Subtype-selective phosphodiesterase PET ligands

亚型选择性磷酸二酯酶 PET 配体

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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。作为一种主要的营地特异性水解酶，PDE7在调节中起重要作用包括阿尔茨海默氏病（AD）在内的多种神经退行性疾病中的免疫和炎症反应。 PDE7治疗不仅改善了AD转基因模型的记忆和行为，而且暴露了下降脑Aβ沉积，增强的Aβ降解并增加了tau磷酸化。作用机理是通过AD中的营地特异性神经响应介导。正电子发射tomograhy（PET）能够在体内量化生化过程以及合适的PDE7配体将大大改善我们的理解在不同的病理生理AD条件下，这种cAMP介导的信号传导的否则，否则是离体无法访问的（破坏性）分析。 PET对生命大脑中PDE7的量化也将提供分布评估，靶向新的PDE7靶向神经疗法的目标参与和剂量占用。迄今为止，没有成功的例子已经证明了人类中的PDE7图像，这代表了我们研究这一点的能力的严重缺陷靶标在体内。因此，我们建议开发一种新型的PDE7 PET配体，该配体可以作为第一个成功的空白填充该空白并翻译成像工具。我们是在跨物种宠物研究中开发PDE7特异性配体的首批组，包括[11C] P7-2104 然而，由于体内边缘结合特异性，该配体因体内的边缘结合而停产。在我们的第二个我们确定了铅分子P7-2526，该铅分子表现出高结合亲和力和出色的选择性。我们的初步评估证实，我们通过实现：1）实质性改进的结合亲和力，代表迄今为止的最佳化合物； 2）高目标特异性（特异性富含PDE7的纹状体中的高摄取和pde7-poor小脑/pons的特异性由LC-MS和Western印迹验证）。尽管P7-2526是新的PDE7靶向配体的有前途的领先优势，但进一步对于转换跨物种，可以感觉到使用适当的脑动力学提高结合特异性的优化（啮齿动物和非人类隐私）成像研究以实现最佳的PDE7量化药物发现和广告患者的临床翻译。根据P7-2526为医学化学优化提供了有效的铅，作为特定目标，我们将设计并准备一个专注于PDE7特异性调制器的库，可用于标记11C或18F的标签，并评估它们在啮齿动物和非人类素数中量化PDE7活性和药物挑战期间变化的能力也作为尸检后人脑组织中的放射自显影和生物学验证。这项工作的影响不仅是为了开发第一个成功的高亲和力和选择性PDE7 PET配体，以研究神经退行性疾病 - 相关的生物过程，但最终也通过较高物种的PET成像验证来推进这种配体为了潜在的临床翻译和监测新型神经疗法的靶向反应疾病，包括广告。