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.

项目总结。PDE7作为一种主要的camp特异性水解酶，在camp的调控中起着重要的作用