title: 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: OBJECTIVE
  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 [(11)C]tariquidar and [(11)C]elacridar with the Pgp substrate radiotracer (R)-[(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 [(11)C]tariquidar (n = 7), [(11)C]elacridar (n = 6) and (R)-[(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
  [(11)C]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). [(11)C]Elacridar and (R)-[(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 [(11)C]tariquidar, [(11)C]elacridar and (R)-[(11)C]verapamil.
  
  
  CONCLUSIONS
  Among the tested radiotracers, [(11)C]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp. Therefore [(11)C]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours.
authors: Health & Environment Department, Molecular Medicine, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors: Thomas
authors: T
authors: Wanek
authors: Claudia
authors: C
authors: Kuntner
authors: Jens P
authors: JP
authors: Bankstahl
authors: Marion
authors: M
authors: Bankstahl
authors: Johann
authors: J
authors: Stanek
authors: Michael
authors: M
authors: Sauberer
authors: Severin
authors: S
authors: Mairinger
authors: Sabine
authors: S
authors: Strommer
authors: Volker
authors: V
authors: Wacheck
authors: Wolfgang
authors: W
authors: Löscher
authors: Thomas
authors: T
authors: Erker
authors: Markus
authors: M
authors: Müller
authors: Oliver
authors: O
authors: Langer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000166:Acridines; D000818:Animals; D001692:Biological Transport; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D002250:Carbon Radioisotopes; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005240:Feasibility Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D010641:Phenotype; D049268:Positron-Emission Tomography / Q000379:methods*; D011804:Quinolines; D044005:Tetrahydroisoquinolines; D014700:Verapamil
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D002250:Carbon Radioisotopes; D011804:Quinolines; D044005:Tetrahydroisoquinolines; D004317:Doxorubicin; D014700:Verapamil; C402343:tariquidar; C083501:Elacridar