Reference : Cyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and...
Scientific journals : Article
Human health sciences : Radiology, nuclear medicine & imaging
Cyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies.
Lacan, Goran [> > > >]
Plenevaux, Alain mailto [Université de Liège - ULiège > > Centre de recherches du cyclotron >]
Rubins, Daniel J. [> > > >]
Way, Baldwin M. [> > > >]
Defraiteur, Caroline [> > > >]
Lemaire, Christian mailto [Université de Liège - ULiège > > Centre de recherches du cyclotron >]
Aerts, Joël mailto [Université de Liège - ULiège > > Centre de recherches du cyclotron >]
Luxen, André mailto [Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique de synthèse - Centre de recherches du cyclotron >]
Cherry, Simon R. [> > > >]
Melega, William P. [University of California, Los Angeles - UCLA > Molecular and medical pharmacology > > >]
European Journal of Nuclear Medicine and Molecular Imaging
Springer Science & Business Media B.V.
Yes (verified by ORBi)
New York
[en] 5-HT1A receptor ; positron emission tomography ; hippocampus ; pharmacokinetics ; blood brain barrier
[en] PURPOSE: Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethylpiperaz ine ([(18)F]MPPF) for binding to hydroxytryptamine(1A) (5-HT(1A)) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies. MATERIALS AND METHODS: Each Sprague-Dawley rat (n = 4) received a baseline [(18)F]MPPF microPET scan followed by second scan 2-3 weeks later that included cyclosporine pretreatment (50 mg/kg, i.p.). Maximum a posteriori reconstructed images and volumetric ROIs were used to generate dynamic radioactivity concentration measurements for hippocampus, striatum, and cerebellum, with simplified reference tissue method (SRTM) analysis. Western blots were used to semiquantify P-gp regional distribution in brain. RESULTS: MicroPET studies showed that hippocampus uptake of [(18)F]MPPF was increased after cyclosporine; ex vivo studies showed similar increases in hippocampus and frontal cortex at 30 min, and for heart and kidney at 2.5 and 5 min, without concomitant increases in [(18)F]MPPF plasma concentration. P-gp content in cerebellum was twofold higher than in hippocampus or frontal cortex. CONCLUSIONS: These studies confirm and extend prior ex vivo results (J. Passchier, et al., Eur J Pharmacol, 2000) that showed [(18)F]MPPF as a substrate for P-gp. Our microPET results showed that P-gp modulation of [(18)F]MPPF binding to 5-HT(1A) receptors can be imaged in rat hippocampus. The heterogeneous brain distribution of P-gp appeared to invalidate the use of cerebellum as a nonspecific reference region for SRTM modeling. Regional quantitation of P-gp may be necessary for accurate PET assessment of 5-HT(1A) receptor density when based on tracer uptake sensitive to P-gp modulation.
Centre de Recherches du Cyclotron - CRC ; Molecular and medical pharmacology UCLA
Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS ; University California Los Angeles UCLA
Researchers ; Professionals ; Students

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