Cyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies

  • Goran Laćan
  • Alain Plenevaux
  • Daniel J. Rubins
  • Baldwin M. Way
  • Caroline Defraiteur
  • Christian Lemaire
  • Joel Aerts
  • André Luxen
  • Simon R. Cherry
  • William P. MelegaEmail author
Original Article



Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F]fluorobenzamido]ethylpiperazine ([18F]MPPF) for binding to hydroxytryptamine1A (5-HT1A) 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 [18F]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.


MicroPET studies showed that hippocampus uptake of [18F]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 [18F]MPPF plasma concentration. P-gp content in cerebellum was twofold higher than in hippocampus or frontal cortex.


These studies confirm and extend prior ex vivo results (J. Passchier, et al., Eur J Pharmacol, 2000) that showed [18F]MPPF as a substrate for P-gp. Our microPET results showed that P-gp modulation of [18F]MPPF binding to 5-HT1A 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-HT1A receptor density when based on tracer uptake sensitive to P-gp modulation.


5-HT1A receptor positron emission tomography hippocampus pharmacokinetics blood brain barrier 



The authors thank the entire radiochemistry group (Dr. Nagichettiar Satyamurthy, Director), and Judy Edwards and Dr. Waldemar Ladno of the microPET imaging section (Dr. Arion Chatziioannou, Director) at UCLA.

We also thank Professor Wolfgang Lőscher (University of Veterinary Medicine, Hannover, Germany) and Dr. Erwin van Vliet (Center for Neurosciences, University of Amsterdam, The Netherlands) for their helpful comments regarding P-gp quantification in the rat brain.

This research was supported in part by a contract from the U.S. Department of Energy (DoE) DE-FC03-87ER60615, FRS-FNRS Belgium (grant 3.4557.03F) and the Liege University (“Fonds Spéciaux” projects C-03/72 and C-02/23). A. Plenevaux is a research associate from FRS-FNRS Belgium.

Declaration of compliance for experiments performed

All procedures were performed in accordance with established practices as described in the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996). All protocols were reviewed and approved by the UCLA Chancellor’s Animal Research Committee and Liege University Animal Ethics Committee.

Conflict of Interest statement

None of the authors has a conflict of interest related to the subject of this report.


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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Goran Laćan
    • 1
  • Alain Plenevaux
    • 3
  • Daniel J. Rubins
    • 4
  • Baldwin M. Way
    • 1
  • Caroline Defraiteur
    • 3
  • Christian Lemaire
    • 3
  • Joel Aerts
    • 3
  • André Luxen
    • 3
  • Simon R. Cherry
    • 2
  • William P. Melega
    • 1
    • 5
    Email author
  1. 1.Department of Molecular and Medical PharmacologyUCLALos AngelesUSA
  2. 2.Department of Biomedical EngineeringUC Davis; Cyclotron Research CenterDavisUSA
  3. 3.Cyclotron Research CenterLiège UniversityLiègeBelgium
  4. 4.Merck Research LaboratoriesMerck & Co., IncWest PointUSA
  5. 5.Department of Molecular and Medical Pharmacology23-120 CHS, UCLA School of MedicineLos AngelesUSA

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