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

Autor: Yamasaki T; Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan., Fujinaga M, Kawamura K, Hatori A, Yui J, Nengaki N, Ogawa M, Yoshida Y, Wakizaka H, Yanamoto K, Fukumura T, Zhang MR
Jazyk: angličtina
Zdroj: Nuclear medicine and biology [Nucl Med Biol] 2011 Jul; Vol. 38 (5), pp. 707-14. Date of Electronic Publication: 2011 Mar 03.
DOI: 10.1016/j.nucmedbio.2010.12.012
Abstrakt: Introduction: Topotecan (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, [(11)C]TPT, to evaluate the P-glycoprotein (Pgp)- and breast cancer resistance protein (BCRP)-mediated brain penetration of [(11)C]TPT using small-animal PET.
Methods: [(11)C]TPT was synthesized by the reaction of a desmethyl precursor with [(11)C]CH(3)I. In vitro study using [(11)C]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 [(11)C]TPT was determined using small-animal PET and the dissection method in mice.
Results: The transport of [(11)C]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 [(11)C]TPT was about two times higher than that in wild-type mice. Similarly, the brain penetration of [(11)C]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 [(11)C]TPT, although the radioactivity in the blood decreased with time.
Conclusions: We demonstrated the increase of brain penetration of [(11)C]TPT by deficiency and inhibition of Pgp and BCRP functions using small-animal PET in mice.
(Copyright © 2011 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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