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 -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 (-and -receptor agonist), morphine (-receptor agonist), and buprenorphine (partial agonist at the -receptor and antagonist at the ␦-and -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 ϳ90% 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.Positron emission tomography (PET) with the radioligand, [ 11 C]diprenorphine has been used for over a decade to assess or measure opioid receptor function in human brain. Specific binding of this ligand in vivo can be blocked by the opioid receptor antagonist, naloxone (13 g/kg naloxone resulted in ϳ50% reduction in binding; Melichar et al., 2003) and is locally reduced in conditions expected to result in an increased concentration of endogenous agonist; for example, pain (for review, see Sprenger et al., 2005). We had therefore used PET with [ 11 C]diprenorphine to quantify opioid receptor occupancy in methadone-maintained opiate-dependent patients. Our aim was to address clinical issues in treatment of opioid dependence such as agonist dose-to-outcome, with a view to optimizing treatment strategies but, in the end, found no statistically significant reduction in specific binding compared with control (Melichar et al., 2005). A likely explanation was that clinically relevant doses (18 -90 mg daily) of methadone result in low levels of occupancy of opioid receptors. Other factors considered were receptor trafficking, agonist concentration at the site of action, and, since the predominant form of the opioid receptor in vivo is a low agonist affinity state, the limited ability of agonists to block highaffinity binding of an antagonist radiotracer.

Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

“…The consequence of inhibiting P-gp on the 11 Cdiprenorphine distribution volume remains to be evaluated in vivo. Hume et al suggested that this could be a factor influencing variations in the brain uptake of 11 C-diprenorphine (41). (R,S)-PK11195 has been found to be a potent inhibitor of the human P-gp and BCRP on multidrug resistant cells in vitro (42).…”

Withdrawal from Buprenorphine/Naloxone and Maintenance with a Natural Dopaminergic Agonist: A Cautionary Note

“…Experiments [30] have shown that mu-receptor binding of agonist like morphine or potentially heroin, are significantly reduced with buprenorphine. Although the outcome for short-term therapy is beneficial, in the long term, administration of buprenorphine will result in an attenuation of mu receptor occupancy of the natural opioid enkephalin and will eventually, like naloxone, result in reduced release of DA at the accumbens brain region [31–34].…”

Imaging Endogenous Opioid Peptide Release with [11C]Carfentanil and [3H]Diprenorphine: Influence of Agonist-Induced Internalization

“…Previous studies suggest that because of a proposed high-efficacy and low-occupancy profile of opioid receptor agonists such as methadone, [ 11 C]diprenorphine is not a suitable radioligand for determination of dose-occupancy relationships in vivo. 19,20 Moreover, the ability of methadone to reduce [ 11 C]carfentanil binding has also not been assessed. The occupancy model may not sufficiently describe the changes in binding observed during in vivo competition imaging paradigms; 21 therefore, the cellular processes underpinning these changes warrant further investigation.…”