title: New positron emission tomography tracer [(11)C]carvedilol reveals P-glycoprotein modulation kinetics.
abstract: Imaging of P-glycoprotein (P-gp) function in the blood-brain barrier (BBB) may support development of strategies, which will improve drug delivery to the brain. [(11)C]verapamil has been developed as a positron emission tomography (PET) tracer, to image P-gp function in vivo. Ideally, for the purpose of brain imaging, tracers should have a log P between 0.9 and 2.5. The beta-receptor antagonist carvedilol is a P-gp substrate with a log P=2.0, and can be labeled with [(11)C]. The aim of this study was to determine whether the P-gp substrate [(11)C]carvedilol can be used as a PET tracer for visualisation and quantification of the P-gp function in the BBB. Cellular [(11)C]carvedilol accumulation in GLC(4), GLC(4)/P-gp, and GLC(4)/Adr cells increased three-fold in the GLC(4)/P-gp cells after pretreatment with cyclosporin A (CsA) whereas no effect of MK571 could be determined in the GLC(4)/Adr cells. Ex vivo [(11)C]carvedilol biodistribution studies showed that [(11)C]carvedilol uptake in the brain was increased by CsA. [(11)C]carvedilol uptake in other organs was not affected by CsA. Autoradiography studies of rat brains showed that [(11)C]carvedilol was homogeneously distributed over the brain and that pretreatment with CsA increased [(11)C]carvedilol uptake. In vivo PET experiments were performed with and without P-gp modulation by CsA. P-gp mediated transport was quantified by Logan analysis of the PET data, calculating the distribution volume (DV) of [(11)C]carvedilol in the brain. Logan analysis resulted in excellent fits, revealing that [(11)C]carvedilol is not trapped in the brain. Brain DV of [(11)C]carvedilol showed a dose-dependent increase of maximal three-fold after CsA pretreatment. Above 15 mg kg(-1), no change in DV was found. Compared to [(11)C]verapamil less CsA was needed to reach maximal DV, suggesting that [(11)C]carvedilol kinetics is a more sensitive tool to in vivo measure P-gp function.
authors.affiliation: PET-Center, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Bart
authors.forename: Eli C F
authors.initials: EC
authors.lastname: Dijkers
authors.forename: Theodora D
authors.initials: TD
authors.lastname: Wegman
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
authors.forename: Harry J M
authors.initials: HJ
authors.lastname: Groen
authors.forename: Willem
authors.initials: W
authors.lastname: Vaalburg
authors.forename: Antoon T M
authors.initials: AT
authors.lastname: Willemsen
authors.forename: N Harry
authors.initials: NH
authors.lastname: Hendrikse
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002227:Carbazoles / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D000077261:Carvedilol; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011412:Propanolamines / Q000493:pharmacokinetics*; D051381:Rats; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002227:Carbazoles; D002250:Carbon Radioisotopes; D011412:Propanolamines; D000077261:Carvedilol