Evaluation of the P-glycoprotein- and breast cancer resistance protein-mediated brain penetration of 11C-labeled topotecan using small-animal positron emission tomography

IntroductionTopotecan (TPT) is a camptothecin derivative and is an anticancer drug working as a topoisomerase-I-specific inhibitor. But TPT cannot penetrate through the blood–brain barrier. In this study, we synthesized a new positron emission tomography (PET) probe, [11C]TPT, to evaluate the P-glycoprotein (Pgp)- and breast cancer resistance protein (BCRP)-mediated brain penetration of [11C]TPT using small-animal PET.Methods[11C]TPT was synthesized by the reaction of a desmethyl precursor with [11C]CH3I. In vitro study using [11C]TPT was carried out in MES-SA and doxorubicin-resistant MES-SA/Dx5 cells in the presence or absence of elacridar, a specific inhibitor for Pgp and BCRP. The biodistribution of [11C]TPT was determined using small-animal PET and the dissection method in mice.ResultsThe transport of [11C]TPT to the extracellular side was determined in MES-SA/Dx5 cells exhibiting the expressions of Pgp and BCRP at high levels. This transport was inhibited by coincubation with elacridar. In Mdr1a/b−/−Bcrp1−/− mice, PET results indicated that the brain uptake of [11C]TPT was about two times higher than that in wild-type mice. Similarly, the brain penetration of [11C]TPT in wild-type mice was increased by treatment with elacridar. The radioactivity in the brain of elacridar-treated mice was maintained at a certain level after the injection of [11C]TPT, although the radioactivity in the blood decreased with time.ConclusionsWe demonstrated the increase of brain penetration of [11C]TPT by deficiency and inhibition of Pgp and BCRP functions using small-animal PET in mice.