title: Synthesis, metabolite analysis, and in vivo evaluation of [(11)C]irinotecan as a novel positron emission tomography (PET) probe.
abstract: BACKGROUND
  Irinotecan is a semisynthetic derivative of camptothecin that exerts potent antitumor activity by inhibiting topoisomerase I. Despite much research into the complex pharmacokinetic profile and pharmacodynamic effects of irinotecan, unpredictable and severe side effects are still commonly observed. In this study, we synthesized [(11)C]irinotecan as a positron emission tomography (PET) probe, performed the metabolite analysis, and evaluated the biodistribution and kinetics of [(11)C]irinotecan using small animal PET.
  
  
  METHODS
  [(11)C]Irinotecan was synthesized by two routes using [(11)C]phosgene and [(11)C]carbon dioxide fixation. Metabolites in the plasma of mice following injection of [(11)C] irinotecan were investigated using a combination of column-switching high-performance liquid chromatography (HPLC) and on-line solid-phase extraction (SPE). Whole-body PET studies were conducted in wild-type mice and P-glycoprotein and breast cancer resistance protein (Pgp/Bcrp) knockout mice.
  
  
  RESULTS
  [(11)C]Irinotecan was successfully synthesized by the two abovementioned routes. Decay-corrected radiochemical yields based on [(11)C]carbon dioxide using [(11)C]phosgene and [(11)C]carbon dioxide fixation were 8.8 ± 2.0% (n=8) and 16.9 ± 2.9 % (n=5), respectively. Metabolite analysis of the plasma of mice following injection of [(11)C]irinotecan was successfully performed using the column-switching HPLC and on-line SPE combination resulting in greater than 87 % recovery of radioactivity from HPLC. In the PET study in mice, the radioactivity levels in the brain, liver, and small intestine were slightly increased by inhibition of the Pgp/Bcrp function for more than 30 min after [(11)C]irinotecan injection. This result demonstrated that in vivo behavior of [(11)C] irinotecan and radioactive metabolites are influenced by the Pgp/Bcrp function.
  
  
  CONCLUSIONS
  PET studies using [(11)C]irinotecan combined with metabolite analysis may be a useful tool for evaluating irinotecan pharmacokinetics and toxicity.
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan. kawamur@nirs.go.jp
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Masanao
authors.initials: M
authors.lastname: Ogawa
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Wakizaka
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Katushi
authors.initials: K
authors.lastname: Kumata
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D002250:Carbon Radioisotopes; D060326:Chemistry Techniques, Synthetic; D000077146:Irinotecan; D007700:Kinetics; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*
chemical_list: D002250:Carbon Radioisotopes; D000077146:Irinotecan; D002166:Camptothecin