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

Stina Syvänen; 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

doi:10.1016/j.nucmedbio.2013.05.008

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

Stina Syvänen, 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

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	764-75
Number of pages	12
Journal	Nuclear Medicine and Biology
Volume	40
Issue number	6
DOIs	https://doi.org/10.1016/j.nucmedbio.2013.05.008
Publication status	Published - Aug 2013

Keywords

Animals
Benzazepines
Carbon Radioisotopes
Chronic Disease
Disease Models, Animal
Epilepsy
Female
Gene Expression Regulation
Kinetics
Male
P-Glycoprotein
Phenobarbital
Positron-Emission Tomography
Quinidine
Quinolines
Radiochemistry
Rats
Rats, Sprague-Dawley
Recurrence
Treatment Outcome

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Syvänen, S., Russmann, V., Verbeek, J., Eriksson, J., Labots, M., Zellinger, C., Seeger, N., Schuit, R., Rongen, M., van Kooij, R., Windhorst, A. D., Lammertsma, A. A., de Lange, E. C., Voskuyl, R. A., Koepp, M., & Potschka, H. (2013). [11C]quinidine and [11C]laniquidar PET imaging in a chronic rodent epilepsy model: impact of epilepsy and drug-responsiveness. Nuclear Medicine and Biology, 40(6), 764-75. https://doi.org/10.1016/j.nucmedbio.2013.05.008

@article{1f154ddd6e7d4676b544b8e7ae25e7fd,

title = "[11C]quinidine and [11C]laniquidar PET imaging in a chronic rodent epilepsy model: impact of epilepsy and drug-responsiveness",

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.",

keywords = "Animals, Benzazepines, Carbon Radioisotopes, Chronic Disease, Disease Models, Animal, Epilepsy, Female, Gene Expression Regulation, Kinetics, Male, P-Glycoprotein, Phenobarbital, Positron-Emission Tomography, Quinidine, Quinolines, Radiochemistry, Rats, Rats, Sprague-Dawley, Recurrence, Treatment Outcome",

author = "Stina Syv{\"a}nen and Vera Russmann and Joost Verbeek and Jonas Eriksson and Maaike Labots and Christina Zellinger and Natalie Seeger and Robert Schuit and Marissa Rongen and {van Kooij}, Rolph and Windhorst, {Albert D} and Lammertsma, {Adriaan A} and {de Lange}, {Elizabeth C} and Voskuyl, {Rob A} and Matthias Koepp and Heidrun Potschka",

year = "2013",

month = aug,

doi = "10.1016/j.nucmedbio.2013.05.008",

language = "English",

volume = "40",

pages = "764--75",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

publisher = "Elsevier Inc.",

number = "6",

}

Syvänen, S, Russmann, V, Verbeek, J, Eriksson, J, Labots, M, Zellinger, C, Seeger, N, Schuit, R, Rongen, M, van Kooij, R, Windhorst, AD, Lammertsma, AA, de Lange, EC, Voskuyl, RA, Koepp, M & Potschka, H 2013, '[11C]quinidine and [11C]laniquidar PET imaging in a chronic rodent epilepsy model: impact of epilepsy and drug-responsiveness', Nuclear Medicine and Biology, vol. 40, no. 6, pp. 764-75. https://doi.org/10.1016/j.nucmedbio.2013.05.008

TY - JOUR

T1 - [11C]quinidine and [11C]laniquidar PET imaging in a chronic rodent epilepsy model

T2 - impact of epilepsy and drug-responsiveness

AU - Syvänen, Stina

AU - Russmann, Vera

AU - Verbeek, Joost

AU - Eriksson, Jonas

AU - Labots, Maaike

AU - Zellinger, Christina

AU - Seeger, Natalie

AU - Schuit, Robert

AU - Rongen, Marissa

AU - van Kooij, Rolph

AU - Windhorst, Albert D

AU - Lammertsma, Adriaan A

AU - de Lange, Elizabeth C

AU - Voskuyl, Rob A

AU - Koepp, Matthias

AU - Potschka, Heidrun

PY - 2013/8

Y1 - 2013/8

N2 - 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.

AB - 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.

KW - Animals

KW - Benzazepines

KW - Carbon Radioisotopes

KW - Chronic Disease

KW - Disease Models, Animal

KW - Epilepsy

KW - Female

KW - Gene Expression Regulation

KW - Kinetics

KW - Male

KW - P-Glycoprotein

KW - Phenobarbital

KW - Positron-Emission Tomography

KW - Quinidine

KW - Quinolines

KW - Radiochemistry

KW - Rats

KW - Rats, Sprague-Dawley

KW - Recurrence

KW - Treatment Outcome

U2 - 10.1016/j.nucmedbio.2013.05.008

DO - 10.1016/j.nucmedbio.2013.05.008

M3 - Article

C2 - 23827307

SN - 0969-8051

VL - 40

SP - 764

EP - 775

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

IS - 6

ER -

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

Abstract

Keywords

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