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

Abstract

Oxytocin is known to be implicated in a variety of functions, such as learning, stress, anxiety, feeding, and pain perception. Oxytocin is also important for social memory and attachment, human bonding, sexual and maternal behaviour, and aggression. Human disorders characterized by aberrant social interactions, such as autism and schizophrenia, may also involve abnormal oxytocin levels. GSK712043, GSK711320, and GSK664004, three antagonists exhibiting subnanomolar affinity for the human oxytocin receptor (hOTR) and high selectivity over vasopressin receptors were successfully labelled with carbon-11 with suitable yields (0.5-1GBq @EOS), high molar activity (275-700 GBq/μmol), and radiochemical purities. The in vivo regional uptake of these radiotracers was determined in porcine brain. [ C]GSK711320 baseline scan showed no significant brain uptake, and limited initial uptake was observed following administration of [ C]GSK712043 or [ C]GSK664004. The [ C]GSK712043 and [ C]GSK664004 kinetics were slow and peaked at around 2%ID/L at 90 minutes post-injection. For both tracers, the distribution of activity was homogeneous throughout the brain. All the tracers showed high uptake in the pituitary gland, especially [ C]GSK711320; however, its uptake could not be blocked by pretreatment with the known OTR antagonist, L368,899. In vivo evaluation of these candidates demonstrated that they are not suitable as central OTR PET imaging agents.

LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism

“…MP = 201 °C. 1-[2-Chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (38). Compound 38 was prepared according to general method A, affording a creamy powder (yield 61%).…”

“…Understanding the distribution and functions of this neurotransmitter is crucial for the meaningful interpretation of animal and clinical studies and to rationalize the design of better drug candidates. For instance, no OT-R specific brain penetrating positron emission tomography (PET) probe is currently available. , Furthermore, the only way to get central activity with OT is intranasal (i.n.) administration because, as with most peptides, OT is not orally absorbed, is rapidly metabolized after iv administration (few minutes), and poorly crosses blood–brain barrier except very modestly via the intranasal route. , That is far from ideal in terms of formulation because the actual concentrations of OT being administered and reaching the different brain regions are unknown .…”

“…For instance, no OT-R specific brain penetrating positron emission tomography (PET) probe is currently available. 37,38 Furthermore, the only way to get central activity with OT is intranasal (i.n.) administration because, as with most peptides, OT is not orally absorbed, 39 is rapidly metabolized after iv administration (few minutes), 40 and poorly crosses blood−brain barrier except very modestly via the intranasal route.…”