Dörner Bernd, Kuntner Claudia, Bankstahl Jens P, Bankstahl Marion, Stanek Johann, Wanek Thomas, Stundner Gloria, Mairinger Severin, Löscher Wolfgang, Müller Markus, Langer Oliver, Erker Thomas
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.
J Med Chem. 2009 Oct 8;52(19):6073-82. doi: 10.1021/jm900940f.
With the aim to develop a positron emission tomography (PET) tracer to assess the distribution of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in vivo, the potent third-generation P-gp inhibitor elacridar (1) was labeled with (11)C by reaction of O-desmethyl 1 with [(11)C]-methyl triflate. In vitro autoradiography and small-animal PET imaging of [(11)C]-1 was performed in rats (n = 3), before and after administration of unlabeled 1, as well as in wild-type, Mdr1a/b((-/-)) and Bcrp1((-/-)) mice (n = 3). In PET experiments in rats, administration of unlabeled 1 increased brain activity uptake 5.4-fold, whereas blood activity levels remained unchanged. In Mdr1a/b((-/-)) mice, brain activity uptake was 2.5-fold higher compared to wild-type animals, whereas in Bcrp1((-/-)) mice, brain activity uptake was only 1.3-fold higher. In vitro autoradiography showed that 63% of [(11)C]-1 binding was displaceable by an excess of unlabeled 1. As the signal obtained with [(11)C]-1 appeared to be specific for P-gp at the BBB, its utility for the visualization of cerebral P-gp merits further investigation.
为了开发一种正电子发射断层扫描（PET）示踪剂，以评估体内血脑屏障（BBB）处P-糖蛋白（P-gp）的分布，通过O-去甲基1与[（11）C]-甲基三氟甲磺酸酯反应，用（11）C标记强效第三代P-gp抑制剂艾拉司群（1）。在给予未标记的1之前和之后，以及在野生型、Mdr1a/b（-/-）和Bcrp1（-/-）小鼠（n = 3）中，对[（11）C]-1进行了大鼠（n = 3）的体外放射自显影和小动物PET成像。在大鼠的PET实验中，给予未标记的1使脑摄取活性增加了5.4倍，而血液活性水平保持不变。在Mdr1a/b（-/-）小鼠中，脑摄取活性比野生型动物高2.5倍，而在Bcrp1（-/-）小鼠中，脑摄取活性仅高1.3倍。体外放射自显影显示，过量未标记的1可取代63%的[（11）C]-1结合。由于用[（11）C]-1获得的信号似乎对BBB处的P-gp具有特异性，其用于可视化脑P-gp的效用值得进一步研究。
