Imaging agents for synucleinopathy drug discovery

用于突触核蛋白病药物发现的显像剂

基本信息

批准号：
9318582
负责人：
Jeff Kuret
金额：
$ 18.59万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9318582
关键词：
Address Affect Alzheimer&apos s Disease Amino Acid Sequence Amyloid Amyloid beta-Protein Amyloidosis Appearance Binding Biochemical Biological Markers Biological Testing Brain imaging Brain region Cell physiology Cells Clinical Trials Dementia Deposition Detection Development Disease Disease Progression Drug Kinetics Early identification Elderly Evaluation Generations Goals Human Individual Investigational Therapies Laboratories Lead Lesion Lewy Bodies Lewy Body Dementia Lewy Body Disease Ligand Binding Metabolism Methods Mind Mus Neurites Neurodegenerative Disorders Neurofibrillary Tangles Neurons Neuropil Threads Parkinson Disease Parkinson&apos s Dementia Pathology Patients Performance Pittsburgh Compound-B Play Positron-Emission Tomography Prevalence Process Reagent Research Role Senile Plaques Series Spatial Distribution Specimen Staging System Stilbenes Structure Structure-Activity Relationship Time Tissues alpha synuclein base benzothiazole beta pleated sheet biomarker development disorder subtype drug discovery extracellular imaging agent imaging modality improved in vivo insight patient population patient stratification population stratification protein aggregate radiotracer segregation small molecule stem synucleinopathy tau Proteins tau aggregation validation studies

项目摘要

Project Summary/Abstract Drug discovery efforts targeting dementing illnesses of the elderly have been hampered by a series of failed clinical trials. The negative results could reflect misunderstanding of disease mechanisms, but they also may stem from study of heterogeneous patient populations with disease that had advanced too far to benefit from therapy. According to the latter hypothesis, better stratification of patient populations and identification of early stage disease could greatly improve clinical trial performance. This application seeks to develop small- molecule probes of α-synuclein aggregates that are found in a range of neurodegenerative disorders including Lewy Body Disease (LBD), the second leading cause of dementia in the U.S. Radiotracers based on such compounds could serve to detect pre-mortem disease early in its course, to distinguish forms of synucleinopathy from pure Alzheimer's disease, and to establish disease stage on the basis of pathology spatial distribution. To address this need, an iterative discovery approach involving structure activity relationship analysis is proposed, followed by lead optimization studies. Over the long-term, when combined with emerging therapies for neurodegenerative disorders, direct pre-mortem detection of protein aggregates has the potential to improve drug discovery efforts for dementia.

项目概要/摘要针对老年人痴呆症的药物发现工作受到一系列失败的阻碍临床试验的负面结果可能反映了对疾病机制的误解，但也可能是这样。源于对患有疾病的异质患者群体的研究，这些患者群体的疾病进展太严重而无法从中受益根据后一种假设，可以更好地对患者群体进行分层并进行早期识别。阶段疾病可以极大地提高临床试验性能。 α-突触核蛋白聚集体的分子探针，存在于一系列神经退行性疾病中，包括路易体病（LBD）是美国痴呆症的第二大原因。化合物可以用于在病程早期检测死前疾病，以区分疾病的形式纯阿尔茨海默病的突触核蛋白病，并根据病理学确定疾病阶段为了满足这种需求，涉及结构活动的迭代发现方法。提出了关系分析，然后进行长期先导化合物优化研究。随着神经退行性疾病的新兴疗法，蛋白质聚集体的直接宰前检测有潜力改善痴呆症的药物发现工作。