title: 11C-loperamide and its N-desmethyl radiometabolite are avid substrates for brain permeability-glycoprotein efflux.
abstract: Loperamide, an opiate receptor agonist, does not cross the blood-brain barrier because it is a substrate for the permeability-glycoprotein (P-gp) efflux pump. We evaluated 11C-loperamide as a PET radiotracer to measure P-gp function in vivo.
  
  
  METHODS
  Monkeys were injected with 11C-loperamide, and PET brain images were acquired for 120 min. The baseline scans were followed by scans acquired after administration of either of 2 P-gp inhibitors, (2R)-anti-5-{3-[4-(10,11-dichloromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (DCPQ) or tariquidar. Both the PET scans and ex vivo measurements were obtained in P-gp knockout and wild-type mice.
  
  
  RESULTS
  Pharmacologic inhibition of P-gp in monkeys dose-dependently increased brain activity, with a 3.7-fold effect at the highest DCPQ dose (8 mg/kg intravenously). This increase of brain activity was not caused peripherally, because DCPQ insignificantly changed the plasma concentration and plasma protein binding of radiotracer. Furthermore, the structurally dissimilar inhibitor, tariquidar, also increased brain uptake with potency equal to that of DCPQ. P-gp knockout mice had 3-fold higher brain activity on PET than did wild-type animals. Four radiometabolites were detected in the plasma and brains of ex vivo mice. The most lipophilic radiometabolite was found to be comobile with reference dLop on high-performance liquid chromatography. The brain concentrations of 11C-loperamide and the putative 11C-dLop were about 16-fold greater in P-gp knockout mice than in wild-type mice.
  
  
  CONCLUSIONS
  Both 11C-loperamide and its putative radiometabolite 11C-dLop are avid P-gp substrates. 11C-dLop may be superior to 11C-loperamide in measuring P-gp function at the blood-brain barrier, because further demethylation of 11C-dLop will generate radiometabolites that have little entry into the brain.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-0135, USA. sami.zoghbi@nih.gov
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yasuno
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Hong
authors.forename: Edward
authors.initials: E
authors.lastname: Tuan
authors.forename: Neva
authors.initials: N
authors.lastname: Lazarova
authors.forename: Robert L
authors.initials: RL
authors.lastname: Gladding
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D008139:Loperamide / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D049268:Positron-Emission Tomography
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D008139:Loperamide