title: Low sensitivity of the positron emission tomography ligand [11C]diprenorphine to agonist opiates.
abstract: Previously, we reported minimal opioid receptor occupancy following a clinical dose of the micro-opioid agonist, methadone, measured in vivo using positron emission tomography (PET) with [(11)C]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 (micro- and kappa-receptor agonist), morphine (micro-receptor agonist), and buprenorphine (partial agonist at the micro-receptor and antagonist at the delta- and kappa-receptors), each given at antinociceptive doses. In vivo binding of [(11)C]diprenorphine was not significantly reduced after treatment with the full agonists but was reduced by approximately 90% by buprenorphine. In addition, given that [(11)C]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 [(11)C]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.
authors.affiliation: Hammersmith Imanet Ltd., Hammersmith Hospital, London, United Kingdom.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Hume
authors.forename: Anne R
authors.initials: AR
authors.lastname: Lingford-Hughes
authors.forename: Valerie
authors.initials: V
authors.lastname: Nataf
authors.forename: Ella
authors.initials: E
authors.lastname: Hirani
authors.forename: Rabia
authors.initials: R
authors.lastname: Ahmad
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Davies
authors.forename: David J
authors.initials: DJ
authors.lastname: Nutt
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism; D002047:Buprenorphine / Q000378:metabolism / Q000493:pharmacokinetics; D002250:Carbon Radioisotopes; D002531:Cerebellum / Q000378:metabolism; D003164:Competitive Bidding; D004174:Diprenorphine / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D008032:Limbic System / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000378:metabolism / Q000493:pharmacokinetics; D009292:Narcotic Antagonists; D010098:Oxycodone / Q000378:metabolism / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D016548:Prosencephalon / Q000378:metabolism; D011803:Quinine / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism*; D015203:Reproducibility of Results; D014018:Tissue Distribution
chemical_list: D000701:Analgesics, Opioid; D002250:Carbon Radioisotopes; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D004174:Diprenorphine; D002047:Buprenorphine; D009020:Morphine; D011803:Quinine; D010098:Oxycodone