在宠物射射击仪 MCRC核心并在项目2中进行了评估。 U19中心将需要MCRC核心成员，项目1和 项目2。这将通过一系列每两周的电话会议电话和会议来完成 中心指导委员会，外部联络委员会和NINDS计划人员，如 行政核心。项目1中描述的研究的最终目的是确定用于 在临床核心中描述的翻译成像研究中将进行的不同突触核酸病变。