Synthesis and positron emission tomography studies of carbon-11-labeled imatinib (Gleevec)

Kun Eek Kil, Yu Shin Ding, Kuo Shyan Lin, David Alexoff, Sung Won Kim, Colleen Shea, Youwen Xu, Lisa Muench, Joanna S. Fowler

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Introduction: 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-pyr imidinyl]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-11C-methyl]imatinib was synthesized from [11C]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-11C-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-11C-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′-[18F]fluoro-D-glucose (18FDG) and 3′deoxy-3′-[18F]fluorothymidine (18FLT), [N-11C-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.

Original languageEnglish
Pages (from-to)153-163
Number of pages11
JournalNuclear Medicine and Biology
Issue number2
StatePublished - Feb 2007
Externally publishedYes


  • Carbon-11
  • Drug pharmacokinetics
  • Imatinib (Gleevec)
  • PET


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