In Vitro and In Vivo Characterization of PET Radiotracers for the 4R Variant of Tau

项目2的目标是开发一种用于成像的正电子发射断层扫描（PET）放射性药物 4-重复（4 R）tau蛋白病，包括进行性核上性麻痹（PSP）、皮质基底节变性 (CBD)和家族性额颞叶痴呆（fFTDs）。几种有用的PET剂用于成像混合3R+4 R- 已经报道了阿尔茨海默病（AD）中的tau聚集体，尽管这些药物中没有一种已经证明 可用于非AD 4 R-tau病变中的4 R-tau成像。靶向tau蛋白的新型疾病修饰疗法 为不同Tau蛋白病患者提供新的治疗可能性。成功的治疗策略的关键是 能够区分患有不同tau蛋白病的患者并评估抗tau治疗的功效。 本项目拟开展的研究将采用并行的方法进行先导化合物的识别和优化， 与药物化学和放射化学核心（MCRC）密切合作，以确定新的4 R-tau候选者 放射性配体用于项目2中的后续评价。在4 R-tau蛋白病的组织标本中的结合研究， 其它蛋白病将表征聚集的4 R-tau的候选配体的敏感性和特异性， 确定最有希望的线索，以推进啮齿动物和非人类灵长类动物的体内研究。起初， 项目2将使用两种具有良好4 R-tau结合特性的化合物获得人体组织结合数据， PM-PBB 3和CBD-2115，并将充分确定其在各种人体死后组织中的结合特性。 组织中随后，MCRC将制备一系列PM-PBB 3和CBD-2115的类似物用于体外结合 项目2中的分析，以帮助定义类似物的结构-活性关系（SAR）。MCRC将雇用 其计算化学资源，以帮助指导选择PM-PBB 3和CBD-2115类似物， 合成和随后的评估，并将产生新的先导化合物，用于项目2的测试。体外 项目2中进行的结合试验将测试由 MCRC和帮助细化最影响放射性配体-4 R-tau相互作用的结合位点特征。这些 这些改进将有助于未来MCRC进行的旨在提供新的4 R-tau的计算机筛选研究 用于项目2中测试的配体。项目2将采用体外和体内试验的分阶段方法 表征和评价由MCRC提供的候选4 R-tau PET成像剂的方法， 在PSP和fFTD受试者的首次人体研究中进行后续评价的最有前景的4 R-tau药物 在临床核心

The goal of Project 2 is to develop a positron emission tomography (PET) radiopharmaceutical useful for imaging 4-repeat (4R) tauopathies, which include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and familial frontal temporal dementias (fFTDs). Several useful PET agents for imaging mixed 3R+4R- tau aggregates in Alzheimer's disease (AD) have been reported, although none of these agents has proven useful for imaging 4R-tau in non-AD 4R-tauopathies. Novel disease modifying therapies that target tau offer new treatment possibilities for patients with different tauopathies. Key to a successful therapeutic strategy will be the ability to discriminate patients with different tauopathies and to assess the efficacy of anti-tau treatments. The proposed research in this project will pursue parallel tracks of lead compound identification and optimization, working closely with the Medicinal Chemistry and Radiochemistry Core (MCRC) to identify new 4R-tau candidate radioligands for subsequent evaluation in Project 2. Binding studies in tissue specimens of 4R-tauopathies and other proteinopathies will characterize the sensitivity and specificity of candidate ligands for aggregated 4R-tau, identifying the most promising leads to advance to in vivo studies in rodents and non-human primates. Initially, Project 2 will obtain human tissue binding data using two compounds with favorable 4R-tau binding properties, PM-PBB3 and CBD-2115, and will fully define their binding characteristics in a variety of human post-mortem tissues. Subsequently, the MCRC will prepare a series of analogs of PM-PBB3 and CBD-2115 for in vitro binding assays in Project 2 to help define the structure-activity relationship (SAR) of the analogs. The MCRC will employ its computational chemistry resources to help guide the selection of PM-PBB3 and CBD-2115 analogs for synthesis and subsequent evaluation and will also generate new lead compounds for testing in Project 2. In vitro binding assays conducted in Project 2 will test the predictive power of the in silico studies conducted by the MCRC and help refine binding site features that most influence radioligand-4R-tau interactions. These refinements will assist future in silico screening studies conducted by the MCRC aimed at providing new 4R-tau ligands for testing in Project 2. Project 2 will employ a staged approach using both in vitro and in vivo assay methods to characterize and evaluate candidate 4R-tau PET imaging agents provided by the MCRC, identifying the most promising 4R-tau agents for subsequent evaluation in first-in-human studies of PSP and fFTD subjects in the Clinical Core.