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NEUROPHARMACOLOGY

Low Sensitivity of the Positron Emission Tomography Ligand [¹¹C]Diprenorphine to Agonist Opiates

Hammersmith Imanet Ltd., Hammersmith Hospital, London, United Kingdom (S.P.H., V.N., E.H., R.A.); Psychopharmacology Unit, University of Bristol, Bristol, United Kingdom (A.R.L.-H., D.J.N.); and Department of Palliative Medicine, Bristol Haematology and Oncology Centre, Bristol, United Kingdom (A.N.D.)

Previously, we reported minimal opioid receptor occupancy following a clinical dose of the µ-opioid agonist, methadone, measured in vivo using positron emission tomography (PET) with [¹¹C]diprenorphine and subsequently used rats to obtain experimental data in support of a high receptor reserve hypothesis (Melichar et al., 2005). Here, we report on further preclinical studies investigating opioid receptor occupancy with oxycodone (µ- and -receptor agonist), morphine (µ-receptor agonist), and buprenorphine (partial agonist at the µ-receptor and antagonist at the - and -receptors), each given at antinociceptive doses. In vivo binding of [¹¹C]diprenorphine was not significantly reduced after treatment with the full agonists but was reduced by 90% by buprenorphine. In addition, given that [¹¹C]diprenorphine is a non-subtype-specific PET tracer, there was no regional variation that might feasibly be interpreted as due to differences in opioid subtype distribution. The data support minimal competition between the high-efficacy agonists and the non-subtype-selective antagonist radioligand and highlight the limitations of [¹¹C]diprenorphine PET to monitor in vivo occupancy. Alternative means may be needed to address clinical issues regarding opioid receptor occupancy that are required to optimize treatment strategies.

Address correspondence to: David J. Nutt, Psychopharmacology Unit, Dorothy Hodgkin Building, Whitson Street, University of Bristol, Bristol, BS1 3NY, UK. E-mail: david.j.nutt{at}bristol.ac.uk

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