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

Nucl Med Biol. 2010 May;37(4):469-77. doi: 10.1016/j.nucmedbio.2009.10.006. Epub 2010 Apr 7.


Introduction: 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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / deficiency
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Biological Transport / drug effects
  • Blood Proteins / metabolism
  • Brain / diagnostic imaging
  • Brain / drug effects
  • Brain / metabolism
  • Cyclosporine / pharmacology
  • Dose-Response Relationship, Drug
  • Gene Knockout Techniques
  • Halogenation*
  • Male
  • Mice
  • Piperidines / chemistry
  • Piperidines / metabolism*
  • Piperidines / pharmacokinetics
  • Radioactive Tracers
  • Tomography, Emission-Computed, Single-Photon / methods*


  • (123I)-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidine
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Blood Proteins
  • Piperidines
  • Radioactive Tracers
  • Cyclosporine