A comparative small-animal PET evaluation of [ 11C]tariquidar, [ 11C]elacridar and (R)-[ 11C]verapamil for detection of P-glycoprotein-expressing murine breast cancer

Abstract

Purpose: One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphatebinding cassette transporter P-glycoprotein (Pgp). Pgp reduces intracellular concentrations of chemotherapeutic drugs. The aim of this study was to compare the suitability of the radiolabelled Pgp inhibitors [ 11C]tariquidar and [ 11C] elacridar with the Pgp substrate radiotracer (R)-[ 11C] verapamil for discriminating tumours expressing low and high levels of Pgp using small-animal PET imaging in a murine breast cancer model. Methods: Murine mammary carcinoma cells (EMT6) were continuously exposed to doxorubicin to generate a Pgpoverexpressing, doxorubicin-resistant cell line (EMT6AR1.0 cells). Both cell lines were subcutaneously injected into female athymic nude mice. One week after implantation, animals underwent PET scans with [11C]tariquidar (n=7), [ 11C] elacridar (n=6) and (R)-[ 11C]verapamil (n=7), before and after administration of unlabelled tariquidar (15 mg/kg). Pgp expression in tumour grafts was evaluated by Western blotting. Results: [ 11C] Tariquidar showed significantly higher retention in Pgp-overexpressing EMT6AR1.0 compared with EMT6 tumours: the mean±SD areas under the time-activity curves in scan 1 from time 0 to 60 min (AUC 0-60) were 38.8±2.2 min and 25.0±5.3 min (p=0.016, Wilcoxon matched pairs test). [ 11C]Elacridar and (R)-[ 11C]verapamil were not able to discriminate Pgp expression in tumour models. Following administration of unlabelled tariquidar, both EMT6Ar1.0 and EMT6 tumours showed increases in uptake of [ 11C]tariquidar, [ 11C]elacridar and (R)-[ 11C]verapamil. Conclusion: Among the tested radiotracers, [ 11C]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp. Therefore [ 11C]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours. © Springer-Verlag 2011.