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; 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的关键参与者 阿尔茨海默氏病（AD）以来这种酶失调会影响所有主要的广告标志，包括tau 磷酸化，淀粉样蛋白-β产生，神经发生，注射和突触功能。因此药理 GSK3的调节代表了用于治疗AD的有吸引力的治疗方法。正电子发射 断层扫描（PET）能够在体内量化生化过程，合适的GSK3配体将 在不同的病理生理AD下，大大提高了我们对GSK3介导的信号通路的理解 条件，否则通过体内（破坏性）分析无法访问。宠物对活体大脑中GSK3的量化 将评估新GSK3的分配，目标参与和剂量占用 神经治疗学。迄今为止，尚未证明成功的示例以形象gsk3在人类中的毒品 发现和临床用途，代表了我们在体内研究该靶标的能力的严重缺陷。因此，我们 开发一种新型宠物配体可以填补这一空隙的建议，作为第一个翻译成像工具。 我们是在跨物种宠物研究中开发GSK3特异性配体的首批组，包括第一个选择性 配体[11C] PF-367。但是，由于低到中度的大脑吸收和边际结合，该配体被停用 体内特异性。在第二代中，我们确定了一个铅分子GSK3-817，该分子显示出高结合亲和力 和出色的选择性。 GSK3-817的18F异位学是合成的和初步的PET成像研究 确认我们已经克服了GSK3特异性激酶配体开发的两个主要障碍：1） 基本上改良的脑穿透（≥1SUV脑摄取）和2）合理的目标特异性。虽然GSK3- 817是一种有前途的铅分子，用于开发新的GSK3靶向宠物配体，进一步优化 可以感受改善的结合特异性和适当的脑动力学，以用于翻译跨物种（啮齿动物和 非人类初级成像研究以实现用于药物发现和临床翻译的最佳GSK3定量 适用于广告患者。 基于GSK3-817为医学化学优化提供了有效的铅，作为特定目标，我们 将设计和准备一个专注的GSK3特异性调制器库，可用于标记11C或18F（首选）， 并评估其量化GSK3表达和在啮齿动物挑战期间变化的能力 尸检后人脑组织中的假期和生物学验证。这个影响 工作不仅是为了研究神经退行性研究的第一个成功的高度特异性GSK3 PET配体 与疾病相关的生物学过程，但最终通过较高物种的PET成像验证来推进 这种潜在的临床翻译和监测新神经疗法的靶向反应的配体 神经退行性疾病，包括AD。