Subtype-selective phosphodiesterase PET ligands

亚型选择性磷酸二酯酶 PET 配体

• 批准号: 10568308
• 负责人: Steven H Liang
• 金额: $ 78.25万
• 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: 2023-01-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568308
• 关键词: ABCB1 gene; Affinity; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Autopsy; Autoradiography; Behavior; Binding; Binding Proteins; Biochemical Process; Biodistribution; Biological; Biological Assay; Biological Process; Blood specimen; Brain; Central Nervous System Diseases; Cerebellum; Characteristics; Chemistry; Corpus striatum structure; Cyclic AMP; Development; Docking; Dose; Enzymes; Evaluation; Exhibits; Family; Functional disorder; Generations; Goals; Human; Image; Imaging Device; Imaging ligands; Immune response; In Vitro; Inflammatory Response; Kinetics; Knockout Mice; Knowledge; Label; Lead; Libraries; Ligands; Liver Microsomes; Mediating; Memory; Metabolic Clearance Rate; Methylation; Molecular; Monitor; National Institute of Mental Health; Neurodegenerative Disorders; Neuroimmune; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; Plasma Proteins; Play; Pontine structure; Positioning Attribute; Positron; Positron-Emission Tomography; Process; Radiolabeled; Research; Rodent; Role; Scientific Advances and Accomplishments; Selection Criteria; Signal Transduction; Site; Specificity; Testing; Toxic effect; Transgenic Organisms; Translations; United States; Validation; Visualization; Western Blotting; Work; abeta deposition; brain tissue; clinical translation; design; drug discovery; image translation; imaging study; immunoregulation; improved; in vivo; in vivo evaluation; inhibitor; kinetic model; lipophilicity; molecular imaging; mouse model; nervous system disorder; nonhuman primate; novel; phosphoric diester hydrolase; radioligand; response; tau-1; transgenic model of alzheimer disease; uptake

Project Summary. As a major cAMP-specific hydrolyzing enzyme, PDE7 plays a significant role in modulating immune and inflammatory response in a variety of neurodegenerative diseases, including Alzheimer’s disease (AD). PDE7 treatment not only improved the memory and behavior in transgenic models of AD but also exhibited decreased brain Aβ deposition, enhanced Aβ degradation, and decreased tau phosphorylation. The mechanism of action was mediated via the cAMP-specific neuroinmmune response in AD. Positron emission tomograohy (PET) is capable of quantifying biochemical processes in vivo, and a suitable PDE7 ligand would substantially improve our understanding of such cAMP-mediated signaling under different pathophysiological AD conditions, otherwise inaccessible by ex vivo (destructive) analysis. Quantification of PDE7 in living brain by PET would also provide the assessment of distribution, target engagement and dose occupancy of new PDE7-targeted neurotherapeutics. To date, no successful examples have been demonstrated to image PDE7 in human, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to develop a novel PDE7 PET ligand that can fill this void as the first successful and translational imaging tool. We are the first groups to develop PDE7-specific ligands in cross-species PET studies, including [11C]P7-2104 developed in 2021. However, this ligand was discontinued due to marginal binding specificity in vivo. In our 2nd generation, we identified a lead molecule, P7-2526, which showed high binding affinity and excellent selectivity. Our preliminary evaluation confirmed that we have overcome the two major obstacles for PDE7 ligand development by achieving: 1) substantially-improved binding affinity, representing the best compound to date; and 2) high target specificity (characteristic high uptake in PDE7-rich striatum and low in PDE7-poor cerebellum/pons, which was validated by LC-MS and Western blotting). Though P7-2526 is a promising lead for new PDE7-targeted ligands, further optimization for improved binding specificity with proper brain kinetics are sought for translational cross-species (rodents and nonhuman primates) imaging studies to achieve optimal PDE7 quantification for drug discovery and clinical translation for AD patients. On the basis that P7-2526 serves a validated lead for medicinal chemistry optimization, as specific goals, we will design and prepare a focused library of PDE7-specific modulators amenable for labeling with 11C or 18F, and evaluate their ability to quantify PDE7 activity 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 high-affinity and selective PDE7 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。作为一种主要的 cAMP 特异性水解酶，PDE7 在调节 多种神经退行性疾病的免疫和炎症反应，包括阿尔茨海默病（AD）。 PDE7 治疗不仅改善了 AD 转基因模型的记忆和行为，而且表现出下降 大脑 Aβ 沉积，增强 Aβ 降解，减少 tau 磷酸化。作用机制是 AD 中通过 cAMP 特异性神经免疫反应介导。正电子发射断层扫描 (PET) 能够 量化体内生化过程，合适的 PDE7 配体将​​大大提高我们的理解 在不同的病理生理学 AD 条件下，这种 cAMP 介导的信号传导的研究，否则无法通过体外方法获得 （破坏性）分析。通过 PET 对活体大脑中 PDE7 进行定量还可以提供分布评估， 新型 PDE7 靶向神经治疗药物的靶点参与和剂量占用。迄今为止，还没有成功的例子 已被证明可以对人类 PDE7 进行成像，这表明我们研究这一能力的严重缺陷 体内目标。因此，我们建议开发一种新型 PDE7 PET 配体来填补这一空白，作为第一个成功的 和平移成像工具。 我们是第一批在跨物种 PET 研究中开发 PDE7 特异性配体的团队，包括 [11C]P7-2104 于 2021 年开发。然而，由于体内结合特异性有限，该配体已停产。在我们的第二 在一代中，我们鉴定了一个先导分子 P7-2526，它表现出高结合亲和力和优异的选择性。我们的 初步评估证实，我们已经克服了PDE7配体开发的两大障碍： 实现：1）显着提高的结合亲和力，代表迄今为止最好的化合物； 2）高目标 特异性（富含 PDE7 的纹状体特征性高摄取，而缺乏 PDE7 的小脑/脑桥则低摄取，这是 通过 LC-MS 和蛋白质印迹验证）。尽管 P7-2526 是新的 PDE7 靶向配体的有希望的先导，但进一步 寻求优化以提高结合特异性和适当的脑动力学，以实现跨物种的转化 （啮齿类动物和非人类灵长类动物）成像研究，以实现药物发现的最佳 PDE7 定量 AD 患者的临床翻译。 在 P7-2526 为药物化学优化提供经过验证的先导化合物的基础上，作为具体目标，我们将 设计和制备适合用 11C 或 18F 标记的 PDE7 特异性调节剂的重点库，并评估 他们还能够量化啮齿动物和非人类灵长类动物药物挑战期间 PDE7 活性和变化 作为死后人脑组织的放射自显影和生物验证。这项工作的影响不仅 开发第一个成功的高亲和力和选择性PDE7 PET配体，用于神经退行性疾病的研究- 相关的生物过程，但最终，通过高等物种的 PET 成像验证，以推进这种配体 用于潜在的临床转化并监测神经退行性新型神经疗法的目标反应 疾病，包括 AD。