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

Joost Bart, Eli C.F. Dijkers, Theodora D. Wegman, Elisabeth G.E. De Vries, Winette T.A. Van Der Graaf, Harry J.M. Groen, Willem Vaalburg, Antoon T.M. Willemsen, N. Harry Hendrikse

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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.

Original languageEnglish
Pages (from-to)1045-1051
Number of pages7
JournalBritish journal of pharmacology
Issue number8
Publication statusPublished - 1 Dec 2005


  • Blood-brain barrier
  • Chemotherapy
  • Cyclosporin A
  • Distribution volume
  • Modelling
  • Multidrug resistance
  • P-glycoprotein
  • Pharmacokinetic
  • Positron emission tomography
  • Radiopharmacology
  • [ C]carvedilol

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