Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• British journal of pharmacology, 2005-08, Vol.145 (8), p.1045-1051

Ort / Verlag

Oxford, UK: Blackwell Publishing Ltd

Erscheinungsjahr

2005

Link zum Volltext

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 1 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. 2 Cellular [11C]carvedilol accumulation in GLC4, GLC4/P‐gp, and GLC4/Adr cells increased three‐fold in the GLC4/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 [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. 4 Autoradiography studies of rat brains showed that [11C]carvedilol was homogeneously distributed over the brain and that pretreatment with CsA increased [11C]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 [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. British Journal of Pharmacology (2005) 145, 1045–1051. doi:10.1038/sj.bjp.0706283