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IDENTIFICATION OF FLUORESCENT LIGANDS FOR ALPHA SYNUCLEIN FIBRILS

α 突触核蛋白原纤维荧光配体的鉴定

基本信息

批准号：
9789973
负责人：
PAUL T KOTZBAUER
金额：
$ 22.88万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789973
关键词：
Affinity Amyloid beta-Protein Autopsy Autoradiography Binding Binding Sites Biological Assay Biological Markers Brain Clinical Research Data Deposition Development Disease Disease Progression Fluorescence Genes Growth Imaging ligands In Vitro Individual Lead Lewy Bodies Libraries Ligand Binding Ligands Measurement Measures Methods Monitor Mutation Neocortex Neurites Neurofibrillary Tangles Neurons Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathology Pharmaceutical Chemistry Positioning Attribute Positron-Emission Tomography Preparation Property Proteins Radiolabeled Role Seeds Senile Plaques Stains Structure Therapeutic Tissue Stains Tissues Tracer Tritium abeta accumulation accurate diagnosis alpha synuclein base brain tissue density diagnostic accuracy experimental study imaging agent improved in vivo novel novel strategies prevent protein aggregate radioligand radiotracer screening targeted biomarker tau Proteins tau aggregation uptake

项目摘要

Abstract Parkinson's Disease (PD) is defined by the accumulation of alpha-synuclein (Asyn) fibrils in neuronal cytoplasmic and neuritic inclusions known as Lewy bodies and Lewy neurites. The role of Asyn in pathogenesis is supported by the identification of dominant mutations in the gene encoding Asyn (SNCA) in rare familial versions of PD. PD progression, particularly the development of dementia in PD, is associated with more widespread deposition of Asyn throughout the brain, including neocortex. Multiple therapeutic approaches targeting Asyn accumulation are being pursued. 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 PD, and provide a biomarker for disease progression. 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 identify a subset of natively fluorescent compounds in a commercial library. We then use fluorescence measurements to screen natively fluorescent compounds for binding Asyn fibrils in vitro followed by assessment of whether compounds bind to Asyn-containing Lewy bodies in postmortem PD brain tissue sections. A final step is to determine whether compounds selectively bind to Lewy bodies but do not bind to amyloid plaques or neurofibrillary tangles in postmortem brain tissue sections. The project will use this approach to screen 5000 fluorescent compounds. 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