Glycogen synthase kinase 3 ligand discovery for Alzheimer’s disease

糖原合成酶激酶 3 配体发现治疗阿尔茨海默病

• 批准号: 10637434
• 负责人: Steven H Liang
• 金额: $ 232.34万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637434
• 关键词: ABCB1 gene; ABCG2 gene; Abeta synthesis; Affinity; Alzheimer' s Disease; Alzheimer' s disease patient; Autopsy; Autoradiography; Binding; Binding Proteins; Biochemical Process; Biodistribution; Biological; Biological Assay; Biological Process; Blood specimen; Brain; Cells; Characteristics; Chemicals; Chemistry; Clinical; Development; Docking; Dose; Enzymes; Evaluation; Family; Functional disorder; Generations; Glycogen Synthase Kinase 3; Goals; Human; Image; Imaging Device; In Vitro; Inflammation; Kinetics; Knockout Mice; Knowledge; Label; Lead; Libraries; Ligands; Liver Microsomes; Mediating; Molecular; Monitor; National Institute of Mental Health; Neurodegenerative Disorders; Neuroimmune; Penetration; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphotransferases; Plasma; Plasma Proteins; Positron-Emission Tomography; Radiolabeled; Research; Rodent; Role; Safety; Scientific Advances and Accomplishments; Selection Criteria; Signal Pathway; Site; Specificity; Testing; Therapeutic; Toxic effect; Translations; United States; Validation; Work; brain tissue; clinical translation; design; drug discovery; image translation; imaging study; improved; in vivo; in vivo evaluation; kinetic model; lipophilicity; mouse model; neurogenesis; nonhuman primate; novel; pharmacokinetics and pharmacodynamics; pharmacologic; radioligand; response; sample fixation; synaptic function; tau-1; uptake

Project Summary. Glycogen synthase kinase 3 (GSK3) is considered a key player in the pathophysiology of Alzheimer’s disease (AD) since dysregulation of this enzyme influences all the major AD hallmarks, including tau phosphorylation, amyloid-β production, neurogenesis, inflammation and synaptic function. Therefore pharmacological modulation of GSK3 represents an attractive therapeutic approach for the treatment of AD. Positron emission tomography (PET) is capable of quantifying biochemical processes in vivo, and a suitable GSK3 ligand would substantially improve our understanding of GSK3-mediated signaling pathway under different pathophysiological AD conditions, otherwise inaccessible by ex vivo (destructive) analysis. Quantification of GSK3 in living brain by PET would provide the assessment of distribution, target engagement and dose occupancy of new GSK3-targeted neurotherapeutics. To date, no successful examples have been demonstrated to image GSK3 in human for drug discovery and clinical use, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to develop a novel PET ligand that can fill this void, as the first translational imaging tool. We are the first groups to develop GSK3-specific ligands in cross-species PET studies, including the first selective ligand [11C]PF-367. However, this ligand was discontinued due to low-to-moderate brain uptake and marginal binding specificity in vivo. In our 2nd generation, we identified a lead molecule, GSK3-817, which showed high binding affinity and excellent selectivity. An 18F-isotopologue of GSK3-817 was synthesized and preliminary PET imaging studies confirmed that we have overcome two major obstacles for GSK3-specific kinase ligand development by achieving: 1) substantially-improved brain penetration (≥1 SUV brain uptake) and 2) reasonable target specificity. Though GSK3- 817 is a promising lead molecule for the development of new GSK3-targeted PET ligands, further optimization for improved binding specificity and proper brain kinetics are sought for translational cross-species (rodents and nonhuman primates) imaging studies to achieve optimal GSK3 quantification for drug discovery and clinical translation for AD patients. On the basis that GSK3-817 serves a validated lead for medicinal chemistry optimization, as specific goals, we will design and prepare a focused library of GSK3-specific modulators amenable for labeling with 11C or 18F (preferred), and evaluate their ability to quantify GSK3 expression and changes during drug challenge in rodents and nonhuman primates, as well as autoradiography and biological validation in postmortem human brain tissues. The impact of this work is not only to develop the first successful highly-specific GSK3 PET ligand for the study of neurodegenerative disease-related biological processes, but also ultimately, via PET imaging validation in higher species, to advance this ligand for potential clinical translation and monitor target response of novel neurotherapeutics for neurodegenerative diseases, including AD.

项目摘要。糖原合酶激酶 3 (GSK3) 被认为是病理生理学中的关键角色 阿尔茨海默病 (AD)，因为这种酶的失调会影响所有主要的 AD 标志，包括 tau 磷酸化、β 淀粉样蛋白的产生、神经发生、炎症和突触功能。因此药理 GSK3 的调节代表了治疗 AD 的一种有吸引力的治疗方法。正电子发射 断层扫描 (PET) 能够量化体内生化过程，合适的 GSK3 配体将 大大提高了我们对不同病理生理AD下GSK3介导的信号通路的理解 条件，否则无法通过离体（破坏性）分析进行分析。通过 PET 定量活体大脑中的 GSK3 将提供新 GSK3 靶点的分布、靶点参与和剂量占用的评估 神经治疗学。迄今为止，还没有成功的实例证明能够对人体中的 GSK3 进行成像以用于药物 发现和临床应用，代表了我们在体内研究该靶标的能力的显着缺陷。因此，我们 提议开发一种新型 PET 配体来填补这一空白，作为第一个平移成像工具。 我们是第一批在跨物种 PET 研究中开发 GSK3 特异性配体的团队，包括第一个选择性配体 配体[11C]PF-367。然而，由于低至中度的脑摄取和边缘结合，该配体已停止使用 体内特异性。在我们的第二代中，我们鉴定了一个先导分子 GSK3-817，它表现出高结合亲和力 和优良的选择性。合成了 GSK3-817 的 18F 同位素体并进行了初步 PET 成像研究 证实我们已经克服了 GSK3 特异性激酶配体开发的两个主要障碍：1) 显着提高的大脑渗透性（≥1 SUV 大脑摄取）和 2) 合理的目标特异性。虽然GSK3- 817 是一种有前景的先导分子，可用于开发新型 GSK3 靶向 PET 配体，进一步优化 寻求改善的结合特异性和适当的大脑动力学用于跨物种的翻译（啮齿动物和 非人类灵长类动物）成像研究，以实现药物发现和临床转化的最佳 GSK3 定量 对于 AD 患者。 基于 GSK3-817 为药物化学优化提供了经过验证的先导化合物，作为具体目标，我们 将设计和准备一个专门的 GSK3 特异性调节剂库，适合用 11C 或 18F（首选）进行标记， 并评估其在啮齿动物和非人类药物挑战期间量化 GSK3 表达和变化的能力 灵长类动物，以及死后人类脑组织的放射自显影和生物验证。这的影响 工作不仅仅是开发第一个成功的高度特异性 GSK3 PET 配体，用于神经退行性疾病的研究 疾病相关的生物过程，但最终还通过高等物种的 PET 成像验证，以推进 该配体用于潜在的临床转化并监测新型神经治疗药物的靶标反应 神经退行性疾病，包括 AD。