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

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. [ ¹¹C]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 β-receptor antagonist carvedilol is a P-gp substrate with a log P = 2.0, and can be labeled with [ ¹¹C]. The aim of this study was to determine whether the P-gp substrate [ ¹¹C]carvedilol can be used as a PET tracer for visualisation and quantification of the P-gp function in the BBB. Cellular [ ¹¹C]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 [ ¹¹C]carvedilol biodistribution studies showed that [ ¹¹C]carvedilol uptake in the brain was increased by CsA. [ ¹¹C]carvedilol uptake in other organs was not affected by CsA. Autoradiography studies of rat brains showed that [ ¹¹C]carvedilol was homogeneously distributed over the brain and that pretreatment with CsA increased [ ¹¹C]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 [ ¹¹C]carvedilol in the brain. Logan analysis resulted in excellent fits, revealing that [ ¹¹C]carvedilol is not trapped in the brain. Brain DV of [ ¹¹C]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 [ ¹¹C]verapamil less CsA was needed to reach maximal DV, suggesting that [ ¹¹C] carvedilol kinetics is a more sensitive tool to in vivo measure P-gp function.