title: Effect of a P-glycoprotein inhibitor, Cyclosporin A, on the disposition in rodent brain and blood of the 5-HT1A receptor radioligand, [11C](R)-(-)-RWAY.
abstract: Limited brain uptake of radioligands with otherwise optimal properties for imaging brain receptors can be improved by blocking the effect of P-glycoprotein (P-gp), an efflux pump at the blood-brain barrier. Using small animal positron emission tomography (PET), we investigated how P-gp and its blockade with Cyclosporin A (CsA) affect rodent brain uptake of [(11)C](R)-(-)-RWAY, a radioligand for brain 5-HT(1A) receptors. Brain uptake of radioactivity was compared in control and CsA-treated rats as well as P-gp knockout and wild type mice. Parent radioligand and radiometabolite in plasma and brain samples were determined at 30 min after injection of radioligand. PET binding potential (BP) was calculated with a reference tissue model. P-gp knockout mice had 2.5- and 2.8-fold greater brain uptake of [(11)C](R)-(-)-RWAY than wild type ones, measured by in vivo PET and ex vivo tissue sampling, respectively. Similarly, CsA increased rat brain uptake 4.9- and 5.3-fold, in vivo and ex vivo. In addition, CsA increased the plasma free fraction of [(11)C](R)-(-)-RWAY in rats by 2.7-fold. Although CsA increased brain uptake in wild type mice by 2.5-fold, it had no effect on plasma free fraction in knockout animals. Three radiometabolites of [(11)C](R)-(-)-RWAY were uniformly distributed in rat brain, suggesting they were inactive. CsA treatment increased brain uptake of [(11)C](R)-(-)-RWAY and only one of its radiometabolites. Regional rat brain BP increased 27-70% in the CsA-treated rats and the P-gp knockout mice. [(11)C](R)-(-)-RWAY is a P-gp substrate in rat and mouse. The effects of CsA in rats are mediated by both P-gp blockade and displacement of the radiotracer from plasma proteins. Studies with wild type and knockout mice showed that CsA affected only P-gp in this species.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland 20892-0135, USA. liowj@mail.nih.gov
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Shuiyu
authors.initials: S
authors.lastname: Lu
authors.forename: Julie A
authors.initials: JA
authors.lastname: McCarron
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Hong
authors.forename: John L
authors.initials: JL
authors.lastname: Musachio
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000172:deficiency; D000818:Animals; D001381:Azepines / Q000493:pharmacokinetics*; D001667:Binding, Competitive / Q000187:drug effects / Q000235:genetics; D001769:Blood / Q000000981:diagnostic imaging / Q000187:drug effects*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects*; D001931:Brain Mapping; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D051381:Rats; D058829:Serotonin 5-HT1 Receptor Antagonists; D013997:Time Factors
chemical_list: C515279:2, 3, 4, 5, 6, 7-hexahydro-1(4-(1(4-(2-methoxyphenyl)-piperazinyl))-2-phenylbutyry)-1H-azepine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001381:Azepines; D004791:Enzyme Inhibitors; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D016572:Cyclosporine