American Chemical Society
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Synthesis and Small-Animal Positron Emission Tomography Evaluation of [11C]-Elacridar As a Radiotracer to Assess the Distribution of P-Glycoprotein at the Blood−Brain Barrier

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posted on 2009-10-08, 00:00 authored by Bernd Dörner, Claudia Kuntner, Jens P. Bankstahl, Marion Bankstahl, Johann Stanek, Thomas Wanek, Gloria Stundner, Severin Mairinger, Wolfgang Löscher, Markus Müller, Oliver Langer, Thomas Erker
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 11C by reaction of O-desmethyl 1 with [11C]-methyl triflate. In vitro autoradiography and small-animal PET imaging of [11C]-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 [11C]-1 binding was displaceable by an excess of unlabeled 1. As the signal obtained with [11C]-1 appeared to be specific for P-gp at the BBB, its utility for the visualization of cerebral P-gp merits further investigation.