Synthesis, metabolite analysis, and in vivo evaluation of [11C]irinotecan as a novel positron emission tomography (PET) probe
Synthesis, metabolite analysis, and in vivo evaluation of [11C]irinotecan as a novel positron emission tomography (PET) probe
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DOI：
10.1016/j.nucmedbio.2013.03.004
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发表时间：
2013-07-01
影响因子：
3.1
通讯作者：
Zhang, Ming-Rong
中科院分区：
文献类型：
--
作者：
Kawamura, Kazunori;Hashimoto, Hiroki;Zhang, Ming-Rong
简介：伊立替康是喜树碱的半合成衍生物，通过抑制拓扑异构酶 I 发挥有效的抗肿瘤活性。尽管对伊立替康复杂的药代动力学特征和药效学作用进行了大量研究，但仍然经常观察到不可预测的严重副作用。在本研究中，我们合成了[C-11]伊立替康作为正电子发射断层扫描（PET）探针，进行了代谢物分析，并使用小动物PET评估了[C-11]伊立替康的生物分布和动力学。方法：使用[C-11]光气和[11C]二氧化碳固定通过两条路线合成[C-11]伊立替康。采用柱切换高效液相色谱 (HPLC) 和在线固相萃取 (SPE) 相结合的方法研究了注射 [C-11] 伊立替康后小鼠血浆中的代谢物。在野生型小鼠和P-糖蛋白和乳腺癌耐药蛋白(Pgp/Bcrp)敲除小鼠中进行全身PET研究。结果：通过上述两条路线成功合成了[C-11]伊立替康。使用 [C-11] 光气和 [C-11] 二氧化碳固定的基于 [C-11] 二氧化碳的衰变校正放射化学产率分别为 8.8 +/- 2.0% (n = 8) 和 16.9 +/- 2.9 % (n = 5)。使用柱切换 HPLC 和在线 SPE 组合成功地对注射 [C-11]伊立替康后的小鼠血浆进行了代谢分析，结果 HPLC 的放射性回收率超过 87%。在小鼠的 PET 研究中，注射[C-11]伊立替康后抑制 Pgp/Bcrp 功能超过 30 分钟，大脑、肝脏和小肠的放射性水平略有增加。该结果表明[C-11]伊立替康和放射性代谢物的体内行为受到Pgp/Bcrp功能的影响。结论：使用[C-11]伊立替康的PET研究结合代谢物分析可能是评估伊立替康药代动力学和毒性的有用工具。 (C) 2013 Elsevier Inc. 保留所有权利。
Introduction: 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 [C-11]irinotecan as a positron emission tomography (PET) probe, performed the metabolite analysis, and evaluated the biodistribution and kinetics of [C-11]irinotecan using small animal PET.Methods: [C-11]Irinotecan was synthesized by two routes using [C-11]phosgene and [11C]carbon dioxide fixation. Metabolites in the plasma of mice following injection of [C-11] 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: [C-11]Irinotecan was successfully synthesized by the two abovementioned routes. Decay-corrected radiochemical yields based on [C-11]carbon dioxide using [C-11]phosgene and [C-11]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 [C-11]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 [C-11]irinotecan injection. This result demonstrated that in vivo behavior of [C-11] irinotecan and radioactive metabolites are influenced by the Pgp/Bcrp function.Conclusion: PET studies using [C-11]irinotecan combined with metabolite analysis may be a useful tool for evaluating irinotecan pharmacokinetics and toxicity. (C) 2013 Elsevier Inc. All rights reserved.