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

Abstract

We aimed to characterize changes in binding of (-)-[ F]Flubatine to α β *-nicotinic acetylcholine receptors (α β *-nAChRs) during a tobacco cigarette smoking challenge. Displacement of (-)-[ F]Flubatine throughout the brain was quantified as change in (-)-[ F]Flubatine distribution volume (V ), with particular emphasis on regions with low V . Three tobacco smokers were imaged with positron emission tomography (PET) during a 210 min bolus-plus-constant infusion of (-)-[ F]Flubatine. A tobacco cigarette was smoked in the PET scanner ∼125 min after the start of (-)-[ F]Flubatine injection. Equilibrium analysis was used to estimate V at baseline (90-120 min) and after cigarette challenge (180-210 min), at the time of greatest receptor occupancy by nicotine. Smoking reduced V 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 (-)-[ F]Flubatine binding throughout the brain is an important consideration for reference region-based quantification approaches with this tracer. We observed displacement of (-)-[ F]Flubatine binding to α β *-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 (-)-[ F]Flubatine binding and nondisplaceable kinetics in this putative reference region.

Exploring the Metabolism of (+)-[18F]Flubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study †

“…The presented results should be seen in the context of previous metabolism studies on both enantiomers of flubatine and [ 18 F]flubatine [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. In particular, the characterisation of phase I metabolites of (+)- 1 formed by HLM and MLM, as well as the assignment of corresponding incubated with radiometabolites in mouse, published by our group [ 4 ], are highly relevant for the discussion.…”

“…Their development starting from the alkaloid (−)-epibatidine [ 1 ], originally isolated from the poison dart frog Epipedobates anthonyi , has been widely reported [ 2 , 3 , 4 ]. In the framework of preclinical and clinical studies, the metabolism of (−)-[ 18 F] 1 in pigs [ 5 ], rhesus monkeys [ 6 , 7 , 8 ], and in humans [ 3 , 9 , 10 , 11 ] was examined mainly with the purpose of determination of the fraction of unchanged tracer over time to enable a metabolite correction of the PET data obtained. In human, (−)-[ 18 F] 1 showed a high metabolic stability [ 9 ].…”

(+)-[18F]Flubatine as a novel α4β2 nicotinic acetylcholine receptor PET ligand—results of the first-in-human brain imaging application in patients with β-amyloid PET-confirmed Alzheimer’s disease and healthy controls

“…In former studies, we used the corpus callosum as reference region [5,9,10,13]. However, this region is difficult to delineate and in a recently published study, (−)-[ 18 F]Flubatine was displaceable by 21 ± 9% in the corpus callosum in smokers [38], indicating that at least in smokers, a relevant specific binding is available in this region which is known as the region with the lowest amount of α4β2 nAChRs in humans. Thus, the corpus callosum does not seem to be very suitable as reference region for (+)-[ 18 F]Flubatine.…”

PET Imaging of Cholinergic Neurotransmission in Neurodegenerative Disorders

“…A 2-18 F-FA-85380 PET study was performed on smokers. Cigarette smoking to receptor satiety revealed that nicotinic receptor displacement in the corpus callosum was relatively low, at approximately 16% (49), and in a small (2)- 18 F-flubatine PET study (n 5 3) it was approximately 21% (50). This led to the assumption that a4b2 nAChR in the corpus callosum is negligible in nonsmokers but not in smokers.…”