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

Synapse. 2007 Feb;61(2):96-105. doi: 10.1002/syn.20348.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / deficiency
  • Animals
  • Azepines / pharmacokinetics*
  • Binding, Competitive / drug effects
  • Binding, Competitive / genetics
  • Blood / diagnostic imaging
  • Blood / drug effects*
  • Brain / diagnostic imaging
  • Brain / drug effects*
  • Brain Mapping
  • Cyclosporine / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Mice
  • Mice, Knockout
  • Piperazines / pharmacokinetics*
  • Positron-Emission Tomography / methods
  • Rats
  • Serotonin 5-HT1 Receptor Antagonists*
  • Time Factors


  • 2, 3, 4, 5, 6, 7-hexahydro-1(4-(1(4-(2-methoxyphenyl)-piperazinyl))-2-phenylbutyry)-1H-azepine
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Azepines
  • Enzyme Inhibitors
  • Piperazines
  • Serotonin 5-HT1 Receptor Antagonists
  • Cyclosporine