title: Synthesis and positron emission tomography studies of carbon-11-labeled imatinib (Gleevec).
abstract: BACKGROUND
  Imatinib mesylate (Gleevec) is a well known drug for treating chronic myeloid leukemia and gastrointestinal stromal tumors. Its active ingredient, imatinib ([4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]phenyl]benzamide), blocks the activity of several tyrosine kinases. Here we labeled imatinib with carbon-11 as a tool for determining the drug distribution and pharmacokinetics of imatinib, and we carried out positron emission tomography (PET) studies in baboons.
  
  
  METHODS
  [N-(11)C-methyl]imatinib was synthesized from [(11)C]methyl iodide and norimatinib was synthesized by the demethylation of imatinib (isolated from Gleevec tablets) according to a patent procedure [Collins JM, Klecker RW Jr, Anderson LW. Imaging of drug accumulation as a guide to antitumor therapy. US Patent 20030198594A1, 2003]. Norimatinib was also synthesized from the corresponding amine and acid. PET studies were carried out in three baboons to measure pharmacokinetics in the brain and peripheral organs and to determine the effect of a therapeutic dose of imatinib. Log D and plasma protein binding were also measured.
  
  
  RESULTS
  [N-(11)C-methyl]imatinib uptake in the brain is negligible (consistent with P-glycoprotein-mediated efflux); it peaks and clears rapidly from the heart, lungs and spleen. Peak uptake and clearance occur more slowly in the liver and kidneys, followed by accumulation in the gallbladder and urinary bladder. Pretreatment with imatinib did not change uptake in the heart, lungs, kidneys and spleen, and increased uptake in the liver and gallbladder.
  
  
  CONCLUSIONS
  [N-(11)C-methyl]imatinib has potential for assessing the regional distribution and kinetics of imatinib in the human body to determine whether the drug targets tumors and to identify other organs to which the drug or its labeled metabolites distribute. Paired with tracers such as 2'deoxy-2'-[(18)F]fluoro-D-glucose ((18)FDG) and 3'deoxy-3'-[(18)F]fluorothymidine ((18)FLT), [N-(11)C-methyl]imatinib may be a useful radiotracer for planning chemotherapy, for monitoring response to treatment and for assessing the role of drug pharmacokinetics in drug resistance.
authors.affiliation: Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Kun-Eek
authors.initials: KE
authors.lastname: Kil
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
authors.forename: David
authors.initials: D
authors.lastname: Alexoff
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Colleen
authors.initials: C
authors.lastname: Shea
authors.forename: Youwen
authors.initials: Y
authors.lastname: Xu
authors.forename: Lisa
authors.initials: L
authors.lastname: Muench
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
mesh_terms: D000818:Animals; D001549:Benzamides; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D005260:Female; D000068877:Imatinib Mesylate; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D048530:Papio anubis; D010879:Piperazines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D014018:Tissue Distribution; D051598:Whole Body Imaging
chemical_list: D001549:Benzamides; D002250:Carbon Radioisotopes; D010879:Piperazines; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D000068877:Imatinib Mesylate