New positron emission tomography tracer [11C]carvedilol reveals P-glycoprotein modulation kinetics

1 Imaging of P-glycoprotein (P-gp) function in the blood-brain barrier (BBB) may support evelopment of strategies, which will improve drug delivery to the brain. [C-11] 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 [C-11]. The aim of this study was to determine whether the P-gp substrate [C-11] carvedilol can be used as a PET tracer for visualisation and quantification of the P-gp function in the BBB. 2 Cellular [C-11] 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 GLC4/Adr cells. 3 Ex vivo [C-11] carvedilol biodistribution studies showed that [C-11] carvedilol uptake in the brain was increased by CsA. [C-11] carvedilol uptake in other organs was not affected by CsA. 4 Autoradiography studies of rat brains showed that [ C-11] carvedilol was homogeneously distributed over the brain and that pretreatment with CsA increased [C-11] carvedilol uptake. 5 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 [C-11] carvedilol in the brain. Logan analysis resulted in excellent fits, revealing that [C-11] carvedilol is not trapped in the brain. Brain DV of [C-11] 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 [C-11] verapamil less CsA was needed to reach maximal DV, suggesting that [C-11] carvedilol kinetics is a more sensitive tool to in vivo measure P-gp function.