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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 11C-buprenorphine) 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 11C-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 11C-buprenorphine, 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 11C-buprenorphine. 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.
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Submitted on : Monday, May 3, 2021 - 11:30:24 AM
Last modification on : Wednesday, June 2, 2021 - 4:52:05 PM

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Sylvain Auvity, Sébastien Goutal, Fabien Caillé, Dominique Vodovar, Alain Pruvost, et al.. Pharmacokinetic neuroimaging to study the dose-related brain kinetics and target engagement of buprenorphine in vivo. Neuropsychopharmacology, Nature Publishing Group, 2021, 46 (6), pp.1220-1228. ⟨10.1038/s41386-021-00976-w⟩. ⟨cea-03215261⟩

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