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.
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.
|Freeman, S M; Walum, H; Inoue, K et al. (2014) Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus). Neuroscience 273:12-23|
|Modi, Meera E; Connor-Stroud, Fawn; Landgraf, Rainer et al. (2014) Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology 45:49-57|
|Freeman, Sara M; Inoue, Kiyoshi; Smith, Aaron L et al. (2014) The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta). Psychoneuroendocrinology 45:128-41|
|Smith, Aaron L; Freeman, Sara M; Voll, Ronald J et al. (2013) Investigation of an F-18 oxytocin receptor selective ligand via PET imaging. Bioorg Med Chem Lett 23:5415-20|
|Smith, Aaron L; Freeman, Sara M; Voll, Ronald J et al. (2013) Carbon-11 N-methyl alkylation of L-368,899 and in vivo PET imaging investigations for neural oxytocin receptors. Bioorg Med Chem Lett 23:902-6|
|Smith, Aaron L; Freeman, Sara M; Stehouwer, Jeffery S et al. (2012) Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors. Bioorg Med Chem 20:2721-38|