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

• 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
• 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' 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

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）功能障碍与中枢神经系统疾病的病因有关 神经系统疾病，如双相情感障碍、精神分裂症、阿尔茨海默病和帕金森病 疾病，并且是治疗开发的目标。该提案的目标是开发 GSK-3 正电子 发射断层扫描 (PET) 成像剂，用于啮齿类动物和猴脑的体内评估，以便 促进其成功转化为诊断、治疗监测和药物的临床研究 发展。用于 GSK-3 激酶 PET 成像的放射性示踪剂可用于研究其在 精神疾病并加速目标占用研究作为小分子开发的一部分 GSK-3抑制剂作为治疗剂。目前还没有经过验证的 PET 示踪剂可用于体内 监测大脑中的 GSK-3。因此，我们建议开发用于 PET 成像的特定放射性示踪剂 GSK-3 和 选择 1-(7-甲氧基喹啉-4-基)-3-(6-(三氟甲基)吡啶-2-基)脲 (A1070722) 作为第一个 用于测试一组四种结构不同的 GSK-3 配体的候选药物（图 2）。 A1070722是高亲和力 (Ki = 0.6 nM) 和 GSK-3 的选择性配体，对血脑屏障 (BBB) 渗透具有有利的 logP (3.2)。 已知 A1070722 会进入大脑并减少微管相关蛋白 Tau 的磷酸化。我们 合成了 [11C]A1070722（[11C]1，> 40% 收率；> 98% 纯度），在此应用中，我们建议评估 通过 PET 成像观察 [11C]A1070722 在大脑中的体内分布。与 [11C]1 的 PET 评估平行 大鼠，两种基于二氢-3H-吡唑-3-on 的高选择性 GSK-3 配体 2 和 3 以及高亲和力 恶二氮杂苯甲腈配体 (4) 将被合成作为备用候选配体。备用配体将是 进一步测定以确定它们对 GSK-3 的选择性。基于指定标准，包括对 GSK-3 的亲和力 相对于其他靶标，候选物将被放射性标记，并且它们在体内结合 GSK-3 的能力将 通过 microPET 成像在大鼠体内进行测定。这些研究将证明血脑屏障通透性、大脑 大鼠体内的分布、体内稳定性、特异性结合和示踪剂清除。最佳候选者将是 进入猴子 PET 研究，以确定更详细的大脑分布、特异性结合 相对于非特异性结合和示踪动力学模型。将使用猴子研究的重测数据 选择确定结果测量的最佳方法。顺利完成拟议的 研究将导致使用 PET 成像来识别 GSK-3 体内定量的有价值的工具 正常大脑和几种主要脑部疾病的发病机制以及新疗法的开发 针对 GSK-3 的治疗。