In vivo evaluation of [I-123]-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidi ne, an iodinated SPECT tracer for imaging the P-gp transporter

作者：De Bruyne Sylvie; Wyffels Leonie; Boos Terrence L; Staelens Steven; Deleye Steven; Rice Kenner C; De Vos Filip^*

来源：Nuclear Medicine and Biology, 2010, 37(4): 469-477.

DOI：10.1016/j.nucmedbio.2009.10.006

• P-gp
• SPECT
• Brain
• [I-123]-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidi ne

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 [I-123]-4-(2-(bis(4-fluorophenyl)methoxy) ethyl)-1-(4-iodobenzyl)piperidine ([I-123]-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 [I-123]-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 [I-123]-FMIP was explored. mu SPECT images of mice brain after injection of 11.1 MBq [I-123]-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 [I-123]-FMIP with only minor effect on blood activity. [I-123]-FMIP is relative stable in vivo with >80% intact [I-123]-FMIP in brain at 60 min p.i. in the different treatment regiments. A dose-dependent sigmoidal increase in brain uptake of [I-123]-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 [I-123]-FMIP can be applied to assess the efficacy of newly developed P-gp modulators. It is also suggested that [I-123]-FMIP is a promising SPECT tracer for imaging P-gp at the blood-brain barrier.

• 出版日期2010-5