Young Development of a Novel PET Ligand for Detecting Oxytocin Receptors in Brain

描述（由申请人提供）：催产素（OT）是一种神经肽，在动物模型和人类中都涉及社会认知和社会行为的调节。在啮齿类动物中，OT涉及社会信息处理、父母养育和社会联系。在人类中，鼻内OT增强了人际信任、眼神接触、面部记忆和推断他人情绪的能力。这些观察结果以及关注于OT受体（OTR）基因多态性的遗传关联研究表明，OT系统的失调可能导致与一些精神疾病相关的社会认知缺陷，包括自闭症谱系障碍、精神分裂症和抑郁症。尽管它在调节人类社会认知方面发挥着明显的作用，但关于OTR在人类大脑中的定位或其在精神疾病中的失调，人们知之甚少。PET成像技术在OTR体内成像的发展将极大地促进OTR与人类社会认知关系的基础和临床研究。此外，它的应用可能会导致自闭症谱系障碍等疾病的潜在诊断工具的发展，这些疾病目前仅基于行为观察进行诊断。在这项应用中，我们提出了合成和表征候选选择性的小分子OTR PET放射配体，最终目的是为研究大脑中OTR分布与人类社会认知和精神病理之间的关系提供工具。放射化学将重点关注C-14和I-125衍生物进行初步体外和体内评估，然后是C-11和F-18衍生物进行生物分布和PET成像研究。候选化合物对人OTR的亲和力和选择性将使用标准受体结合试验进行检查。候选化合物穿透血脑屏障和标记OTR的能力将通过表达人类OTR的转基因小鼠进行评估。生物分布研究也将在这些转基因小鼠和大鼠中进行。最后，进行恒河猴脑内OTR密度的活体PET成像。因此，本实验可能最终为研究OTR分布、社会认知和精神病理之间的关系提供一个很好的工具。提出的研究计划提出了一个工作假设，即通过对已知的选择性小分子拮抗剂进行微小修饰，可以开发出合适的小分子催产素受体PET配体。

DESCRIPTION (provided by applicant): Oxytocin (OT) is a neuropeptide that has been implicated in the regulation of social cognition and social behavior both in animal models and in humans. In rodents, OT is involved in social information processing, parental nurturing, and social bonding. In humans, intranasal OT enhances interpersonal trust, eye-to-eye contact, memory of faces, and the ability to infer the emotions of others. These observations as well as genetic association studies focusing on polymorphisms of OT receptor (OTR) gene suggest that dysregulation of the OT system may contribute to the social cognitive deficits associated with several psychiatric disorders, including autism spectral disorders, schizophrenia, and depression. Despite its evident role in regulating social cognition in humans, very little is known regarding the localization of OTR in the human brain or its dysregulation in psychiatric disorders. The development of a PET imaging technology for the in vivo imaging of the OTR would greatly enhance basic and clinical research investigating the relationship between OTR and human social cognition. Furthermore, its application may lead to the development of a potential diagnostic tool for disorders such as autism spectrum disorders, which are currently diagnosed solely based on behavioral observations. In this application we proposed to synthesize and characterize candidate selective, small molecule OTR PET radioligands with the ultimate goal of generating tools for investingating the relationship between OTR distribution in the brain and human social cognition and psychopatholgy. Radiochemistry will focus on C-14 and I-125 derivatives for preliminary in vitro and in vivo evaluations followed by C-11 and F-18 derivatives for biodistribution and PET imaging studies. The affinity and selectivity of the canditate compounds for the human OTR will be examined using standard receptor binding assays. The ability of the candidate compounds to penetrate the blood brain barrier and label OTR will be evaluated using transgenic mice expressing the human OTR. Biodistribution studies will also be performed in these transgenic mice as well as rats. Finally, in vivo PET imaging of OTR density within the brain of the rhesus monkey will be performed. Thus, the experiments in this proposal may ultimately provide an excellent tool to investigate the relationship of OTR distribution, social cognition, and psychopathology. The proposed research plan presents the working hypothesis that a suitable small molecule oxytocin receptor PET ligand can be developed through minor modifications of known selective small molecule antagonists. PUBLIC HEALTH RELEVANCE: Oxytocin modulates several aspects social cognition in both animal models and man. There is evidence that dysregulation in the oxytocin system, including oxytocin receptors, may contribute to the social deficits in psychiatric disorders such as autism spectrum disorder, depression and schizophrenia. The development of a PET ligand to detect and quantify oxytocin receptor in the living brain may therefore prove to be a useful tool for examining the relationship between oxytocin receptor distribution and social cognition in psychiatric patients and may lead to a better understanding of the etiology of social deficits in these disorders.