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

• Published in: Nuclear medicine and biology 2013-08, Vol.40 (6), p.764-775
• Main Authors: Syvänen, Stina, Russmann, Vera, Verbeek, Joost, Eriksson, Jonas, Labots, Maaike, Zellinger, Christina, Seeger, Natalie, Schuit, Robert, Rongen, Marissa, van Kooij, Rolph, Windhorst, Albert D, Lammertsma, Adriaan A, de Lange, Elizabeth C, Voskuyl, Rob A, Koepp, Matthias, Potschka, Heidrun
• Format: Article
• Language: English
• Subjects: [11C]laniquidar; [11C]quinidine; [C-11]laniquidar; [C-11]quinidine; Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Benzazepines - blood; Benzazepines - chemistry; Benzazepines - metabolism; Carbon Radioisotopes; Chronic Disease; Disease Models, Animal; Epilepsy; Epilepsy - blood; Epilepsy - diagnostic imaging; Epilepsy - drug therapy; Epilepsy - metabolism; Female; Gene Expression Regulation; Kinetics; Male; P-glycoprotein; Phenobarbital - pharmacology; Phenobarbital - therapeutic use; Positron emission tomography; Positron-Emission Tomography - methods; Quinidine - blood; Quinidine - chemistry; Quinidine - metabolism; Quinolines - blood; Quinolines - chemistry; Quinolines - metabolism; Quinolines - pharmacology; Quinolines - therapeutic use; Radiochemistry; Radiology; Rats; Rats, Sprague-Dawley; Recurrence; Treatment Outcome
• ISSN: 0969-8051; 1872-9614; 1872-9614
• DOI: 10.1016/j.nucmedbio.2013.05.008

Abstract 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 [11 C]quinidine and [11 C]laniquidar. Methods Metabolism and brain kinetics of both [11 C]quinidine and [11 C]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 [11 C]quinidine was metabolized rapidly, whereas [11 C]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 [11 C]quinidine and [11 C]laniquidar brain concentrations. In the epileptic subgroup “non-responders”, brain uptake of [11 C]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 [11 C]laniquidar differences between epileptic and control animals were only evident at baseline conditions but not after tariquidar pretreatment. Conclusions We confirmed that both [11 C]quinidine and [11 C]laniquidar are P-glycoprotein substrates. At full P-gp blockade, tariquidar pre-treatment only demonstrated slight differences for [11 C]quinidine between drug-resistant and drug-sensitive animals.