Imaging agents for synucleinopathy drug discovery

项目总结/摘要 针对老年痴呆症的药物发现努力受到一系列失败的阻碍， 临床试验阴性结果可能反映了对疾病机制的误解，但它们也可能 源于对患有进展太快而无法受益的疾病的异质性患者人群的研究 疗法根据后一种假设，更好地对患者人群进行分层并识别早期 疾病分期可以大大提高临床试验的效果。该应用程序旨在开发小型- 在一系列神经退行性疾病中发现的α-突触核蛋白聚集体的分子探针， 路易体病（Lewy Body Disease，LBD）是美国痴呆症的第二大原因。 化合物可以用于在其过程的早期检测死前疾病， 突触核蛋白病从纯粹的阿尔茨海默病，并建立疾病阶段的病理基础上， 空间分布为了满足这一需求，涉及结构活动的迭代发现方法 提出了关系分析，其次是铅优化研究。从长远来看，结合起来 随着神经退行性疾病的新兴疗法， 有可能改善痴呆症的药物发现工作。

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.