Synthesis of imatinib, a tyrosine kinase inhibitor, labeled with carbon-14,Journal of Labelled Compounds and Radiopharmaceuticals

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Synthesis of imatinib, a tyrosine kinase inhibitor, labeled with carbon-14
Journal of Labelled Compounds and Radiopharmaceuticals ( IF 0.9 ) Pub Date : 2020-02-05 , DOI: 10.1002/jlcr.3830
Julie Kang ₁ , Jun Young Lee ₂ , Jeong-Hoon Park ₂ , Dong-Jo Chang ₁

Affiliation

Imatinib (Gleevec®) is a multiple tyrosine kinase inhibitor that decreases the activity of the fusion oncogene called BCR-ABL (Breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog) and is clinically used for the treatment of chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL). Small molecule drugs, such as imatinib, can bind to several cellular proteins including the target proteins in the cells, inducing undesirable effects along with the effects against the disease. In this study, we report the synthetic optimization for 14 C-labeling and radiosynthesis of [14 C]imatinib to analyze binding with cellular proteins using accelerator mass spectroscopy (AMS). 14 C-labeling of imatinib was performed by the synthesis of 14 C-labeld 2-aminopyrimidine intermediate using [14 C]guanidine·HCl, which includes an in-situ reduction of an inseparable byproduct for easy purification by HPLC, followed by a cross-coupling reaction with aryl bromide precursor. The radiosynthesis of [14 C]imatinib (specific activity, 631 MBq/mmol; radiochemical purity, 99.6%) was achieved in six steps with a total chemical yield of 29.2%.

中文翻译：

碳 14 标记酪氨酸激酶抑制剂伊马替尼的合成

伊马替尼 (Gleevec®) 是一种多重酪氨酸激酶抑制剂，可降低名为 BCR-ABL（断点簇区域蛋白 - Abelson 鼠白血病病毒癌基因同源物）的融合癌基因的活性，临床上用于治疗慢性粒细胞白血病 (CML)和急性淋巴细胞白血病（ALL）。小分子药物，如伊马替尼，可以与多种细胞蛋白结合，包括细胞中的靶蛋白，除了对抗疾病的作用外，还会引起不良反应。在这项研究中，我们报告了 [14 C]伊马替尼的 14 C 标记和放射合成的合成优化，以使用加速器质谱 (AMS) 分析与细胞蛋白质的结合。伊马替尼的 14 C 标记是通过使用 [14 C]胍·HCl 合成 14 C 标记的 2-氨基嘧啶中间体进行的，其中包括原位还原不可分离的副产物，以便于通过 HPLC 纯化，然后进行交叉-与芳基溴前体的偶联反应。 [14 C]伊马替尼的放射合成（比活性，631 MBq/mmol；放射化学纯度，99.6%）分六步完成，总化学产率为29.2%。

更新日期：2020-02-05

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