Development of GSK-3beta PET radioligands for in vivo imaging in brain

开发用于脑体内成像的 GSK-3beta PET 放射性配体

基本信息

批准号：
9350410
负责人：
JAYA PRABHAKARAN
金额：
$ 23.76万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-09 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9350410
关键词：
Adult Affinity Alzheimer&apos s Disease Animals Back Binding Biological Assay Bipolar Disorder Blood - brain barrier anatomy Brain Brain Diseases Brain imaging Central Nervous System Diseases Characteristics Clinical Clinical Research Data Development Diagnosis Disease Progression Dissection Drug Targeting Etiology Evaluation Functional disorder Glycogen (Starch) Synthase Glycogen Synthase Kinase 3 Goals Image Imagery Kinetics Lead Ligand Binding Ligands Link Lithium MAPT gene Malignant Neoplasms Measures Medicine Mental disorders Methods Modeling Monitor Monkeys Mood Disorders Mood stabilizers National Institute of Mental Health Neurodegenerative Disorders Outcome Outcome Measure Parkinson Disease Pathogenesis Pathogenicity Penetration Permeability Pharmacology Phosphorylation Phosphotransferases Play Positron-Emission Tomography Process Protein Kinase Protein-Serine-Threonine Kinases Radiolabeled Rattus Reproducibility Rodent Role Salts Scanning Scheme Schizophrenia Signal Transduction Specific qualifier value Specificity Sprague-Dawley Rats Structure Testing Therapeutic Agents Time Tissues Tracer Translations Urea accurate diagnosis analog base design disease diagnosis drug development flexibility glycogen synthase kinase 3 beta imaging agent imaging study in vitro Assay in vivo in vivo imaging inhibitor/antagonist innovation male method development microPET nanomolar non-invasive imaging novel therapeutics programs radiochemical radioligand radiotracer small molecule inhibitor targeted treatment therapeutic development tool uptake

项目摘要

Dysfunction of glycogen synthase-3 (GSK-3 or ser9-pGSK3β) has been linked to the etiology of central nervous system diseases such as bipolar disorder, schizophrenia, Alzheimer's disease and Parkinson's disease and is a target for therapeutic development. The goal of this proposal is to develop a GSK-3 positron emission tomography (PET) imaging agent for in vivo evaluation in rodent and monkey brains in order to facilitate its successful translation into clinical studies of diagnosis, treatment monitoring and drug development. A radiotracer for PET imaging of the GSK-3 kinase could be used both for study of its role in psychiatric disorders and accelerate target occupancy studies as part of the development of small molecule inhibitors of GSK-3 as therapeutic agents. At present there is no validated PET tracer available for the in vivo monitoring of GSK-3 in brain. Hence we propose to develop specific radiotracers for PET imaging GSK-3 and have selected 1-(7-methoxyquinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea (A1070722) as the first candidate for testing from a set of four structurally diverse GSK-3 ligands (Figure 2). A1070722 is a high affinity (Ki = 0.6 nM) and selective ligand for GSK-3 with favorable logP (3.2) for blood brain barrier (BBB) penetration. A1070722 is known to enter brain and reduces phosphorylation of microtubule-associated protein Tau. We synthesized [11C]A1070722 ([11C]1, > 40% yield; > 98% purity) and in this application we propose to evaluate the in vivo distribution of [11C]A1070722 in brain by PET imaging. Parallel to the PET evaluation of [11C]1 in rats, two highly selective dihydro-3H-pyrazol-3-on based GSK-3 ligands 2 & 3 and a high affinity oxadiazabenzonitrile ligand (4) will be synthesized as back-up candidate ligands. The back-up ligands will be further assayed to determine their selectivity to GSK-3. Based on specified criteria including affinity for GSK-3 relative to other targets, the candidates will be radiolabeled and their in vivo ability to bind GSK-3 will be determined in rats in vivo with microPET imaging. These studies will prove the BBB permeability, brain distribution, in vivo stability, specific binding and tracer clearance in rats. The optimal candidate will then be advanced to PET studies in monkeys for determination of more detailed brain distribution, specific binding relative to nonspecific binding and tracer kinetic modeling. Test-retest data from the monkey study will be used to choose an optimal method for determining the outcome measure. Successful completion of the proposed studies would lead to the identification of a valuable tool for in vivo quantification of GSK-3 using PET imaging in the normal brain and pathogenesis of several major brain disorders and development of new therapeutic treatments targeting GSK-3.

糖原合酶-3（GSK-3或SER9-PGSK3β）的功能障碍已与中央病因有关神经系统探索，例如躁郁症，精神分裂症，阿尔茨海默氏病和帕金森氏症疾病，是治疗性发育的阻滞剂。明天的排放（PET）成像在啮齿动物和猴子大脑中进行体内评估的成像衰老促进其成功转化为诊断，治疗监测和吸毒的临床研究开发用于GSK-3激酶的PET成像的放射性示例可以研究作为小分子发展的一部分，精神疾病和加速目标占用研究 GSK-3作为治疗剂的抑制剂。监测大脑中的GSK-3。已经选择了1-（7-甲氧基醇蛋白-4-基）-3-（6-（三氟甲基）吡啶-2-基）尿素（A1070722）从四个不同的多种gsk-3配体中进行测试的候选者（图2）。（Ki = 0.6 nm）和GSK-3的选择性配体，具有有利的LOGP（3.2），用于血液脑屏障（BBB）穿透。已知A1070722进入大脑并减少微管相关蛋白TAU的磷酸化合成[11C] A1070722（[11C] 1，> 40％的收率通过PET成像的[11C] A1070722的体内分布。大鼠，两个高度选择性的二氢-3H-pyrazol-3-on基于GSK-3配体2＆3d A高亲和力黄选择性配体（4）将被合成为备用配体。进一步测定了其对GSK-3的选择性。相对于其他目标，候选者将是放射标记的，其在体内结合GSK-3的能力将为在体内用微型材料成像确定。分布，体内稳定性，特异性结合和示踪剂清除率。先进到猴子的宠物研究，以确定更详细的大脑分布，特定的结合相对于非特异性结合和示踪剂动力学建模。选择一种确定结果量的最佳方法。研究将导致使用PET成像的体内定量GSK-3的体内定量识别有价值的工具在正常的大脑和几种主要疾病的发病机理和新治疗的发育针对GSK-3的治疗方法。