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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

基本信息

批准号：
10241513
负责人：
CHESTER A MATHIS
金额：
$ 33.23万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10241513
关键词：
Affinity Alzheimer&apos s Disease Alzheimer&apos s disease therapy Amyloid beta-Protein Animals Applications Grants Autopsy Binding Binding Proteins Binding Sites Biochemical Biodistribution Biological Assay Brain Characteristics Chemistry Clinical Clinical Trials Cryoelectron Microscopy Data 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 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 base 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 predictive test radioligand radiotracer response scaffold screening targeted treatment tau Proteins tau aggregation tau interaction

项目摘要

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