Mapping opioid receptor occupancy on different serum levels of sustained-release naltrexone by PET imaging

Abstract

Aims Naltrexone is a competitive opioid antagonist that effectively blocks the action of heroin and other opioid agonists. It has no abuse potential, mild and transient side effects, and thus appears an ideal pharmacotherapy for opioid dependence. Sustained-release naltrexone formulations are now available that provide long-acting opioid blockade. However, further research is warranted, especially data concerning opioid receptor (OR) occupancy on different plasma levels of naltrexone. Positron emission tomography (PET) is a unique imaging modality for studying functional processes in vivo and is used in this study to map OR occupancy on different plasma concentrations of naltrexone in rats. Methods Eleven rats were implanted with a single tablet of 1,95 mg naltrexone. OR occupancy data was acquired at baseline, a few days after implantation (week 1) and in week 6 by PET imaging, using the partial agonist [18F]BPN, the agonist [18F]PEO, and the antagonist [18F]DPN, all OR ligands. Blood samples were obtained in connection with PET imaging to monitor naltrexone plasma levels. Results The naltrexone plasma concentrations were above the therapeutic level (1 ng/ml) for five out of six animals for the 6-week study period. Measuring OR occupancy by an antagonist PET ligand showed constant values across subjects, while the naltrexone plasma concentrations had large inter-subject variability. Conclusions Mapping OR occupancy by an antagonist PET tracer appears to be a better measurement of the protective drug effect of naltrexone than plasma levels