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

Tau 4R 变体 PET 放射性示踪剂的体外和体内表征

• 批准号: 10649667
• 负责人: CHESTER A MATHIS
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-24 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10649667
• 关键词: Affinity; Alzheimer' s Disease; Alzheimer' s disease therapy; Amyloid beta-Protein; Animals; Applications Grants; Autopsy; Autoradiography; Binding; Binding Proteins; Binding Sites; Biochemical; Biodistribution; Biological Assay; Brain; Characteristics; Chemistry; Clinical; Clinical Trials; Cryoelectron Microscopy; Data; Derivation procedure; Development; Disease; Docking; Drug Kinetics; Evaluation; Feedback; Frontotemporal Dementia; Future; Goals; Human; Image; Imaging Device; In Vitro; Lead; Ligands; Metabolic; Methods; Microtubules; Mutation; Natural History; Pathologic; Pathology; Patients; Pharmaceutical Chemistry; Positron-Emission Tomography; Progressive Supranuclear Palsy; Property; Radiochemistry; Radiopharmaceuticals; Recommendation; Reporting; Research; Resources; Rodent; Rodent Model; Sensitivity and Specificity; Series; Specimen; Structure; Structure-Activity Relationship; Tauopathies; Testing; Therapeutic; Therapeutic Agents; Tissue Sample; Tissues; Transgenic Organisms; Treatment Efficacy; Variant; Work; analog; brain tissue; computational chemistry; corticobasal degeneration; density; efficacy evaluation; first-in-human; human tissue; imaging agent; imaging properties; imaging study; improved; in silico; in vitro testing; in vivo; meetings; nonhuman primate; novel; preclinical study; radioligand; radiotracer; response; scaffold; screening; targeted treatment; tau Proteins; tau aggregation; tau interaction

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.

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(4R)神经病，包括进行性核上性瘫痪(PSP)、皮质基底膜变性 (CBD)和家族性额叶颞叶痴呆(FFTD)。用于混合3R+4R-成像的几种有用的PET试剂 阿尔茨海默病(AD)中的tau聚集体已有报道，尽管这些药物都没有得到证实 可用于非AD 4R-tau病的4R-tau成像。针对tau提供的新的疾病修改疗法 为患有不同肌萎缩侧索硬化症的患者提供新的治疗可能性。成功的治疗策略的关键是 有能力区分患有不同tau病的患者，并评估抗tau治疗的疗效。 本项目拟议的研究将沿着铅化合物识别和优化的并行轨道进行， 与药物化学和放射化学核心(MCRC)密切合作，确定新的4R-tau候选 在项目2中用于后续评估的放射性配体。4R-tauopathy和4R-tauopathy组织标本的结合研究 其他蛋白质病将表征聚集的4R-tau候选配体的敏感性和特异性， 确定最有希望的基因有助于推进啮齿动物和非人类灵长类动物的体内研究。最初， 项目2将使用两种具有良好的4R-tau结合特性的化合物来获得人体组织结合数据， PM-PBB3和CBD-2115，并将在各种人类尸检中充分确定它们的结合特征 纸巾。随后，MCRC将制备一系列PM-PBB3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PM-PBB3和CBD-2115类似物的选择 合成和随后的评估，还将产生新的先导化合物，用于项目2的测试。 在项目2中进行的结合分析将测试由 MCRC和有助于改进对放射性配体-4R-tau相互作用影响最大的结合位点特征。这些 改进将有助于未来由马华中心进行的旨在提供新的4R-tau的电子扫描筛查研究 项目2中用于测试的配体。项目2将采用分阶段的方法，使用体外和体内试验 方法对MCRC提供的候选4R-tau PET显像剂进行表征和评价，鉴定 最有前景的4R-tau试剂在PSP和fFTD患者的首次人体研究中的后续评估 在临床核心中。