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

基本信息

批准号：
10023219
负责人：
ROBERT H MACH
金额：
$ 106.94万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10023219
关键词：
Affinity Alzheimer&apos 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 Deposition Development Disease Disease Progression Genes Goals Human Image Imaging ligands In Vitro Individual Kinetics Label Laboratories Lead Levodopa Lewy Bodies Lewy Body Dementia 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&apos 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

项目摘要

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：开发用于突触核蛋白病成像的 α 突触核蛋白 PET 放射性配体项目1的目标是进行一系列体外结合研究、体内脑摄取和PET成像评估放射性示踪剂对聚集 α 突触核蛋白 (Asyn) 进行成像的过程中的研究突触核蛋白病，包括帕金森病 (PD)、路易体痴呆 (DLB) 和多种该项目中评估的化合物将通过 in silico ultrahigh 进行鉴定。在医学领域进行的通量筛选和传统构效关系 (SAR) 研究该项目中描述的化学和放射化学 (MCRC) 核心包括三种不同类型：1) 使用放射性配体筛选不同结合的 Asyn 原纤维中的“计算机命中” 2) 原纤维的体外结合测定证实了鉴定对 PD 和 MSA 组织中 ASyn 的亲和力小于 50 nM 的新先导化合物；以及，3) 间接和作为 MCRC 核心靶向或更多中 SAR 研究的一部分而开发的化合物的直接结合测定 Asyn 原纤维中的结合位点的化合物对 Asyn 具有高亲和力并且与其他化合物相比具有良好的选择性。蛋白质病（Abeta、tau 和 TDP43）将进展到一系列体外放射自显影和体内研究作为识别人类转化成像研究合适候选者的一种手段。项目 1 的功能是交叉验证对 4R tau 具有高亲和力的潜在 PET 放射性示踪剂 MCRC 核心并在项目 2 中进行评估。本研究目标的成功实现 U19 中心将要求 MCRC 核心成员、项目 1 和项目 2。这将通过一系列每两周一次的电话会议和委员会会议来完成中心指导委员会、外部联络委员会和 NINDS 项目工作人员，如项目 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化成像研究中进行不同的突触核蛋白病。