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

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 {kappa}-receptor agonist), morphine (µ-receptor agonist), and buprenorphine (partial agonist at the µ-receptor and antagonist at the {delta}- and {kappa}-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.