title: An evaluation of central penetration from a peripherally administered oxytocin receptor selective antagonist in nonhuman primates.
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 [18F] 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.
authors.affiliation: Silvio O. Conte Center for Oxytocin and Social Cognition, Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA; Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA 30322, USA; Center for Systems Imaging, Emory University, 1841 Clifton Road NE, Atlanta, GA 30322, USA. Electronic address: asmit53@emory.edu.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Smith
authors.affiliation: Silvio O. Conte Center for Oxytocin and Social Cognition, Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Hasse
authors.initials: H
authors.lastname: Walum
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
authors.forename: Fawn
authors.initials: F
authors.lastname: Connor-Stroud
authors.affiliation: California National Primate Research Center, University of California, Davis, CA 95616, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Freeman
authors.affiliation: Silvio O. Conte Center for Oxytocin and Social Cognition, Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Silvio O. Conte Center for Oxytocin and Social Cognition, Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Parr
authors.affiliation: Silvio O. Conte Center for Oxytocin and Social Cognition, Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA; Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA 30322, USA; Center for Systems Imaging, Emory University, 1841 Clifton Road NE, Atlanta, GA 30322, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Goodman
authors.affiliation: Silvio O. Conte Center for Oxytocin and Social Cognition, Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Young
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes; D007273:Injections, Intramuscular; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography; D015363:Quinolones / Q000097:blood / Q000134:cerebrospinal fluid / Q000138:chemical synthesis / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000097:blood / Q000134:cerebrospinal fluid / Q000138:chemical synthesis / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000097:blood / Q000134:cerebrospinal fluid / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C000625534:ALS-I-41; D005462:Fluorine Radioisotopes; D015363:Quinolones; D019275:Radiopharmaceuticals; D018045:Receptors, Oxytocin; D013449:Sulfonamides
keywords: Cerebrospinal fluid; Oxytocin antagonist; Oxytocin receptor; PET imaging; Rhesus macaque