Synthesis and positron emission tomography studies of carbon-11-labeled imatinib (Gleevec)
Synthesis and positron emission tomography studies of carbon-11-labeled imatinib (Gleevec)
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DOI：
10.1016/j.nucmedbio.2006.11.004
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发表时间：
2007-02-01
影响因子：
3.1
通讯作者：
Fowler, Joanna S.
中科院分区：
文献类型：
--
作者：
Kil, Kun-Eek;Ding, Yu-Shin;Fowler, Joanna S.
前言：甲磺酸伊马替尼（格列卫）是治疗慢性粒细胞白血病和胃肠道间质瘤的常用药物。其活性成分伊马替尼（[4-[（4-甲基-1-哌嗪基）甲基]-N-[4-甲基-3-[[4-（3-吡啶基）-2-嘧啶基]氨基]苯基]苯甲酰胺）阻断几种酪氨酸激酶的活性。在这里，我们用碳-11标记伊马替尼作为确定伊马替尼的药物分布和药代动力学的工具，我们在狒狒中进行了正电子发射断层扫描（PET）研究。以[C-11]碘甲烷为原料合成[N-C-11-甲基]利马替尼，伊马替尼经脱甲基反应合成诺马替尼（从格列卫片剂中分离）根据专利程序[柯林斯JM，Klecker RW Jr，安德森LW.药物蓄积的成像作为抗肿瘤治疗的指南。美国专利20030198594 A1，2003]。Norimatinib也是由相应的胺和酸合成的。在三只狒狒中进行PET研究，以测量脑和外周器官中的药代动力学，并确定治疗剂量伊马替尼的效果。Log D和血浆蛋白binding.Results：[N-C-11-甲基]伊马替尼在脑中的摄取是可以忽略不计的（与P-糖蛋白介导的外排一致），它的峰值和清除迅速从心脏，肺和脾脏。在肝脏和肾脏中的峰值摄取和清除速度较慢，随后在胆囊和膀胱中蓄积。用伊马替尼预处理没有改变摄取在心脏，肺，肾和脾，并增加摄取在肝脏和gallades.Conclusions：[N-C-11-methyl]伊马替尼有潜力评估伊马替尼在人体内的区域分布和动力学，以确定是否药物靶向肿瘤，并确定其他器官的药物或其标记的代谢产物分布。与示踪剂如2-脱氧-2-[F-18]氟-D-葡萄糖（（18）FDG）和3 '-脱氧-3'-[F-18]氟胸苷（（FLT）-F-18）配对，[N-C-11-甲基]伊马替尼可能是一种有用的放射性示踪剂，用于规划化疗，监测对治疗的反应和评估药物药代动力学在耐药性中的作用。(c)2007年爱思唯尔公司All rights reserved.
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-l-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-C-11-methyl]limatinib was synthesized from [C-11]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 20030198594AI, 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-C-11-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-C-11-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-[F-18]fluoro-D-glucose ((18)FDG) and 3'-deoxy-3'-[F-18]fluorothymidine ((FLT)-F-18), [N-C-11-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. (c) 2007 Elsevier Inc. All rights reserved.