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

• 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
• Journal Title: Bioorganic and Medicinal Chemistry Letters
• Volume: Volume 23, Number 3
• Publisher: Elsevier | 2013-02-01, Pages 902-906
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.bmcl.2012.10.116
• Subjects: Biology, Neuroscience; Health Sciences, Radiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Physical Sciences; Chemistry, Medicinal; Chemistry, Organic; Pharmacology & Pharmacy; Chemistry; Oxytocin; Vasopressin; PET imaging; L-368,899; Pituitary; Receptor imaging; BLOOD-BRAIN-BARRIER; GENE OXTR; ASSOCIATION; VASOPRESSIN; ANTAGONIST; AUTISM

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.