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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：
10581664
负责人：
PAUL T KOTZBAUER
金额：
$ 23.63万
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581664
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 Cytoplasm 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 Stains Structure Therapeutic Tissue Stains Tissues Tracer Tritium Work abeta accumulation accurate diagnosis alpha synuclein biomarker development brain tissue clinical diagnosis corticobasal degeneration density diagnostic accuracy disease mechanisms study experimental study imaging agent improved in vivo monomer novel novel strategies personalized approach prevent protein aggregation radioligand radiotracer screening targeted biomarker tau Proteins tau aggregation 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.

摘要多系统萎缩（MSA）是一种神经退行性疾病，其定义为α-淀粉样蛋白的积累，神经胶质细胞质内含物（GCI）中的突触核蛋白（Asyn）纤维。Asyn纤维的积累是一个特征与帕金森病共享，其中Asyn纤维积聚在神经元细胞质和神经炎包涵体中叫做路易体和路易神经突来自遗传学、尸检和疾病机制研究的证据支持脱辅基原纤维作为治疗靶点。它也是生物标志物开发的目标。首要任务是开发一种PET成像剂，可以量化Asyn在活体中的沉积，作为生物标志物，临床研究中的目标参与。Asyn PET显像剂还可以提高诊断的准确性。诊断MSA，并提供疾病进展的生物标志物。在本申请中，我们建议筛选并鉴定用于开发用于MSA的Asyn显像剂的新先导物。我们开发了一种新的筛选方法一种鉴定可作为开发Asyn成像的先导化合物的新化合物的方法剂这种新方法使用荧光测量来筛选天然荧光化合物，在体外结合Asyn原纤维，然后评估化合物是否结合到含有Asyn的GCI中。死后MSA脑组织切片最后一步是确定化合物是否选择性地结合到 GCI，但不结合其他类型的病理性纤维积累在死后的脑组织切片。发现具有所需性质的化合物将用氚放射性标记，以进一步使用放射性配体结合测定和放射自显影来表征它们的结合特性。化合物在该项目中确定的，可以用作进一步研究的线索，以开发Asyn成像剂。结果该项目还将进一步优化这种新的筛选方法，以确定具有成像剂所需的结合性质。