PET ligand discovery for arginine vasopressin

精氨酸加压素的 PET 配体发现

• 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
• 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

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。V1 A特异性精氨酸加压素受体近年来成为中枢神经系统研究的热点 当受体基因和自闭症谱系障碍（ASD）之间的关联被确定时。失调 V1 A活性已被认为是ASD病理生理学的基本机制。最近的研究 揭示了V1 A拮抗剂可以调节AVP激素的作用，从而解决了V1 A的潜在根本原因。 ASD发展。PET能够量化体内的生物化学过程，并且合适的V1 A PET配体将 大大提高了我们对不同病理生理条件下V1 A介导AVP信号传导的理解， 否则无法通过离体（破坏性）分析，特别是在高等物种中。生活中V1 A的定量 PET脑成像将提供新V1 A的分布和表达以及靶向参与的评估， 有针对性的神经疗法迄今为止，还没有成功的例子被证明可以对V1 A特异性AVP进行成像 对于人使用，代表我们在体内研究V1 A的该靶点的能力的显著不足。所以我们 建议开发一种新的PET配体，可以填补这一空白，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V1 A特异性AVP配体[11 C]PF-184563。虽然这 尽管化合物显示出高效力和优异的选择性，但由于低脑渗透性，其不太可能被追求。在我们 第二代，我们鉴定了先导分子V1 A-214，其显示出显著改善的结合亲和力， 在所有其他主要CNS靶标中具有出色的靶标选择性。合成V1 A-214的11 C-同位素体， 初步的PET成像研究证实，我们已经克服了V1 A特异性PET配体的两个主要障碍， 通过实现：1）高脑摄取（>1 SUV）和2）经人V1 A细胞验证的高靶特异性 线和阻断研究在体内，和异质性摄取一致的V1 A区在中枢神经系统。虽然V1 A- 214是一个很有前途的先导分子，用于开发新的V1 A靶向PET配体，由于物种差异， 进一步优化翻译跨物种（未处理/人源化V1 A小鼠和非人灵长类动物）成像 研究寻求在活脑中实现最佳AVP（V1 A亚基）定量，用于药物发现和临床应用。 ASD患者的生物标志物。 基于V1 A-214作为药物化学优化的经验证先导，作为特定目标，我们 将设计和制备适合用11 C或18F标记的V1 A特异性拮抗剂的集中文库， 评价它们在细胞实验中定量V1 A特异性AVP活性和变化的能力，幼稚和人源化 V1 A小鼠和非人灵长类动物，以及死后NHP/人的放射自显影和生物学验证 脑组织这项工作的影响不仅是开发了第一个成功的高亲和力和选择性V1 A特异性 PET配体用于ASD相关生物过程的研究，也最终通过PET成像验证在更高 物种，以推进这种配体作为潜在的临床生物标志物，并用于监测新的靶向反应。 用于神经发育疾病和神经精神障碍（包括ASD）的治疗剂。