title: Synthesis and evaluation of [11C]XR9576 to assess the function of drug efflux transporters using PET.
abstract: OBJECTIVE
  XR9576 (tariquidar) is an anthranilic acid derivative and potent P-glycoprotein (P-gp) inhibitor. XR9576 has undergone phase I and II studies as combined chemotherapy against cancer. XR9576 has been developed as a useful therapeutic agent but not as a PET probe. We therefore developed [(11)C]XR9576 as a PET probe and assessed whether PET studies using [(11)C]XR9576 are a promising approach to assess P-gp function primarily.
  
  
  METHODS
  We synthesized [(11)C]XR9576 by methylation of 7-O-desmethyl XR9576 with [(11)C]methyl iodide. In in vivo tissue distribution, the effects of co-injection with XR9576 on the uptake of [(11)C]XR9576 in mice were investigated. PET studies using [(11)C]XR9576 were performed in P-gp and/or Bcrp knockout mice as well as in wild-type mice. Metabolites of [(11)C]XR9576 were measured in the brain and plasma of mice.
  
  
  RESULTS
  [(11)C]XR9576 was successfully synthesized with suitable radioactivity for injection as well as appropriate radiochemical purity and stability. In in vivo tissue distribution, the brain uptake of [(11)C]XR9576 significantly increased about tenfold of control on co-injection with >10 mg/kg of XR9576. In PET studies, the AUC(brain) ([0-60 min]) in P-gp and P-gp/Bcrp knockout mice was 2- and 11-fold higher than that in wild-type mice. [(11)C]XR9576 showed a high metabolic stability (>90% unchanged form) in the brain and plasma of mice 30 min after injection. These results suggest that a tracer amount of [(11)C]XR9576 behave as the P-gp and Bcrp substrate, and the increased brain uptake or AUC(brain) of [(11)C]XR9576 correlates with P-gp and Bcrp functions.
  
  
  CONCLUSIONS
  PET studies using [(11)C]XR9576 may be a promising approach for evaluating deficiency of the function of drug efflux transporters targeting intracranial diseases and tumors.
authors.affiliation: Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan. kawamur@nirs.go.jp
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Fujiko
authors.initials: F
authors.lastname: Konno
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanamoto
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Wakizaka
authors.forename: Makoto
authors.initials: M
authors.lastname: Takei
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nengaki
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Fukumura
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes; D007267:Injections; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011804:Quinolines / Q000097:blood / Q000138:chemical synthesis* / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D011804:Quinolines; C402343:tariquidar