Pharmacokinetic neuroimaging to study the dose-related brain kinetics and target engagement of buprenorphine in vivo

Abstract

A wide range of buprenorphine doses are used for either pain management or maintenance therapy in opioid addiction. The complex in vitro profile of buprenorphine, with affinity for µ-, δ-and κ-opioid receptors (OR), makes it difficult to predict its dose-related neuropharmacology in vivo. In rats, microPET imaging and pretreatment by OR antagonists were performed to assess the binding of radiolabeled buprenorphine (microdose 11 Cbuprenorphine) to OR subtypes in vivo (n=4 per condition). The µ-selective antagonist naloxonazine (10 mg/kg) and the non-selective OR-antagonist naloxone (1 mg/kg) blocked the binding of 11 C-buprenorphine while pretreatment by the δ-selective (naltrindole, 3 mg/kg) or the κ-selective antagonist (norbinaltorphimine, 10 mg/kg) did not. In four macaques, PET imaging and kinetic modeling enabled description of the regional brain kinetics of 11 Cbuprenorphine, co-injected with increasing doses of unlabeled buprenorphine. No saturation of the brain penetration of buprenorphine was observed for doses up to 0.11 mg/kg. Regional differences in buprenorphine-associated receptor occupancy were observed. Analgesic doses of buprenorphine (0.003 and 0.006 mg/kg) respectively occupied 20% and 49% of receptors in the thalamus while saturating the low but significant binding observed in cerebellum and occipital cortex. Occupancy >90% was achieved in most brain regions with plasma concentrations >7 µg/L. PET data obtained after co-injection of an analgesic dose of buprenorphine (0.003 mg/kg) predicted the binding potential of microdose 11 Cbuprenorphine. This strategy could be further combined with pharmacodynamic exploration or pharmacological MRI to investigate the neuropharmacokinetics and neuroreceptor correlate, at least at µ-OR, of the acute effects of buprenorphine in humans.

Amoxapine-Loaded Solid Lipid Nanoparticles with Superior Preclinical Pharmacokinetics for Better Brain Delivery: LC-MS/MS and GC-MS Analysis

“…Twelve rats were administered pure AMX in a 0.25% CMC suspension, and the remaining 12 were given an equivalent dose of AMX-SLNs (4 mg/kg). The animals were sacrificed at each pharmacokinetic point: 0.5, 1.5, 2.5, 3, and 6 h, with the brain samples collected in phosphate-buffered saline at pH 7.4 and stored at −20 °C until further analysis. , …”

“…The animals were sacrificed at each pharmacokinetic point: 0.5, 1.5, 2.5, 3, and 6 h, with the brain samples collected in phosphate-buffered saline at pH 7.4 and stored at −20 °C until further analysis. 59…”

Brain PET imaging using 11C-flumazenil and 11C-buprenorphine does not support the hypothesis of a mutual interaction between buprenorphine and benzodiazepines at the neuroreceptor level

“…11 C-Buprenorphine was synthesized in-house according to the method described by Lever et al 28 with minor modifications previously described. 26 Ready-to-inject 11 C-buprenorphine (1.8-3.5 GBq, decay-corrected radiochemical yield: 15%) was obtained with a radiochemical purity above 98% and a molar activity of 28 GBq/lmol at end of synthesis (EOS). 11 C-Flumazenil was synthesized based on a previously published method.…”

“…25 We recently validated 11 C-buprenorphine in rodents and non-human primates as a mean to specifically address the neuropharmacokinetics and binding of buprenorphine to its CNS targets in vivo. 26,27 Blocking experiments performed in rats suggested that the specific binding of 11 Cbuprenorphine in the brain predominantly corresponds to its interaction with MORs rather than with other OR subtypes. 26 In the present study, the hypothesis of a mutual DDI between buprenorphine and diazepam, a widely used benzodiazepine, was investigated at the neuroreceptor level using brain PET imaging, according to a cross-over design in non-human primates.…”

“…26,27 Blocking experiments performed in rats suggested that the specific binding of 11 Cbuprenorphine in the brain predominantly corresponds to its interaction with MORs rather than with other OR subtypes. 26 In the present study, the hypothesis of a mutual DDI between buprenorphine and diazepam, a widely used benzodiazepine, was investigated at the neuroreceptor level using brain PET imaging, according to a cross-over design in non-human primates. The impact of a pharmacological dose of buprenorphine on BzR was assessed using 11 C-flumazenil PET imaging.…”