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(GSK3)被认为在糖尿病的病理生理过程中起关键作用。 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，淀粉样蛋白-β的产生，神经发生，炎症和突触功能。因此，药理学 GSK3的调节是治疗AD的一种有吸引力的治疗方法。正电子发射 断层扫描(PET)能够量化体内的生化过程，合适的GSK3配体将 实质上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，否则无法通过体外(破坏性)分析。活体脑内GSK3的PET定量研究 将提供对新的GSK3靶向的分布、靶参与和剂量占用的评估 神经治疗学。到目前为止，还没有成功的例子证明GSK3在人体内用于药物成像 发现和临床应用，代表了我们在体内研究这个靶点的能力的一个重大不足。因此，我们 建议开发一种新型的PET配体来填补这一空白，作为第一个翻译成像工具。 我们是第一批在跨物种PET研究中开发GSK3特异性配体的小组，包括第一个选择性的 配体[11C]PF-367。然而，由于低到中等的脑摄取和边缘结合，这种配体被停止使用 体内特异性。在我们的第二代中，我们发现了一个铅分子，GSK3-817，它显示出高结合亲和力 和极好的选择性。合成了GSK3-817的~(18)F-同位素，并进行了初步的PET成像研究 确认我们已经克服了GSK3特异的激酶配体开发的两个主要障碍：1) 显著提高了脑渗透率(≥1、SUV脑摄取)和2)合理的靶标特异性。虽然GSK3- 817是一种很有前途的先导分子，可用于开发新的GSK3靶向的PET配体，进一步优化 为翻译的跨物种(啮齿动物和 非人灵长类动物)成像研究，以实现药物发现和临床翻译的最佳GSK3定量 适用于AD患者。 在GSK3-817作为药物化学优化的有效先导的基础上，作为具体目标，我们 将设计和准备可用于11C或18F标记的GSK3特定调节器的聚焦文库(首选)， 并评估它们量化GSK3在啮齿动物和非人类药物攻击过程中的表达和变化的能力 灵长类动物，以及死后人脑组织的放射自显影和生物学验证。这件事的影响 工作不仅是开发出第一个成功的高特异性GSK3 PET配体，用于研究神经退行性变 疾病相关的生物学过程，但最终也通过PET成像在高等物种中验证，以推动 该配体用于潜在的临床翻译和监测新的神经疗法的靶向反应 神经退行性疾病，包括阿尔茨海默病。