Whole-body dynamic PET-MR imaging unveils the biodistribution and tissue kinetics of ¹¹C-buprenorphine in

Complete text of publication follows: Aim/Introduction: Buprenorphine is a partial agonist of the μ-opioid receptors used for the management of severe pain or opioid-addiction maintenance therapy. PET imaging using radiolabeled buprenorphine offers a unique tool to noninvasively study the brain and tissue distribution in vivo and provide information regarding the clinical pharmacokinetics (PK) of this compound. We here report the first-in-human use of ¹¹C-buprenorphine obtained from a preliminary study in healthy subjects (EudraCT n.2017-001897-41). Materials and Methods: Buprenorphine was radiolabeled with carbon-11 at its O-methyl position to provide pharmaceutical grade ¹¹C-buprenorphine (9.7 GBq/μmol). Three healthy male volunteers (mean age 27 years) received an i.v. bolus of ¹¹C-buprenorphine (208.3±72.4 MBq). Injection was immediately followed by repeated whole-body PET-MR scans acquired on a GE Signa PET-MR system during 90 min. PET images were reconstructed in order to provide whole-body dynamic PET images (with frames ranging from 2 to 16 min) automatically co-registered to MRI. Volumes of interests were drawn using Pmod software to yield decay-corrected time-activity curves in selected organs. Maximal uptake of the radioactivity in organs is expressed as the percentage of injected dose per volume (%ID.cm^-3±standard deviation). Results: In early and intermediate frames, prominent distribution sites were the liver (0.0108±0.0040 %ID.cm^-3)and the gallbladder and bile ducts (0.1652±0.1873 %ID.cm^-3), consistent with the known hepato-biliary clearance of buprenorphine. ¹¹C-buprenorphine was then secreted in the duodenum and progressively moved to the jejunum (0.0185±0.0162 %ID. cm^-3) at the final frames. Accumulation of the radioactivity in the urinary bladder was relatively low (0.0353±0.0184 %ID. cm^-3 at final frame) suggesting a modest urinary excretion. The distribution of ¹¹C-buprenorphine to the brain cortex was obvious (0.0028±0.0002 %ID.cm^-3) and consistent with the distribution of μ-opioid-receptors. A so far unreported uptake of ¹¹C-buprenorphine was observed in the myocardium (0.0021±0.0002 %ID.cm^-3). None of the 3 subjects experienced any adverse effects. Conclusion: This pilot clinical PET-MR study revealed the tissue kinetics ¹¹C-buprenorphine for the first time in humans. Imaging data are consistent with the known PK features of buprenorphine. This study confirmed the favorable safety profile of the procedure and the adequate brain uptake for opioid receptors imaging. The binding of ¹¹C-buprenorphine in the myocardium is consistent with the local expression of opioid receptors and the opioidergic regulation of cardiovascular function and myocardial stress resistance. This may pave the way for the study of opioid-receptor systems in organs other than the central nervous system