title: In vivo evaluation of [123I]-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidine, an iodinated SPECT tracer for imaging the P-gp transporter.
abstract: BACKGROUND
  P-glycoprotein (P-gp) is an energy-dependent transporter that contributes to the efflux of a wide range of xenobiotics at the blood-brain barrier playing a role in drug-resistance or therapy failure. In this study, we evaluated [(123)I]-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidine ([(123)I]-FMIP) as a novel single photon emission computed tomography (SPECT) tracer for imaging P-gp at the brain in vivo.
  
  
  METHODS
  The tissue distribution and brain uptake as well as the metabolic profile of [(123)I]-FMIP in wild-type and mdr1a (-/-) mice after pretreatment with physiological saline or cyclosporin A (CsA) (50 mg/kg) was investigated. The influence of increasing doses CsA on brain uptake of [(123)I]-FMIP was explored. microSPECT images of mice brain after injection of 11.1 MBq [(123)I]-FMIP were obtained for different treatment strategies thereby using the Milabs U-SPECT-II.
  
  
  RESULTS
  Modulation of P-gp with CsA (50 mg/kg) as well as mdr1a gene depletion resulted in significant increase in cerebral uptake of [(123)I]-FMIP with only minor effect on blood activity. [(123)I]-FMIP is relative stable in vivo with >80% intact [(123)I]-FMIP in brain at 60 min p.i. in the different treatment regiments. A dose-dependent sigmoidal increase in brain uptake of [(123)I]-FMIP with increasing doses of CsA was observed. In vivo region of interest-based SPECT measurements correlated well with the observations of the biodistribution studies.
  
  
  CONCLUSIONS
  These findings indicate that [(123)I]-FMIP can be applied to assess the efficacy of newly developed P-gp modulators. It is also suggested that [(123)I]-FMIP is a promising SPECT tracer for imaging P-gp at the blood-brain barrier.
authors.affiliation: Laboratory for Radiopharmacy, Ghent University, 9000 Ghent, Belgium.
authors.forename: Sylvie
authors.initials: S
authors.lastname: De Bruyne
authors.forename: Leonie
authors.initials: L
authors.lastname: Wyffels
authors.forename: Terrence L
authors.initials: TL
authors.lastname: Boos
authors.forename: Steven
authors.initials: S
authors.lastname: Staelens
authors.forename: Steven
authors.initials: S
authors.lastname: Deleye
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Filip
authors.initials: F
authors.lastname: De Vos
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055786:Gene Knockout Techniques; D054879:Halogenation; D008297:Male; D051379:Mice; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D011849:Radioactive Tracers; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: C551482:(123I)-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001798:Blood Proteins; D010880:Piperidines; D011849:Radioactive Tracers; D016572:Cyclosporine