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

Purpose One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphate-binding 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 [C-11]tariquidar and [C-11]elacridar with the Pgp substrate radiotracer (R)-[C-11]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 Pgp-overexpressing, 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 [C-11]tariquidar (n = 7), [C-11]elacridar (n = 6) and (R)-[C-11]verapamil (n = 7), before and after administration of unlabelled tariquidar (15 mg/kg). Pgp expression in tumour grafts was evaluated by Western blotting. Results [C-11]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). [C-11]Elacridar and (R)-[C-11]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 [C-11]tariquidar, [C-11]elacridar and (R)-[C-11]verapamil. Conclusion Among the tested radiotracers, [C-11]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp. Therefore [C-11]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours.