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。糖原合成酶激酶3（GSK 3）被认为是糖尿病的病理生理学中的关键参与者。 阿尔茨海默病（AD），因为这种酶的失调影响所有主要的AD标志，包括tau蛋白 在一些实施方案中，神经元参与了蛋白质磷酸化、淀粉样蛋白-β产生、神经发生、炎症和突触功能。因此，药理学 GSK 3的调节代表了治疗AD的有吸引力的治疗方法。正电子发射 断层扫描（PET）能够量化体内的生化过程，并且合适的GSK 3配体将 大大提高了我们对不同病理生理AD下GSK 3介导信号通路的理解 条件下，否则无法通过离体（破坏性）分析。通过PET定量活体脑中的GSK 3 将提供对新GSK 3靶向药物的分布、靶向作用和剂量占用的评估 神经治疗学到目前为止，还没有成功的例子被证明可以在人体中成像GSK 3用于药物治疗。 发现和临床应用，代表了我们在体内研究该靶点的能力的显著不足。所以我们 建议开发一种新的PET配体，可以填补这一空白，作为第一个平移成像工具。 我们是第一个在跨物种PET研究中开发GSK 3特异性配体的团队，包括第一个选择性 配体[11 C]PF-367。然而，由于低至中度脑摄取和边缘结合， 体内特异性。在我们的第二代中，我们鉴定了一个先导分子GSK 3 -817，其显示出高结合亲和力 和优良的选择性。合成GSK 3 -817的18F-同位素体，并进行初步PET成像研究。 证实了我们已经克服了GSK 3特异性激酶配体开发的两个主要障碍，实现了：1） 显著改善的脑渗透（≥1 SUV脑摄取）和2）合理的靶点特异性。虽然GSK 3- 817是开发新的GSK 3靶向PET配体的有前景的先导分子，进一步优化用于 对于翻译的跨物种（啮齿动物和哺乳动物）， 非人灵长类动物）成像研究，以实现用于药物发现和临床转化的最佳GSK 3定量 对于AD患者。 基于GSK 3 -817作为药物化学优化的有效先导，作为特定目标，我们 将设计和制备适合用11 C或18F（优选）标记的GSK 3特异性调节剂的聚焦文库， 并评估其在啮齿类动物和非人类中定量GSK 3表达和药物激发期间变化的能力 灵长类动物，以及放射自显影和死后人脑组织的生物学验证。这样做的影响 这项工作不仅是开发第一个成功的高特异性GSK 3 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，通过PET成像验证在高等物种，以推进 这种配体用于潜在的临床翻译和监测新的神经治疗剂的靶向反应， 神经退行性疾病，包括AD。