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

The aim of this study was to determine if the brain uptake of 4-(2'-methoxy phenyl)-1-[2'-(N-2"-pyridinyl)-p-[F-18]fluorobenzamido]ethylpiperazine ([F- 18]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 a ntagonist [F-18]MPPF (2 MBq, S.A. > 110 TBq/mmol) after treatment with sali ne (controls) or with the 5-HT1A receptor antagonist 1-(2'-methoxyphenyl)-4 -[4-(2-phtalimido)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 p rior to injection of [F-18]MPPF. The distribution of F-18-derived radioactivity corresponded to regional 5-H T1A receptor density as known from autoradiography. Modulation of P-glycopr otein with cyclosporin A caused a 5- to 10-fold increase in the uptake of [ F-18]MPPF. Tissue/cerebellum ratios in the brain correlated with receptor d ensities determined by in vitro autoradiography. Measurements of plasma rad ioactivity showed that the increased brain uptake of [F-18]MPPF is partiall y 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 exper iments in wild type and mdr1a(-/-) knockout mice confirmed that [F-18]MPPF is a substrate for P-glycoprotein. (C) 2000 Elsevier Science B.V. All right s reserved.