title: [11C]quinidine and [11C]laniquidar PET imaging in a chronic rodent epilepsy model: impact of epilepsy and drug-responsiveness.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Stina
authors.initials: S
authors.lastname: Syvänen
authors.forename: Vera
authors.initials: V
authors.lastname: Russmann
authors.forename: Joost
authors.initials: J
authors.lastname: Verbeek
authors.forename: Jonas
authors.initials: J
authors.lastname: Eriksson
authors.forename: Maaike
authors.initials: M
authors.lastname: Labots
authors.forename: Christina
authors.initials: C
authors.lastname: Zellinger
authors.forename: Natalie
authors.initials: N
authors.lastname: Seeger
authors.forename: Robert
authors.initials: R
authors.lastname: Schuit
authors.forename: Marissa
authors.initials: M
authors.lastname: Rongen
authors.forename: Rolph
authors.initials: R
authors.lastname: van Kooij
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: de Lange
authors.forename: Rob A
authors.initials: RA
authors.lastname: Voskuyl
authors.forename: Matthias
authors.initials: M
authors.lastname: Koepp
authors.forename: Heidrun
authors.initials: H
authors.lastname: Potschka
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001552:Benzazepines / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D002250:Carbon Radioisotopes; D002908:Chronic Disease; D004195:Disease Models, Animal; D004827:Epilepsy / Q000097:blood / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D007700:Kinetics; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology / Q000627:therapeutic use; D049268:Positron-Emission Tomography / Q000379:methods*; D011802:Quinidine / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D011804:Quinolines / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011854:Radiochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001552:Benzazepines; D002250:Carbon Radioisotopes; D011804:Quinolines; D011802:Quinidine; C402343:tariquidar; C411474:laniquidar; D010634:Phenobarbital
keywords: Epilepsy; P-glycoprotein; Positron emission tomography; [(11)C]laniquidar; [(11)C]quinidine