PET ligand discovery for arginine vasopressin

精氨酸加压素的 PET 配体发现

基本信息

批准号：
10641669
负责人：
Steven H Liang
金额：
$ 121.41万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-10 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641669
关键词：
ABCB1 gene ASD patient Affinity Argipressin Autopsy Autoradiography Binding Binding Proteins Biochemical Process Biodistribution Biological Biological Process Blood specimen Brain Cell Line Central Nervous System Chemistry Chinese Hamster Ovary Cell Development Docking Dose Evaluation Functional disorder Generations Hormones Human Image Imaging Device In Vitro Kinetics Knockout Mice Label Lead Libraries Ligands Liver Microsomes Measures Mediating Medical Mental disorders Messenger RNA Methylation Modeling Molecular Monitor Mus National Institute of Mental Health Neurodevelopmental Disorder Pathway interactions Penetration Permeability Pharmaceutical Chemistry Plasma Plasma Proteins Positron-Emission Tomography Radioactive Radiolabeled Radioligand Assay Receptor Gene Research Rodent Scientific Advances and Accomplishments Selection Criteria Signal Transduction Site Specificity Techniques Testing Toxic effect Transgenic Organisms Translations United States V1a vasopressin receptor Validation Vasopressins Work antagonist argipressin receptor autism spectrum disorder brain tissue clinical biomarkers design drug discovery experimental study image translation imaging study improved in vitro Assay in vivo lipophilicity mouse model neuropsychiatric disorder nonhuman primate novel novel therapeutics pharmacokinetics and pharmacodynamics radiotracer response species difference stable cell line tool uptake

项目摘要

Project Summary. The V1A-specific arginine vasopressin receptor has recently become the focus of CNS research when an association between the receptor gene and autism spectrum disorder (ASD) is identified. Dysregulation of V1A activity has been suggested as a fundamental mechanism underlying ASD pathophysiology. Recent studies revealed that V1A antagonists can regulate the effect of the AVP hormone, thereby tackling a potential root cause of ASD development. PET is capable of quantifying biochemical processes in vivo, and a suitable V1A PET ligand would substantially improve our understanding of V1A-mediated AVP signaling under different pathophysiological conditions, otherwise inaccessible by ex vivo (destructive) analysis, particularly in higher species. Quantification of V1A in living brain by PET would provide the assessment of distribution and expression and target engagement of new V1A- targeted neurotherapeutics. To date, no successful examples have been demonstrated to image V1A-specific AVP for human use, representing a significant deficiency of our ability to study this target in vivo for V1A. Therefore, we propose to develop a novel PET ligand that can fill this void, as the first translational imaging tool. The PI has recently developed a novel V1A-specific AVP ligand [11C]PF-184563 at MGH in 2021. While this compound showed high potency and excellent selectivity, it is not likely pursued due to low brain penetration. In our 2nd generation, we identified a lead molecule, V1A-214, which showed substantially-improved binding affinity and excellent target selectivity among all other major CNS targets. An 11C-isotopologue of V1A-214 was synthesized and preliminary PET imaging studies confirmed that we have overcome two major obstacles for V1A-specific PET ligand development by achieving: 1) high brain uptake (>1 SUV) and 2) high target specificity validated by human V1A cell lines and blocking studies in vivo, and heterogenous uptake consistent with V1A regions in the CNS. Though V1A- 214 is a promising lead molecule for the development of new V1A-targeted PET ligands, due to species difference, further optimization for translational cross-species (naïve/humanized V1A mice and nonhuman primates) imaging studies are sought to achieve optimal AVP (V1A subunit) quantification in the living brain for drug discovery and clinical biomarker for ASD patients. On the basis that V1A-214 serves a validated lead for medicinal chemistry optimization, as specific objectives, we will design and prepare a focused library of V1A-specific antagonists amenable for labeling with 11C or 18F, and evaluate their ability to quantify V1A-specific AVP activity and changes in cellular experiments, naïve and humanized V1A mice and nonhuman primates, as well as autoradiography and biological validation in postmortem NHP/human brain tissues. The impact of this work is not only to develop the first successful high-affinity and selective V1A-specific PET ligand for the study of ASD-related biological processes, but also ultimately, via PET imaging validation in higher species, to advance this ligand as a potential clinical biomarker and for monitoring target response of novel therapeutics for neurodevelopmental diseases and neuropsychiatric disorders, including ASD.

项目摘要 V1A 特异性精氨酸加压素受体最近已成为中枢神经系统研究的焦点。当受体基因与自闭症谱系障碍（ASD）之间存在关联时。 V1A 活性被认为是 ASD 病理生理学的基本机制。研究表明，V1A 拮抗剂可以调节 AVP 激素的作用，从而打破了 AVP 激素的潜在根本原因。 ASD 开发能够量化体内生化过程，并且合适的 V1A PET 配体将大大提高了我们对不同病理生理条件下 V1A 介导的 AVP 信号传导的理解，否则无法通过离体（破坏性）分析进行分析，特别是在高等物种中对活体 V1A 进行定量。通过 PET 检测大脑将提供新 V1A- 的分布和表达以及目标参与的评估迄今为止，还没有成功的例子可以对 V1A 特异性 AVP 进行成像。供人类使用，这表明我们体内研究 V1A 靶标的能力存在显着缺陷。提议开发一种新型 PET 配体来填补这一空白，作为第一个平移成像工具。 PI 最近于 2021 年在 MGH 开发了一种新型 V1A 特异性 AVP 配体 [11C]PF-184563。化合物显示出高效力和出色的选择性，但由于脑渗透率低，不太可能被采用。第二代，我们鉴定了一个先导分子 V1A-214，它显示出显着改善的结合亲和力，并且合成了 V1A-214 的 11C 同位素异体，并在所有其他主要 CNS 靶标中具有出色的靶标选择性。初步 PET 成像研究证实，我们已经克服了 V1A 特异性 PET 配体的两大障碍通过实现以下目标进行开发：1) 高脑摄取量 (>1 SUV) 和 2) 由人类 V1A 细胞验证的高目标特异性线和体内阻断研究，以及与 CNS 中 V1A 区域一致的异质摄取。由于物种差异，214 是开发新的 V1A 靶向 PET 配体的有前途的先导分子，进一步优化跨物种转化（幼稚/人源化 V1A 小鼠和非人灵长类动物）成像研究正在寻求在活体大脑中实现最佳 AVP（V1A 亚基）定量，以用于药物发现和临床 ASD 患者的生物标志物。基于 V1A-214 为药物化学优化提供了经过验证的先导化合物，作为具体目标，我们将设计和制备适合用 11C 或 18F 标记的 V1A 特异性拮抗剂的重点文库，以及评估他们量化 V1A 特异性 AVP 活性和细胞实验（幼稚和人源化）中变化的能力 V1A 小鼠和非人类灵长类动物，以及死后 NHP/人类的放射自显影和生物验证这项工作的影响不仅在于首次成功开发出高亲和力和选择性的 V1A 特异性。 PET 配体用于研究 ASD 相关的生物过程，但最终也通过 PET 成像验证在更高的种，以推进该配体作为潜在的临床生物标志物并用于监测新型药物的靶标反应神经发育疾病和神经精神疾病（包括自闭症谱系障碍）的治疗。