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

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.

Radiosynthesis and evaluation of 1‐substituted 3‐(2,3‐dihydro‐1H‐inden‐2‐yl)‐6‐(1‐ethylpropyl)‐(3R,6R)‐2,5‐piperazinedione derivatives as PET tracers for imaging the central oxytocinergic system

“…[ 11 C]GSK711320 did not appear to significantly enter the brain; the higher activity uptake was seen in the pituitary gland and in the choroid plexus with no brain region demonstrating a high accumulation and retention of radioactivity. Similar high uptake in these regions and low CNS uptake has been observed with previously reported oxytocin radiotracers, 18,20,21 and [ 3 H] oxytocin has also been shown to bind to the neural lobe of the pituitary; 29 this binding was however demonstrated to be associated to binding to neurophysins.…”

“…14,15 For in vivo SPECT imaging, Gallium-67 labelled OT has been reported. 16 Recently, several candidate molecules were evaluated for in vivo imaging of the central OTR; [17][18][19][20][21][22] however, despite some encouraging in vitro results, PET imaging studies showed either no significant brain uptake or a limited CNS distribution that did not correspond to the expected OTR distribution.…”

An evaluation of central penetration from a peripherally administered oxytocin receptor selective antagonist in nonhuman primates

“…This report confirms the variance in brain penetration of [ 18 F]ALS-I-41 between animal models as, previously reported, no significant brain penetration of [ 18 F]ALS-I-41 was detected in titi monkey models. [53] However, the data from the various rat scans does lead to the hypothesis that if a 30 minute continuous IV infusion of [ 18 F]ALS-I-41 is performed with a macaque model then an image with improved resolution may be obtained.…”

Pair bond formation leads to a sustained increase in global cerebral glucose metabolism in monogamous male titi monkeys (Callicebus cupreus)

“…The neurochemicals which are responsible for the higher rCGM in some regions remain to be confirmed. Chemically specific PET ligands are available for some of these (such as dopamine D1 and D2 receptors); however, there is still no OT receptor PET ligand (Smith et al, 2016), and no easily available V1a receptor PET ligand. Finally, the neural basis of other aspects of the pair-bond, such as separation distress and mate-guarding (or “jealousy”), also remain to be considered.…”