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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Fig. 1: Impact of selected opioid antagonists on the regional binding of 11C-buprenorphine in vivo in rats.
Fig. 2: Parametric PET data of 11C-buprenorphine obtained from the co-injection study in macaques.
Fig. 3: Correlation between 11C-buprenorphine VT measured during the co-injection study and the corresponding microdose 11C-buprenorphine VT in macaques.
Fig. 4: Correlation of outcome parameters derived from the kinetic modeling of 11C-buprenorphine PET data obtained in macaques using microdose or therapeutic dose of buprenorphine.

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Acknowledgements

We gratefully thank Jérôme Cayla, Vincent Brulon, and Maud Goislard for technical assistance.

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SA, MB, DV, and NT contributed to conception of the work, data analysis, and manuscript writing. SA, SG, and AP contributed to data acquisition. CW, MT, and CL helped for PET and MR imaging analysis. FC performed radiochemistry.

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Correspondence to Nicolas Tournier.

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Auvity, S., Goutal, S., Caillé, F. et al. Pharmacokinetic neuroimaging to study the dose-related brain kinetics and target engagement of buprenorphine in vivo. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-00976-w

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