Evaluation of P-glycoprotein (abcb1a/b) modulation of [18F]fallypride in MicroPET imaging studies

[F-18]Fallypride ([F-18]FP) is an important and routinely used D-2/D-3 antagonist for quantitative imaging of dopaminergic neurotransrnission in vivo. Recently it was shown that the brain uptake of the structurally related [C-11]raclopride is modulated by P-glycoprotein (P-gp), an important efflux transporter at the blood brain barrier. The purpose of this study was to determine whether the brain uptake of [F-18]FP is influenced by P-gp. For examination of this possible modulation microPET studies were performed in a rat and a mouse model. Hence, [F-18]FP was applied to Sprague Dawley rats, half of them being treated with the P-gp inhibitor cyclosporine A (CsA). In a second experimental series the tracer was applied to three different groups of FVB/N mice: wild type, P-gp double knockout (abcbl a/1 b (-/-)) and CsA-treated mice. In CsA-treated Sprague Dawley rats [F-18]FP showed an elevated standard uptake value in the striatum compared to the control animals. In FVB/N mice a similar effect was observed, showing an increasing uptake from wild type to CsA-treated and double knockout mice. Since genetically or pharmacologically induced reduction of P-gp activity increased the uptake of [F-18]FP markedly, we conclude that [F-18]FP is indeed a substrate of P-gp and that the efflux pump modulates its brain uptake. This effect if true for humans may have particular impact on clinical studies using [F-18]FP for assessment of D-2/3 receptor occupancy by antipsychotic drugs. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. (C) 2013 Elsevier Ltd. All rights reserved.