Carbon-11 N-methyl alkylation of L-368,899 and in vivo PET imaging investigations for neural oxytocin receptors

• Type of Material: Article
• Authors: Aaron Smith, Emory University; Sara M. Freeman, Yerkes National Primate Research Center; Ronald Voll, Emory University; Larry Young, Emory University; Mark Goodman, Emory University
• Language: English
• Date: 2013-02-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmcl.2012.10.116
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry Letters
• ISSN: 0960-894X
• Volume: 23
• Issue: 3
• Start Page: 902
• End Page: 906
• Grant/Funding Information: We also acknowledge NIH MH064692 (LJY) and the National Center for Research Resources P51RR165 (currently P51OD11132) to YNPRC.; This research was funded by the National Institute of Mental Health through grant 5 R21 MH090776.
• Keywords: AUTISM; PET imaging; Chemistry, Medicinal; L-368,899; Life Sciences & Biomedicine; Pharmacology & Pharmacy; GENE OXTR; ASSOCIATION; VASOPRESSIN; Pituitary; Oxytocin; BLOOD-BRAIN-BARRIER; ANTAGONIST; Receptor imaging; Chemistry; Vasopressin; Physical Sciences; Science & Technology; Chemistry, Organic
• Research Categories: Health Sciences, Radiology; Biology, Neuroscience

Abstract

Compound L-368,899 was successfully alkylated with [11C] iodomethane to generate the oxytocin receptor selective (2R)-2-amino-N-((2S)-7, 7-dimethyl-1-(((4-(o-tolyl)piperazin-1-yl)sulfonyl)methyl)bicyclo[2.2.1] heptan-2-yl)-N-[11C]methyl-3-(methylsulfonyl)propanamide ([ 11C]1) with very high radiochemical purity and high specific activity. PET imaging studies were performed with [11C]1 to investigate brain penetration and oxytocin receptor uptake using rat and cynomolgus monkey models. For rat baseline scans, brain penetration was observed with [11C]1, but no specific uptake could be distinguished in the brain region. By administering a peptide oxytocin receptor selective antagonist for peripheral blocking of oxytocin receptors, the uptake of [11C]1 was amplified in the rat brain temporarily to enable some visual uptake within the rat brain. A baseline scan of [11C]1 in a cynomolgus monkey model resulted in no detectable specific uptake in anticipated regions, but activity did accumulate in the choroid plexus.