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Neuropharmacology. 2014 Sep;84:152-8. doi: 10.1016/j.neuropharm.2013.04.062. Epub 2013 Aug 29.

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

Author information

1
Institute of Nuclear Chemistry, Johannes Gutenberg-University, Fritz-Strassmann-Weg 2, D-55128 Mainz, Germany. Electronic address: piel@uni-mainz.de.
2
Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. Electronic address: ulrich.schmitt@unimedizin-mainz.de.
3
Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. Electronic address: Nicole.Bausbacher@unimedizin-mainz.de.
4
Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. Electronic address: buchholz@nuklear.klinik.uni-mainz.de.
5
Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany. Electronic address: ggruender@ukaachen.de.
6
Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. Electronic address: hiemke@uni-mainz.de.
7
Institute of Nuclear Chemistry, Johannes Gutenberg-University, Fritz-Strassmann-Weg 2, D-55128 Mainz, Germany. Electronic address: frank.roesch@uni-mainz.de.

Abstract

[(18)F]Fallypride ([(18)F]FP) is an important and routinely used D2/D3 antagonist for quantitative imaging of dopaminergic neurotransmission in vivo. Recently it was shown that the brain uptake of the structurally related [(11)C]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 [(18)F]FP is influenced by P-gp. For examination of this possible modulation microPET studies were performed in a rat and a mouse model. Hence, [(18)F]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 (abcb1a/1b (-/-)) and CsA-treated mice. In CsA-treated Sprague Dawley rats [(18)F]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 [(18)F]FP markedly, we conclude that [(18)F]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 [(18)F]FP for assessment of D2/3 receptor occupancy by antipsychotic drugs. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'.

KEYWORDS:

Cyclosporine A; Dopamine D(2)/D(3) receptors; P-Glycoprotein; Positron emission tomography; [(18)F]fallypride

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