title: Evaluation of P-glycoprotein (abcb1a/b) modulation of [(18)F]fallypride in MicroPET imaging studies.
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'.
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg-University, Fritz-Strassmann-Weg 2, D-55128 Mainz, Germany. Electronic address: piel@uni-mainz.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Piel
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. Electronic address: ulrich.schmitt@unimedizin-mainz.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schmitt
authors.affiliation: Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. Electronic address: Nicole.Bausbacher@unimedizin-mainz.de.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bausbacher
authors.affiliation: Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. Electronic address: buchholz@nuklear.klinik.uni-mainz.de.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Buchholz
authors.affiliation: Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany. Electronic address: ggruender@ukaachen.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gründer
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. Electronic address: hiemke@uni-mainz.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hiemke
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg-University, Fritz-Strassmann-Weg 2, D-55128 Mainz, Germany. Electronic address: frank.roesch@uni-mainz.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Rösch
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D051379:Mice; D018345:Mice, Knockout; D049268:Positron-Emission Tomography / Q000295:instrumentation / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001549:Benzamides; D004791:Enzyme Inhibitors; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D016572:Cyclosporine; C095122:multidrug resistance protein 3; C507084:Abcb1b protein, mouse; C574003:fallypride
keywords: Cyclosporine A; Dopamine D(2)/D(3) receptors; P-Glycoprotein; Positron emission tomography; [(18)F]fallypride