title: Cyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies.
abstract: OBJECTIVE
  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]ethylpiperazine ([(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.
  
  
  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.
authors.affiliation: Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095-1735, USA.
authors.forename: Goran
authors.initials: G
authors.lastname: Laćan
authors.forename: Alain
authors.initials: A
authors.lastname: Plenevaux
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rubins
authors.forename: Baldwin M
authors.initials: BM
authors.lastname: Way
authors.forename: Caroline
authors.initials: C
authors.lastname: Defraiteur
authors.forename: Christian
authors.initials: C
authors.lastname: Lemaire
authors.forename: Joel
authors.initials: J
authors.lastname: Aerts
authors.forename: André
authors.initials: A
authors.lastname: Luxen
authors.forename: Simon R
authors.initials: SR
authors.lastname: Cherry
authors.forename: William P
authors.initials: WP
authors.lastname: Melega
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000493:pharmacokinetics*; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010879:Piperazines; D011725:Pyridines; D044282:Receptor, Serotonin, 5-HT1A; D016572:Cyclosporine; C416325:4-(2'-methoxyphenyl)-1-(2'-(N-2'-pyridinyl)-p-(18F)fluorobenzamido )ethylpiperazine