title: Transport of selected PET radiotracers by human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2): an in vitro screening.
abstract: Radiolabeled compounds used for brain imaging with PET must readily cross the blood-brain barrier (BBB) to reach their target. Efflux transporters at the BBB-P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP)-could limit their uptake by the brain.
  
  
  METHODS
  We developed and validated an in vitro model using MDCKII cells transfected with human multidrug resistance (MDR1) or BCRP genes and assessed the transport of selected PET ligands by the concentration equilibrium technique. The tested compounds included befloxatone, (R,S)-CGP-12177, clorgyline, R-(-)-deprenyl, diprenorphine, DPA-714, fallypride, flumazenil, 2-fluoro-A-85380, LBT-999, loperamide, p-MPPF, PE2I, Pittsburgh compound B (PIB), (R,S)-PK11195, raclopride, R-(+)-verapamil, and WAY-100635. The assays were performed using the nonradioactive form of each compound (ultraviolet high-performance liquid chromatography analysis) and, when available, the (18)F-labeled analogs (γ-counting).
  
  
  RESULTS
  Befloxatone appeared to be transported solely by BCRP. Loperamide, verapamil, and diprenorphine were the only P-gp substrates. Other ligands were transported by neither P-gp nor BCRP.
  
  
  CONCLUSIONS
  The present method can readily be used to screen new-compound transport by P-gp or BCRP, even before any radiolabeling. Compounds that were previously thought to be transported by P-gp in rodents, such as p-MPPF, WAY-100635, and flumazenil, cannot be considered substrates of human P-gp. The impact of BCRP and P-gp at the BBB on the transport of befloxatone and diprenorphine in vivo remains to be evaluated with PET.
authors.affiliation: CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France. nicolas.tournier@cea.fr
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tournier
authors.forename: Héric
authors.initials: H
authors.lastname: Valette
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Peyronneau
authors.forename: Wadad
authors.initials: W
authors.lastname: Saba
authors.forename: Sébastien
authors.initials: S
authors.lastname: Goutal
authors.forename: Bertrand
authors.initials: B
authors.lastname: Kuhnast
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D001693:Biological Transport, Active / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D019275:Radiopharmaceuticals