Initial investigation of three selective and potent small molecule oxytocin receptor PET ligands in New World monkeys

• Type of Material: Article
• Authors: Aaron Smith, Emory University; Sara M. Freeman, University of California Davis; Todd E. Barnhart, University of Wisconsin; David H Abbott, University of Wisconsin; Elizabeth O. Ahlers, University of Wisconsin; David L. Kukis, University of California Davis; Karen L. Bales, University of California Davis; Mark Goodman, Emory University; Larry Young, Emory University
• Language: English
• Date: 2016-07-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier Ltd.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmcl.2016.04.097
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry Letters
• ISSN: 0960-894X
• Volume: 26
• Issue: 14
• Start Page: 3370
• End Page: 3375
• Grant/Funding Information: Additional support was provided by the Office of Research Infrastructure Programs/OD P51OD011132 to YNPRC.; We would like to acknowledge the funding support for this research from NIMH- R21MH090776 and NIH 1P50MH100023-01 to LJY.
• Keywords: Pharmacology & Pharmacy; INTRANASAL OXYTOCIN; VASOPRESSIN; Chemistry; Chemistry, Organic; Titi monkey; Vasopressin; SALIVARY-GLAND; Vasopressin receptor; Oxytocin receptor; Physical Sciences; AUTISM SPECTRUM DISORDERS; Oxytocin; NEUROANATOMICAL DISTRIBUTION; Marmoset; Life Sciences & Biomedicine; RANDOMIZED CONTROLLED-TRIAL; MESSENGER-RNA; GENE OXTR; BEHAVIOR; Chemistry, Medicinal; PET imaging; EXPRESSION; Science & Technology
• Research Categories: Health Sciences, Toxicology; Health Sciences, Medicine and Surgery

Abstract

The neuropeptide oxytocin is part of a neuroendocrine system that has physiological effects ranging from ensuring uterine myometrial contractions at parturition and post-partum mammary gland milk ejection to the modulation of neural control of social relationships. This initial study was performed to investigate the potential use of positron emission tomography (PET) for localizing oxytocin receptors in two New World primates. Three biomarkers for PET (1–3) that are known to have high affinity and selectivity for the human oxytocin receptor were investigated in the common marmoset (Callithrix jacchus) via PET imaging. Brain penetration, and uptake in the salivary gland area were both observed with biomarkers 2 and 3. No brain penetration was observed with 1, but uptake was observed more specifically in several peripheral endocrine glands compared to 2 or 3. Biomarker 2, which displayed the best brain penetration of the three biomarkers in the marmoset, was then investigated in the monogamous coppery titi monkey (Callicebus cupreus) in a brain scan and a limited full body scan. No significant brain penetration of 2 was observed in the titi monkey, but significant uptake was observed in various locations throughout the periphery. Metabolism of 2 was suspected to have been significant based upon HPLC analysis of blood draws, but parent compound was still present near the end of the scan. Follow-up investigations will focus on next generation biomarkers bearing improved binding characteristics and brain penetrability as well as investigating tissue in regions where biomarker uptake was observed.