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cAMP特异性的主要水解酶，PDE7在细胞周期调控中发挥着重要作用 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治疗不仅改善了转基因AD模型的记忆和行为，而且还表现出下降的趋势 脑Aβ沉积，促进Aβ降解，降低tau磷酸化。其作用机制是 在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 量化体内的生化过程，并选择合适的PDE7配体，将大大提高我们对 这种cAMP介导的信号在不同的病理生理AD条件下，否则不能通过体外获得 (破坏性)分析。通过PET对活体脑中PDE7的定量也将提供分布的评估， 以PDE7为靶向的新神经疗法的靶向参与和剂量占有率。到目前为止，还没有成功的例子 已经被证明在人类体内对PDE7成像，这代表了我们研究这一点的能力的一个重大缺陷 活体靶标。因此，我们建议开发一种新型的PDE7 PET配体，作为第一次成功地填补这一空白 和平移成像工具。 我们是第一批在跨物种PET研究中开发PDE7特异性配体的小组，包括[11C]P7-2104 开发于2021年。然而，由于体内边际结合的特异性，该配体被终止。在我们的第二个 生成后，我们鉴定出一个前导分子P7-2526，它具有高的结合亲和力和良好的选择性。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)大大提高了结合亲和力，代表了迄今为止最好的化合物；以及2)高目标 特异性(在富含PDE7的纹状体中具有高摄取率，在PDE7缺乏的小脑/桥中低摄取率的特征是 经LC-MS和Western blotting验证)。尽管P7-2526是新的PDE7靶向配体的一个有希望的先导，但进一步 对于翻译的跨物种，寻求具有适当脑动力学的改进的结合专一性的优化 (啮齿动物和非人灵长类)成像研究，以实现药物发现和治疗的最佳PDE7定量 AD患者的临床翻译。 在P7-2526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PDE7特异性调节器的焦点文库，并评估 他们在啮齿动物和非人灵长类动物身上量化PDE7活性和药物挑战期间变化的能力也是如此 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 为研究神经退行性疾病，开发首个成功的高亲和力和选择性的PDE7 PET配体- 相关的生物学过程，但最终也通过在高等物种中进行PET成像验证来促进这种配体 用于潜在的临床翻译和监测神经退行性变的新神经疗法的靶向反应 疾病，包括阿尔茨海默病。