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Imaging Ligands for Alpha-Synuclein Fibril Accumulation in Multiple System Atrophy

多系统萎缩中α-突触核蛋白原纤维积累的成像配体

基本信息

批准号：
10452228
负责人：
PAUL T KOTZBAUER
金额：
$ 19.69万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452228
关键词：
Address Affinity Alzheimer&apos s Disease Amyloid beta-Protein Animal Model Autopsy Autoradiography Binding Biological Assay Biological Markers Clinical Clinical Research Competitive Binding Cytoplasmic Inclusion Data Deposition Development Diagnosis Disease Disease Progression Fluorescence Frontotemporal Dementia Genetic Growth High Prevalence Imaging ligands In Vitro Individual Lewy Bodies Lewy neurites Libraries Ligands Measurement Measures Methods Molecular Diagnosis Monitor Multiple System Atrophy Neurodegenerative Disorders Neurons Parkinson Disease Pathologic Pathology Positron-Emission Tomography Preparation Progressive Supranuclear Palsy Property Protein Biosynthesis Proteins Radiolabeled Seeds Stains Structure Therapeutic Tissue Stains Tissues Tracer Tritium Work abeta accumulation accurate diagnosis alpha synuclein base biomarker development brain tissue clinical diagnosis corticobasal degeneration density diagnostic accuracy disease mechanisms study experimental study imaging agent improved in vivo novel novel strategies personalized approach prevent protein aggregation radioligand radiotracer screening targeted biomarker tau Proteins therapeutic development therapeutic target therapy development

项目摘要

Abstract Multiple System Atrophy (MSA) is a neurodegenerative disorder defined by the accumulation of alpha- synuclein (Asyn) fibrils in glial cytoplasmic inclusions (GCIs). The accumulation of Asyn fibrils is a feature shared with Parkinson disease, where Asyn fibrils accumulate in neuronal cytoplasmic and neuritic inclusions known as Lewy bodies and Lewy neurites. Evidence from genetic, autopsy and disease mechanism studies support Asyn fibrils as a therapeutic target. It is also a target for biomarker development. A leading priority is to develop a PET imaging agent that can quantify the deposition of Asyn in living individuals, as a biomarker for target engagement in clinical studies. An Asyn PET imaging agent would also improve the accuracy of diagnosis for MSA, and provide a biomarker for disease progression. In this application we propose to screen and identify novel leads for developing an Asyn imaging agent for MSA. We developed a new screening approach to identify novel compounds that can be pursued as leads for the development of an Asyn imaging agent. This new approach uses fluorescence measurements to screen natively fluorescent compounds for binding Asyn fibrils in vitro followed by assessment of whether compounds bind to Asyn-containing GCIs in postmortem MSA brain tissue sections. A final step is to determine whether compounds selectively bind to GCIs but do not bind to other types of pathologic fibril accumulation in postmortem brain tissue sections. Compounds found to have the desired properties will be radiolabeled with tritium in order to further characterize their binding properties using radioligand binding assays and autoradiography. The compounds identified in the project can be used as leads in further studies to develop an Asyn imaging agent. Results from the project will also enable further optimization of this new screening approach to identify compounds with the binding properties needed for an imaging agent.

摘要