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 1with [11C]-methyl triflate. In vitro autoradiography and small-animal PET imaging of [11C]-1was 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 1increased 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]-1binding was displaceable by an excess of unlabeled 1. As the signal obtained with [11C]-1appeared to be specific for P-gp at the BBB, its utility for the visualization of cerebral P-gp merits further investigation. [ABSTRACT FROM AUTHOR]