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Radiotracer Development for Investigation of Correlations of Oxytocin Receptor Density and Social Behavior Disorders

Author: Aaron Smith, PhD

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. Collaborator Larry Young has shown that in rodents, OT is involved in social information processing, parental nurturing behavior, and social bonding. In humans, intranasal administration of OT enhances interpersonal trust, memory of faces, eye to eye contact, and the ability to infer the emotions of others. Variation in OT receptor (OTR) distribution in the brain has been associated with variation in social behaviors in animal models. Thus it is possible that dysregulation of the OT system, including OTR distribution in the brain, may contribute to the social cognitive deficits characterizing several psychiatric disorders, including autism spectrum disorders (ASD), schizophrenia, and depression.

Recent genetic association studies have reported that polymorphisms in the OT receptor (OTR) gene may contribute to the social cognitive deficits in autism. 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 potential dysregulation in psychiatric disorders.

The development of PET radioligands for in vivo imaging of OTR would greatly enhance basic and clinical research investigating function of the OTR in regulating human social cognition. We expect that the application of PET imaging, a vital tool for the investigation and diagnosis of a variety of central nervous system and behavioral disorders, will lead to new insights into the potential relationship between OTR dysregulation and social cognitive deficits in a variety of psychiatric disorders. 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.

The primary goal of the project is to develop small molecule oxytocin receptor PET radioligands(s) through in vitro and in vivo evaluation of candidate compounds.

Figure 1

The image shows the result of an in vitro study in which our novel ligands outcompeted known potent radioactive peptides, [I-125]ornithine vasotocin and [I-125]linear vasopressin, for the oxytocin and vasopressin receptors on slices of vole brain tissue.  As the molar concentration of our ligands increased (from top to bottom) the radioactive peptide was blocked from receptor binding sites, in a visual demonstration of the binding affinity of these ligands.

Project Team

Co Pi’s – Larry Young and Mark Goodman.  Team members: Aaron Smith, Sara Freeman, Ron Voll, Kiyoshi Inoue, Larry Williams, Eugene Malveaux, and Mel Camp.

Publications

Small molecule I-125 radioligands for oxytocin brain receptor autoradiography, J. Med. Chem. - Submitted