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

描述(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参与了社会认知和社会行为的调节。在啮齿动物中，OT参与社会信息处理、父母养育和社会纽带。在人类中，鼻腔OT增强了人与人之间的信任、眼神接触、对面孔的记忆以及推断他人情绪的能力。这些观察结果以及关注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多种精神障碍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起着明显的作用，但对于它在人脑中的定位或在精神障碍中的调节失调，人们知之甚少。利用正电子发射计算机断层扫描(PET)技术对OTR进行活体成像，将极大地促进研究OTR与人类社会认知之间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，用于自闭症谱系障碍等疾病，目前仅根据行为观察来诊断这些疾病。在这一应用中，我们建议合成和表征候选的选择性小分子OTRPET放射性配体，最终目标是生成工具，用于研究OTR在大脑中的分布与人类社会认知和精神病理学之间的关系。放射化学将重点放在C-14和I-125衍生物上，用于初步的体外和体内评估，然后是C-11和F-18衍生物，用于生物分布和PET成像研究。将使用标准的受体结合分析来检验烛酸盐化合物对人类OTR的亲和力和选择性。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。还将在这些转基因小鼠和大鼠身上进行生物分布研究。最后，将进行恒河猴脑内OTR密度的活体PET成像。因此，这项建议中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。所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的修饰，可以开发出合适的小分子催产素受体PET配体。 公共卫生相关性：在动物模型和人类中，催产素都在几个方面调节社会认知。有证据表明，包括催产素受体在内的催产素系统的失调，可能会导致自闭症谱系障碍、抑郁症和精神分裂症等精神障碍的社会缺陷。因此，开发一种PET配体来检测和量化活脑中的催产素受体，可能被证明是一种有用的工具，可以检验精神疾病患者催产素受体分布与社会认知之间的关系，并可能有助于更好地理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.