Cyclosporine, a P-glycoprotein modulator, increases [¹⁸F]MPPF uptake in rat brain and peripheral tissues: MicroPET and ex vivo studies

Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2″-pyridinyl)-p-[ ¹⁸F]fluorobenzamido]ethylpiperazine ([¹⁸F]MPPF) for binding to hydroxytryptamine_1A (5-HT_1A) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies. Each Sprague-Dawley rat (n∈=∈4) received a baseline [ ¹⁸F]MPPF microPET scan followed by second scan 2-3 weeks later that included cyclosporine pretreatment (50 mg/kg, i.p.). Maximum a posteriori reconstructed images and volumetric ROIs were used to generate dynamic radioactivity concentration measurements for hippocampus, striatum, and cerebellum, with simplified reference tissue method (SRTM) analysis. Western blots were used to semiquantify P-gp regional distribution in brain. MicroPET studies showed that hippocampus uptake of [¹⁸F]MPPF was increased after cyclosporine; ex vivo studies showed similar increases in hippocampus and frontal cortex at 30 min, and for heart and kidney at 2.5 and 5 min, without concomitant increases in [¹⁸F]MPPF plasma concentration. P-gp content in cerebellum was twofold higher than in hippocampus or frontal cortex. These studies confirm and extend prior ex vivo results (J. Passchier, et al., Eur J Pharmacol, 2000) that showed [¹⁸F]MPPF as a substrate for P-gp. Our microPET results showed that P-gp modulation of [¹⁸F]MPPF binding to 5-HT_1A receptors can be imaged in rat hippocampus. The heterogeneous brain distribution of P-gp appeared to invalidate the use of cerebellum as a nonspecific reference region for SRTM modeling. Regional quantitation of P-gp may be necessary for accurate PET assessment of 5-HT_1A receptor density when based on tracer uptake sensitive to P-gp modulation.