Cyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies
Cyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies
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DOI：
10.1007/s00259-008-0832-z
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发表时间：
2008-12-01
影响因子：
9.1
通讯作者：
Melega, William P.
中科院分区：
文献类型：
--
作者：
Lacan, Goran;Plenevaux, Alain;Melega, William P.
目的P-糖蛋白（P-gp）调节剂环孢菌素（cyclosporine）预处理可增加脑摄取4-（2 '-甲氧基苯基）-1-[2'-（N-2”-吡啶基）-p-[F-18]氟苯甲酰氨基]乙基哌嗪（[F-18]MPPF）与羟色胺（1A）（5-HT 1A）受体结合。材料和方法每只Sprague-Dawley大鼠（n = 4）接受基线[F-18] MPPF microPET扫描，然后在2-3周后进行第二次扫描，其中包括环孢菌素预处理（50 mg/kg，i. p.）。使用最大后验重建图像和体积ROI生成海马、纹状体和小脑的动态放射性浓度测量值，并进行简化参考组织法（SRTM）分析。结果MicroPET研究显示，环孢素A治疗后海马对[F-18] MPPF的摄取增加;离体研究显示，环孢素A治疗后30 min，海马和额叶皮质对[F-18] MPPF的摄取增加，心脏和肾脏对[F-18] MPPF的摄取在2.5 min和5 min时也增加，但血浆[F-18] MPPF浓度没有增加。结论这些研究证实并扩展了先前的离体结果（J. Passchier等人，Eur J Pharmacol，2000），该研究表明[F-18] MPPF是P-gp的底物。我们的microPET结果表明，P-gp调节[F-18] MPPF结合5-HT 1A受体可以在大鼠海马成像。P-gp的异质性脑分布似乎使小脑作为SRTM建模的非特异性参考区域的使用无效。当基于对P-gp调节敏感的示踪剂摄取时，P-gp的区域定量对于5-HT 1A受体密度的准确PET评估可能是必要的。
Purpose Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)1-[2'-(N-2"-pyridinyl)-p-[F-18]fluorobenzamido]ethylpiperazine ([F-18]MPPF) for binding to hydroxytryptamine(1A) (5-HT1A) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies.Materials and methods Each Sprague-Dawley rat (n = 4) received a baseline [F-18] 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.Results MicroPET studies showed that hippocampus uptake of [F-18] 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 [F-18] MPPF plasma concentration. P-gp content in cerebellum was twofold higher than in hippocampus or frontal cortex.Conclusions These studies confirm and extend prior ex vivo results (J. Passchier, et al., Eur J Pharmacol, 2000) that showed [F-18] MPPF as a substrate for P-gp. Our microPET results showed that P-gp modulation of [F-18] MPPF binding to 5-HT1A 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-HT1A receptor density when based on tracer uptake sensitive to P-gp modulation.