An evaluation of central penetration from a peripherally administered oxytocin receptor selective antagonist in nonhuman primates

• Type of Material: Article
• Authors: Aaron Smith, Emory University; Hasse Walum, Emory University; Fawn C Connor-Stroud, Emory University; Sara M. Freeman, University of California; Kiyoshi Inoue, Emory University; Lisa Parr, Emory University; Mark Goodman, Emory University; Larry J Young, Emory University
• Language: English
• Date: 2017-01-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016. Published by Elsevier Ltd.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmc.2016.10.035
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry
• ISSN: 0968-0896
• Volume: 25
• Issue: 1
• Start Page: 305
• End Page: 315
• Grant/Funding Information: This research was supported by NIH grant 1P50MH100023 to LJY. Additional funding was provided by NIH OD P51OD11132 to YNPRC.
• Keywords: Science & Technology; NEUROHYPOPHYSEAL HORMONES; PLASMA; Pharmacology & Pharmacy; PET imaging; Chemistry, Medicinal; REWARD; SOCIAL RECOGNITION; Life Sciences & Biomedicine; BRAIN; INTRANASAL OXYTOCIN; Oxytocin receptor; BEHAVIOR; Physical Sciences; MALE PRAIRIE VOLES; Cerebrospinal fluid; Oxytocin antagonist; Chemistry, Organic; PARTNER; Rhesus macaque; SYSTEM; Chemistry; Biochemistry & Molecular Biology
• Research Categories: Health Sciences, Public Health; Biology, Physiology

Abstract

The physiology of the oxytocin receptor has increasingly become a focus of scientific investigation due to its connection with social behavior and psychiatric disorders with impairments in social funciton. Experimental utilization of small molecule and peptide antagonists for the oxytocin receptor has played a role in deciphering these biological and social behavior connections in rodents. Described herein is the evaluation of a potent and selective oxytocin receptor antagonist, ALS-I-41, and details to consider for its use in nonhuman primate behavioral pharmacology experiments utilizing intranasal or intramuscular administration. The central nervous system penetration and rate of metabolism of ALS-I-41 was investigated via mass spectroscopy analysis of cerebrospinal fluid and plasma in the rhesus macaque after intranasal and intramuscular administration. Positron emission tomography was also utilized with [ 18 F] ALS-I-41 in a macaque to verify observed central nervous system (CNS) penetration and to further evaluate the effects of administration rate on CNS penetration of Sprague-Dawley rats in comparison to previous studies.