Influence of P-glycoprotein on brain uptake of [18F]MPPF in rats

Eur J Pharmacol. 2000 Nov 3;407(3):273-80. doi: 10.1016/s0014-2999(00)00752-4.


The aim of this study was to determine if the brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F]fluorobenzamido ]ethylpiperazine ([18F]MPPF), a radioligand for the imaging of 5-HT1A receptors, is influenced by the action of P-glycoprotein. Anesthetized male Wistar rats were injected i.v. with the 5-HT1A receptor antagonist [18F]MPPF (2 MBq, S.A.>110 TBq/mmol) after treatment with saline (controls) or with the 5-HT1A receptor antagonist 1-(2'-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190) (2.5 mg/kg i.v.). After 60 min, the animals were sacrificed and 13 areas of the brain were dissected for ex vivo gamma counting. The regional distribution of radioactivity was also assessed in brain slices using a storage phosphor system. Modulation of P-glycoprotein was achieved by injection of cyclosporin A (50 mg/kg) 30 min prior to injection of [18F]MPPF.The distribution of 18F-derived radioactivity corresponded to regional 5-HT1A receptor density as known from autoradiography. Modulation of P-glycoprotein with cyclosporin A caused a 5- to 10-fold increase in the uptake of [18F]MPPF. Tissue/cerebellum ratios in the brain correlated with receptor densities determined by in vitro autoradiography. Measurements of plasma radioactivity showed that the increased brain uptake of [18F]MPPF is partially due to a rise in ligand delivery after treatment with cyclosporin A (area under the curve, AUC, increased by a factor of 1.8). Biodistribution experiments in wild type and mdr1a(-/-) knockout mice confirmed that [18F]MPPF is a substrate for P-glycoprotein.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Aminopyridines / chemistry
  • Aminopyridines / metabolism*
  • Animals
  • Brain / drug effects*
  • Brain / metabolism
  • Cyclosporine / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Piperazines / chemistry
  • Piperazines / metabolism*
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists / metabolism*
  • Serotonin Antagonists / pharmacology
  • Tissue Distribution


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Aminopyridines
  • Enzyme Inhibitors
  • Piperazines
  • Pyridines
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists
  • 1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 4-(2' methoxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-fluorobenzamido)ethyl)piperazine
  • Cyclosporine