Investigation of an F-18 oxytocin receptor selective ligand via PET imaging

Abstract

The compound 1-(1-(2-(2-(2-fluoroethoxy)-4-(piperidin-4-yloxy)phenyl)acetyl)piperidin-4-yl)-3,4-dihydroquinolin- 2(1H)-one (1) was synthesized and positively evaluated in vitro for high potency and selectivity with human oxytocin receptors. The positron emitting analogue, [F-18]1, was synthesized and investigated in vivo via PET imaging using rat and cynomolgus monkey models. PET imaging studies in female Sprague–Dawley rats suggested [F-18]1 reached the brain and accumulated in various regions of the brain, but washed out too rapidly for adequate quantification and localization. In vivo PET imaging studies in a male cynomolgus monkey suggested [F-18]1 had limited brain penetration while specific uptake of radioactivity significantly accumulated within the vasculature of the cerebral ventricles in areas representative of the choroid plexus.

Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies

“…Recent PET imaging in rats has identified a potential ligand to look at OXT receptor density, 91 which may give better insight into the receptor densities in humans, although recent research by the same group has also shown that this particular radiotracer may have limited brain penetration in primates. 92 There is evidence linking midbrain and mesolimbic DA with the effects of OXT on the processing of social stimuli. Some evidence suggests that DA is involved in mediating some of the same maternal behaviours that are exhibited under the influence of OXT 93,94 as well as pair bonding.…”

“…[109][110][111][112] In addition, preclinical studies have shown that dopaminergic fibres may regulate OXT release 113,114 and that the receptor binding sites and neuronal fibres of both of these neurochemicals reside in the same regions of the central nervous system and are often next to each other. 92,99,115 Further evidence suggests that, at least in the ventral and dorsal striatum, DA D2 receptors and OXT are heteromers with facilitatory receptor-to-receptor interactions. 116 Although most studies reporting links between DA and OXT have been performed in a preclinical population and most evidence for an association between DA and OXT in humans is speculative, a few recent studies in humans have also shown these 2 systems to be more directly associated.…”

The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta)

“…Sets of three adjacent sections were incubated in three different conditions: radioligand alone, radioligand plus SR49059 (Tocris, Minneapolis, MN), or radioligand plus ALS-II-69. SR49059 is a small molecule selective antagonist for the human AVPR1A (Gal et al, 1993), while ALS-II-69 is a small molecule selective antagonist for the human OXTR (A. L. Smith et al, 2013b).…”

Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus)

“…Specifically, sections were incubated for 1 hr with one of two different radioligands: 50 pM 125 I-LVA to target AVPR1a or 50 pM 125 I-OVTA to target OXTR. Sets of three adjacent sections were co-incubated in three different competitive binding treatments for each radioligand: (i) 50 pM radioligand alone, (ii) 50 pM radioligand plus 10 nM SR49059, which is a human-selective AVPR1a ligand (Tocris, Minneapolis, MN; (Gal et al, 1993), or (iii) 50 pM radioligand plus 20 nM ALS-II-69, which is a human-selective OXTR ligand synthesized by our own lab (Smith et al, 2013). These unlabeled competitors were incubated at concentrations that were determined by previous competitive binding pharmacology experiments to be ideal for displacing the OXTR ligand from the human AVPR1a or displacing the AVPR1a ligand from the human OXTR, and thus increasing the specificity of the radioligand signal (Freeman et al, in press).…”