UNLABELLED: P-glycoprotein (P-gp) is an ATP-dependent efflux pump protecting the body against xenobiotics. A P-gp substrate (7) and an inhibitor (6) were labeled with (11)C, resulting in potential tracers of P-gp function and expression. METHODS: 6 and 7 were labeled using (11)CH(3)I. (11)C-verapamil was prepared as published previously, using (11)C-methyl triflate. MicroPET scans (with arterial sampling) and biodistribution studies were performed in rats pretreated with saline, cyclosporin A (CsA, 50 mg/kg), or cold 6 (15 mg/kg). RESULTS: The radiochemical yields of (11)C-6 and (11)C-7 were approximately 30% with a total synthesis time of 45 min. Cerebral distribution volumes (DV) of (11)C-6 (2.35 +/- 0.11) and (11)C-7 (1.86 +/- 0.15) in saline-treated rats were higher than of (11)C-verapamil (0.64 +/- 0.12). DVs of (11)C-7 and (11)C-verapamil were significantly increased by CsA (to 5.26 +/- 0.14 and 5.85 +/- 0.32, respectively). The DV of (11)C-6 was reduced by cold 6 (to 1.65 +/- 0.03). Its uptake was also reduced (up to 67%) in several peripheral organs that express P-gp. CONCLUSIONS: (11)C-7 is a novel tracer of P-gp function with higher baseline uptake than (11)C-verapamil. Upregulation of P-gp function in response to treatment (which is hard to detect with (11)C-verapamil) may be detectable using (11)C-7 and PET. Because (11)C-6 shows specific binding in target organs, this compound is the first PET tracer allowing measurement of P-gp expression.
UNLABELLED: P-glycoprotein (P-gp) is an ATP-dependent efflux pump protecting the body against xenobiotics. A P-gp substrate (7) and an inhibitor (6) were labeled with (11)C, resulting in potential tracers of P-gp function and expression. METHODS: 6 and 7 were labeled using (11)CH(3)I. (11)C-verapamil was prepared as published previously, using (11)C-methyl triflate. MicroPET scans (with arterial sampling) and biodistribution studies were performed in rats pretreated with saline, cyclosporin A (CsA, 50 mg/kg), or cold 6 (15 mg/kg). RESULTS: The radiochemical yields of (11)C-6 and (11)C-7 were approximately 30% with a total synthesis time of 45 min. Cerebral distribution volumes (DV) of (11)C-6 (2.35 +/- 0.11) and (11)C-7 (1.86 +/- 0.15) in saline-treated rats were higher than of (11)C-verapamil (0.64 +/- 0.12). DVs of (11)C-7 and (11)C-verapamil were significantly increased by CsA (to 5.26 +/- 0.14 and 5.85 +/- 0.32, respectively). The DV of (11)C-6 was reduced by cold 6 (to 1.65 +/- 0.03). Its uptake was also reduced (up to 67%) in several peripheral organs that express P-gp. CONCLUSIONS: (11)C-7 is a novel tracer of P-gp function with higher baseline uptake than (11)C-verapamil. Upregulation of P-gp function in response to treatment (which is hard to detect with (11)C-verapamil) may be detectable using (11)C-7 and PET. Because (11)C-6 shows specific binding in target organs, this compound is the first PET tracer allowing measurement of P-gp expression.
Authors: Florian Bauer; Claudia Kuntner; Jens P Bankstahl; Thomas Wanek; Marion Bankstahl; Johann Stanek; Severin Mairinger; Bernd Dörner; Wolfgang Löscher; Markus Müller; Thomas Erker; Oliver Langer Journal: Bioorg Med Chem Date: 2010-06-22 Impact factor: 3.641
Authors: Bernd Dörner; Claudia Kuntner; Jens P Bankstahl; Thomas Wanek; Marion Bankstahl; Johann Stanek; Julia Müllauer; Florian Bauer; Severin Mairinger; Wolfgang Löscher; Donald W Miller; Peter Chiba; Markus Müller; Thomas Erker; Oliver Langer Journal: Bioorg Med Chem Date: 2011-02-26 Impact factor: 3.641
Authors: Bernd Dörner; Claudia Kuntner; Jens P Bankstahl; Marion Bankstahl; Johann Stanek; Thomas Wanek; Gloria Stundner; Severin Mairinger; Wolfgang Löscher; Markus Müller; Oliver Langer; Thomas Erker Journal: J Med Chem Date: 2009-10-08 Impact factor: 7.446
Authors: Severin Mairinger; Thomas Wanek; Claudia Kuntner; Yaprak Doenmez; Sabine Strommer; Johann Stanek; Elena Capparelli; Peter Chiba; Markus Müller; Nicola A Colabufo; Oliver Langer Journal: Nucl Med Biol Date: 2012-09-13 Impact factor: 2.408
Authors: Pavitra Kannan; Victor W Pike; Christer Halldin; Oliver Langer; Michael M Gottesman; Robert B Innis; Matthew D Hall Journal: Mol Pharm Date: 2013-05-02 Impact factor: 4.939