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

摘要 多系统萎缩(MSA)是一种神经退行性疾病，其定义是 胶质细胞胞质内包涵体中的突触核蛋白(Asyn)纤维。异步性纤维的堆积是一个特征。 与帕金森病相同，在帕金森病中，Asyn纤维聚集在神经元胞浆和神经元包涵体中 称为路易小体和路易神经突起。来自遗传、尸检和疾病机制研究的证据 支持Asyn原纤作为治疗靶点。它也是生物标记物开发的目标。当务之急是 开发一种PET显像剂，可以定量Asyn在活体体内的沉积，作为 临床研究中的目标参与。一种Asyn PET显像剂也将提高 诊断MSA，并为疾病进展提供生物标志物。在本应用程序中，我们建议筛选 并为开发MSA的ASYN显像剂寻找新的线索。我们开发了一种新的筛查方法 一种识别可作为ASYN成像开发线索的新化合物的方法 探员。这一新方法使用荧光测量来筛选天然的荧光化合物 体外结合Asyn纤维，然后评估化合物是否与含有Asyn的GCIS结合 尸检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 但不与死后脑组织切片中其他类型的病理性纤维堆积有关。 被发现具有所需性质的化合物将被放射性标记为氚，以便进一步 使用放射性配基结合分析和放射自显影来表征它们的结合特性。这些化合物 该项目中确定的可以作为进一步研究开发ASYN显像剂的线索。结果来自 该项目还将进一步优化这一新的筛选方法，以利用 成像剂所需的结合性能。

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.