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参与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，眼睛对眼睛的接触，面孔记忆以及推断他人情绪的能力。 这些观察结果以及专注于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几种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OTR在调节人类社会认知中具有明显的作用，但关于OTR在人脑中的定位或其在精神疾病中的失调知之甚少。 用于OTR的体内成像的PET成像技术的发展将极大地增强调查OTR与人类社会认知之间的关系的基础和临床研究。 此外，它的应用可能会导致开发一种潜在的诊断工具，用于治疗自闭症谱系障碍等疾病，目前仅根据行为观察进行诊断。 在本申请中，我们提出合成和表征候选选择性小分子OTR PET放射性配体，最终目标是产生用于研究脑中OTR分布与人类社会认知和精神病理学之间关系的工具。 放射化学将侧重于C-14和I-125衍生物的初步体外和体内评价，然后是C-11和F-18衍生物的生物分布和PET成像研究。 将使用标准受体结合测定法检查候选化合物对人OTR的亲和力和选择性。 将使用表达人OTR的转基因小鼠评价候选化合物穿透血脑屏障和标记OTR的能力。 还将在这些转基因小鼠和大鼠中进行生物分布研究。 最后，将进行恒河猴脑内OTR密度的体内PET成像。 因此，本研究的实验可能最终提供一个很好的工具来研究OTR分布、社会认知和精神病理学之间的关系。 拟议的研究计划提出了工作假设，即可以通过对已知的选择性小分子拮抗剂进行微小修改来开发合适的小分子催产素受体PET配体。 公共卫生相关性：催产素在动物模型和人类中调节社会认知的几个方面。有证据表明，催产素系统（包括催产素受体）的失调可能导致精神障碍（如自闭症谱系障碍、抑郁症和精神分裂症）的社会缺陷。 因此，PET配体的发展，以检测和定量催产素受体在活的大脑中可能被证明是一个有用的工具，用于检查催产素受体分布和社会认知之间的关系，在精神病患者，并可能导致更好地了解这些疾病的社会缺陷的病因。

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.