European Journal of Nuclear Medicine and Molecular Imaging, 2012, Vol.39(1), pp.149-159
Byline: Thomas Wanek (1), Claudia Kuntner (1), Jens P. Bankstahl (2), Marion Bankstahl (2), Johann Stanek (1,3), Michael Sauberer (1), Severin Mairinger (1,3,4), Sabine Strommer (3), Volker Wacheck (3), Wolfgang Loscher (2), Thomas Erker (4), Markus Muller (3), Oliver Langer (1,3) Keywords: Multidrug resistance; P-glycoprotein; Positron emission tomography; [[.sup.11]C]Tariquidar; [[.sup.11]C]Elacridar; (R)[-[.sup.11]C]Verapamil Abstract: 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 [[.sup.11]C]tariquidar and [[.sup.11]C]elacridar with the Pgp substrate radiotracer (R)[-[.sup.11]C]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 [[.sup.11]C]tariquidar (n=7), [[.sup.11]C]elacridar (n=6) and (R)[-[.sup.11]C]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.sub.0--60) were 38.8+-2.2 min and 25.0+-5.3 min (p=0.016, Wilcoxon matched pairs test). [[.sup.11]C]Elacridar and (R)[-[.sup.11]C]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 [[.sup.11]C]tariquidar, [[.sup.11]C]elacridar and (R)[-[.sup.11]C]verapamil. Conclusion Among the tested radiotracers, [[.sup.11]C]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp. Therefore [[.sup.11]C]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours. Author Affiliation: (1) Health & Environment Department, Molecular Medicine, AIT Austrian Institute of Technology GmbH, 2444, Seibersdorf, Austria (2) Department of Pharmacology, Toxicology & Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany (3) Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (4) Department of Medicinal Chemistry, University of Vienna, Vienna, Austria Article History: Registration Date: 09/09/2011 Received Date: 24/05/2011 Accepted Date: 09/09/2011 Online Date: 08/10/2011 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00259-011-1941-7) contains supplementary material, which is available to authorized users.
Multidrug resistance ; P-glycoprotein ; Positron emission tomography ; [C]Tariquidar ; [C]Elacridar ; ()-[C]Verapamil
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