title: Imaging P-glycoprotein function in rats using [(11)C]-N-desmethyl-loperamide.
abstract: OBJECTIVE
  One mechanism that may be responsible for drug resistance in epilepsy is the upregulation of P-glycoprotein (P-gp), a drug efflux pump, at the epileptogenic focus. In this study, we sought to evaluate the potential of a recently developed P-gp PET radiotracer, [(11)C]N-desmethyl-loperamide ([(11)C]dLop), for measuring P-gp function in the rat brain.
  
  
  METHODS
  The precursor to [(11)C]dLop was synthesized in two steps from commercially available starting materials and subsequently radiolabeled in one step using [(11)C]methyl iodide. [(11)C]dLop was then administered to two groups of rats, controls (n = 4) and those treated with a P-gp inhibitor (n = 8). Cyclosporin A (CsA, 50 mg/kg, n = 3) and tariquidar (TQ, 20 mg/kg, n = 5) were both used as P-gp inhibitors. MicroPET brain scans were performed for 120 min with arterial blood sampling. A one-tissue compartment model was used to estimate the distribution volume of radiotracer as the outcome measure of P-gp function.
  
  
  RESULTS
  Plasma levels of parent [(11)C]dLop decreased rapidly to <0.1 mean standardized uptake value (SUV) at 60 min. In controls, brain uptake of [(11)C]dLop was very low (<0.1 mean SUV). In contrast, the mean SUVs were significantly higher in rats treated with CsA (0.51) or TQ (0.22). Estimation of distribution volumes was stable by 70 min. Estimated distribution volumes were significantly larger after P-gp inhibition (CsA = 7.3, TQ = 4.7) compared to controls (no inhibitor = 2.1).
  
  
  CONCLUSIONS
  The rat brain demonstrates significantly increased uptake of [(11)C]dLop after P-gp inhibition. [(11)C]dLop is a substrate of P-gp, and will serve as a promising radiotracer for studying P-gp function in the future.
authors.affiliation: Department of Radiology, Columbia University Medical Center, 180 Fort Washington Ave. HP 3-305, New York, NY 10032, USA. mdf2104@columbia.edu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Farwell
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Chong
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Iida
authors.forename: Sung A
authors.initials: SA
authors.lastname: Bae
authors.forename: Balu
authors.initials: B
authors.lastname: Easwaramoorthy
authors.forename: Masanori
authors.initials: M
authors.lastname: Ichise
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D007700:Kinetics; D008139:Loperamide / Q000031:analogs & derivatives*; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D011804:Quinolines; C419149:N-demethylloperamide; D008139:Loperamide; D016572:Cyclosporine; C402343:tariquidar