title: Evaluation of the P-glycoprotein- and breast cancer resistance protein-mediated brain penetration of 11C-labeled topotecan using small-animal positron emission tomography.
abstract: BACKGROUND
  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.
authors: Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors: Tomoteru
authors: T
authors: Yamasaki
authors: Masayuki
authors: M
authors: Fujinaga
authors: Kazunori
authors: K
authors: Kawamura
authors: Akiko
authors: A
authors: Hatori
authors: Joji
authors: J
authors: Yui
authors: Nobuki
authors: N
authors: Nengaki
authors: Masanao
authors: M
authors: Ogawa
authors: Yuichiro
authors: Y
authors: Yoshida
authors: Hidekatsu
authors: H
authors: Wakizaka
authors: Kazuhiko
authors: K
authors: Yanamoto
authors: Toshimitsu
authors: T
authors: Fukumura
authors: Ming-Rong
authors: MR
authors: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes; D045744:Cell Line, Tumor; D055786:Gene Knockout Techniques; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049268:Positron-Emission Tomography; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D019772:Topotecan / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D009363:Neoplasm Proteins; D044005:Tetrahydroisoquinolines; D019772:Topotecan; C083501:Elacridar