Evaluation of (-)-[¹⁸ F]Flubatine-specific binding: Implications for reference region approaches

We aimed to characterize changes in binding of (-)-[¹⁸ F]Flubatine to α₄ β₂ *-nicotinic acetylcholine receptors (α₄ β₂ *-nAChRs) during a tobacco cigarette smoking challenge. Displacement of (-)-[¹⁸ F]Flubatine throughout the brain was quantified as change in (-)-[¹⁸ F]Flubatine distribution volume (V_T ), with particular emphasis on regions with low V_T . Three tobacco smokers were imaged with positron emission tomography (PET) during a 210 min bolus-plus-constant infusion of (-)-[¹⁸ F]Flubatine. A tobacco cigarette was smoked in the PET scanner ∼125 min after the start of (-)-[¹⁸ F]Flubatine injection. Equilibrium analysis was used to estimate V_T at baseline (90-120 min) and after cigarette challenge (180-210 min), at the time of greatest receptor occupancy by nicotine. Smoking reduced V_T by 21 ± 9% (average ±SD) in corpus callosum, 17 ± 9% in frontal cortex, 36 ± 11% in cerebellum, and 22 ± 10% in putamen. The finding of displaceable (-)-[¹⁸ F]Flubatine binding throughout the brain is an important consideration for reference region-based quantification approaches with this tracer. We observed displacement of (-)-[¹⁸ F]Flubatine binding to α₄ β₂ *-nicotinic acetylcholine receptors in corpus callosum by a tobacco cigarette challenge. We conclude that reference region approaches utilizing corpus callosum should first perform careful characterization of displaceable (-)-[¹⁸ F]Flubatine binding and nondisplaceable kinetics in this putative reference region.