Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans

E. A. Rabiner, John Beaver, Aidan Makwana, G. Searle, C Long, P. J. Nathan, R. D. Newbould, J. Howard, S. R. Miller, M. A. Bush, S. Hill, R. Reiley, J. Passchier, R. N. Gunn, P. M. Matthews, E. T. Bullmore

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Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the μ-OR sub-type. In a sample of healthy volunteers, we used 11 C-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 507.10 ng ml -1) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-Β-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption.

Original languageEnglish
Pages (from-to)826-835
Number of pages10
JournalMolecular Psychiatry
Issue number8
Publication statusPublished - Aug 2011
Externally publishedYes


  • experimental medicine
  • functional MRI
  • neuropharmacology
  • pharmacodynamics
  • pharmacokinetics
  • positron emission tomography

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