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，PDE 7在调节细胞凋亡中起重要作用。 免疫和炎症反应在多种神经退行性疾病，包括阿尔茨海默病（AD）。 PDE 7治疗不仅改善了AD转基因模型的记忆和行为，而且还表现出降低了AD转基因模型的记忆和行为。 脑Aβ沉积，增强Aβ降解和降低tau磷酸化。作用机制为 介导的cAMP特异性神经免疫应答。正电子发射断层扫描（PET）能够 定量体内生化过程，合适的PDE 7配体将大大提高我们的理解 这种cAMP介导的信号传导在不同的病理生理学AD条件下，否则无法通过离体 （破坏性）分析。通过PET定量活脑中的PDE 7也将提供分布的评估， 新的PDE 7靶向神经治疗剂的靶向接合和剂量占用。迄今为止，没有成功的例子 已经被证明可以在人体中对PDE 7成像，这代表了我们研究这一点的能力的显著不足。 体内靶向。因此，我们建议开发一种新型的PDE 7 PET配体，作为第一个成功的配体，可以填补这一空白 和平移成像工具。 我们是第一个在跨物种PET研究中开发PDE 7特异性配体的团队，包括[11 C]P7-2104 于2021年开发。然而，由于体内的边缘结合特异性，该配体被中断。在我们的第二 第二代，我们鉴定了一个先导分子，P7-2526，其显示出高结合亲和力和优异的选择性。我们 初步评估证实，我们已经克服了PDE 7配体开发的两个主要障碍， 实现：1）显著改善的结合亲和力，代表迄今为止最好的化合物;和2）高靶向 特异性（在富含PDE 7的纹状体中特征性高摄取，而在PDE 7贫乏的小脑/脑桥中低摄取， 通过LC-MS和蛋白质印迹验证）。虽然P7-2526是新的PDE 7靶向配体的有希望的先导，但进一步 对于翻译跨物种， （啮齿动物和非人灵长类动物）成像研究，以实现药物发现的最佳PDE 7定量， 为AD患者进行临床翻译。 基于P7-2526作为药物化学优化的经验证先导，作为具体目标，我们将 设计并制备适合用11 C或18F标记的PDE 7特异性调节剂的聚焦文库，并评估 他们在啮齿动物和非人灵长类动物中定量PDE 7活性和药物激发期间变化的能力，以及 作为死后人脑组织的放射自显影和生物学验证。这项工作的影响不仅是 开发第一个成功的高亲和力和选择性PDE 7 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PET成像验证在更高的物种，以推进这种配体 用于神经退行性疾病的新型神经治疗剂的潜在临床转化和监测靶反应 疾病，包括AD。