[¹¹C]quinidine and [¹¹C]laniquidar PET imaging in a chronic rodent epilepsy model: Impact of epilepsy and drug-responsiveness

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• 作者：Stina Syv?nen ; Vera Russmann ; Joost Verbeek ; Jonas Eriksson ; Maaike Labots ; Christina Zellinger ; Natalie Seeger ; Robert Schuit ; Marissa Rongen ; Rolph van Kooij ; Albert D. Windhorst ; Adriaan A. Lammertsma ; Elizabeth C. de Lange ; Rob A. Voskuyl ; Matthias Koepp ; Heidrun Potschka
• 关键词：Positron emission tomography ; [11C]quinidine ; [11C]laniquidar ; P-glycoprotein ; Epilepsy
• 刊名：Nuclear Medicine and Biology
• 出版年：2013
• 出版时间：August, 2013
• 年：2013
• 卷：40
• 期：6
• 页码：764-775
• 全文大小：1727 K

文摘

Introduction

To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [¹¹C]quinidine and [¹¹C]laniquidar.

Methods

Metabolism and brain kinetics of both [¹¹C]quinidine and [¹¹C]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into ¡°responders¡± and ¡°non-responders¡±. Additional experiments were performed following pre-treatment with the P-glycoprotein modulator tariquidar.

Results

[¹¹C]quinidine was metabolized rapidly, whereas [¹¹C]laniquidar was more stable. Brain concentrations of both radiotracers remained at relatively low levels at baseline conditions. Tariquidar pre-treatment resulted in significant increases of [¹¹C]quinidine and [¹¹C]laniquidar brain concentrations. In the epileptic subgroup ¡°non-responders¡±, brain uptake of [¹¹C]quinidine in selected brain regions reached higher levels than in electrode-implanted control rats. However, the relative response to tariquidar did not differ between groups with full blockade of P-glycoprotein by 15 mg/kg of tariquidar. For [¹¹C]laniquidar differences between epileptic and control animals were only evident at baseline conditions but not after tariquidar pretreatment.

Conclusions

We confirmed that both [¹¹C]quinidine and [¹¹C]laniquidar are P-glycoprotein substrates. At full P-gp blockade, tariquidar pre-treatment only demonstrated slight differences for [¹¹C]quinidine between drug-resistant and drug-sensitive animals.