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

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.