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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Carmine Marzano, Imanova Ltd, Imperial College London, Hammersmith Hosp
  • ,
  • Steen Jakobsen
  • Cristian Salinas, Imanova Ltd, Imperial College London, Hammersmith Hosp
  • ,
  • Sac Pham Tang, Imanova Ltd, Imperial College London, Hammersmith Hosp
  • ,
  • Dirk Bender
  • Jan Passchier, Imanova Ltd, Imperial College London, Hammersmith Hosp
  • ,
  • Christophe Plisson, Imanova Ltd, Imperial College London, Hammersmith Hosp

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/mu mol), and radiochemical purities. The in vivo regional uptake of these radiotracers was determined in porcine brain. [C-11]GSK711320 baseline scan showed no significant brain uptake, and limited initial uptake was observed following administration of [C-11]GSK712043 or [C-11]GSK664004. The [C-11]GSK712043 and [C-11]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-11]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.

Original languageEnglish
JournalJournal of Labelled Compounds and Radiopharmaceuticals
Volume60
Issue12
Pages (from-to)556-565
Number of pages10
ISSN0362-4803
DOIs
Publication statusPublished - Oct 2017

    Research areas

  • CNS disorders, oxytocin receptor, porcine brain, radioligand, UPPER SPINAL-CORD, BINDING-SITES, NONHUMAN-PRIMATES, H-3 OXYTOCIN, BRAIN, RECEPTORS, VASOPRESSIN, LOCALIZATION, POTENT, 2,5-DIKETOPIPERAZINES

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