Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans
Résumé
Opioid neurotransmission plays a key role in mediating reward-related behaviours. Opioid receptor antagonists such as naltrexone (NTX) can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel opioid receptor (OR) ligand, which behaves as an inverse agonist at the μ-OR subtype. In a sample of healthy volunteers, we used [11C]-carfentanil PET to measure opioid receptor occupancy and functional MRI to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain opioid receptors (GSK1521498 EC50 = 7.10 ng/ml) 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-naltrexol (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 opioid receptor 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-receptor occupancy 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 over-eating and other disorders of compulsive consumption.
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