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：
10356395
负责人：
Steven H Liang
金额：
$ 104.31万
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/10356395
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 Chemistry Chinese Hamster Ovary Cell Development Disease 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 Neuraxis Pathway interactions Penetration Permeability Pharmaceutical Chemistry Plant Roots 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 base brain tissue clinical biomarkers design drug discovery experimental study 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CNS研究的重点当发现受体基因与自闭症谱系障碍（ASD）之间的关联时。失调的 V1A活性被认为是ASD病理生理学基础的基本机制。最近的研究揭示了V1a拮抗剂可以调节AVP Horseone的影响，从而解决了潜在的根本原因 ASD发展。 PET能够在体内量化生化过程，合适的V1A PET配体将在不同的病理生理条件下，大大提高了我们对V1A介导的AVP信号传导的理解，否则，可以通过体内（破坏性）分析，尤其是在较高的物种中无法访问。 V1A生活中的V1A量化 PET的大脑将评估分布和表达以及新的V1A-的目标参与有针对性的神经疗法。迄今为止，尚未证明成功的示例以图像V1A特异性AVP 对于人类使用，代表了我们在体内研究该靶标的V1a的能力的严重缺陷。因此，我们提议开发一种新型的宠物配体，可以填补这一空白，作为第一个翻译成像工具。 PI最近开发了一种新颖的V1A特异性AVP配体[11C] PF-184563在2021年的MGH。化合物表现出很高的效力和出色的选择性，由于脑穿透力较低，因此不可能追求它。在我们的第二代，我们确定了一个铅分子V1A-214，该分子显示出实质性改良的结合亲和力和所有其他主要中枢神经系统目标之间的良好目标选择性。合成了V1A-214的11C-异位学和初步宠物成像研究证实，我们已经克服了V1A特异性PET配体的两个主要障碍通过实现的开发：1）高脑吸收（> 1 SUV）和2）由人V1A细胞验证的高目标特异性线和阻断体内研究的研究，以及与中枢神经系统中V1A区域一致的异质吸收。虽然v1a- 214是由于物种差异而开发新的V1A靶向宠物配体的有前途的铅分子，对翻译的跨物种（幼稚/人源化的V1A小鼠和非人类隐私）成像的进一步优化感觉到研究以实现活大脑中的最佳AVP（V1A亚基）用于药物发现和临床 ASD患者的生物标志物。根据V1A-214为医学化学优化提供了有效的铅，作为特定目标，我们将设计和准备一个专注的V1A特异性拮抗剂库，可用于标记11C或18F，并且评估其量化V1A特异性AVP活性的能力以及细胞实验的变化，幼稚和人性化 V1A小鼠和非人类灵长类动物，以及尸检后NHP/人类的自显影和生物学验证脑组织。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V1A特定的宠物配体用于研究与ASD相关的生物过程，但最终通过较高的PET成像验证物种，将这种配体作为潜在的临床生物标志物，并用于监测新颖的目标反应神经发育疾病和神经精神疾病的治疗剂，包括ASD。