18F-Labeled Pyrido[3,4-d]pyrimidine as an Effective Probe for Imaging of L858R Mutant Epidermal Growth Factor Receptor.
18F-Labeled Pyrido[3,4-d]pyrimidine as an Effective Probe for Imaging of L858R Mutant Epidermal Growth Factor Receptor.
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18F 标记的吡啶并[3,4-d]嘧啶作为 L858R 突变表皮生长因子受体成像的有效探针。
DOI：
10.1021/acsmedchemlett.6b00520
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
and Hideo Saji
中科院分区：
文献类型：
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作者：
Hiroyuki Kimura;Haruka Okuda;Masumi Ishiguro;Kenji Arimitsu;Akira Makino;Ryuichi Nishii;Anna Miyazaki;Yusuke Yagi;Hiroyuki Watanabe;Ikuo Kawasaki;Masahiro Ono;and Hideo Saji
在非小细胞肺癌患者中，常发现表皮生长因子受体（EGFR）L858R突变，使用EGFR酪氨酸激酶抑制剂的分子靶向治疗对患者有效。然而，该治疗经常因二次突变而产生耐药性，其中约50%是T790M突变。因此，预测EGFR是否会发生二次突变的能力极其重要。我们合成了一种新型放射性氟化4-(苯胺基)吡啶并[3,4-d]嘧啶衍生物([18F]APP-1)，并评估了其作为正电子发射断层扫描(PET)成像探针区分肿瘤突变差异的潜力。 EGFR 抑制测定、细胞摄取和生物分布研究表明，[ 18F]APP-1 特异性结合 L858R 突变体 EGFR，但不结合 L858R/T790M 突变体。最后，在使用[18F]APP-1对荷瘤小鼠进行PET成像研究时，H3255肿瘤（L858R突变体）比H1975肿瘤（L858R/T790M突变体）更清晰地显现。
In nonsmall-cell lung carcinoma patients, L858R mutation of epidermal growth factor receptor (EGFR) is often found, and molecular target therapy using EGFR tyrosine kinase inhibitors is effective for the patients. However, the treatment frequently develops drug resistance by secondary mutation, of which approximately 50% is T790M mutation. Therefore, the ability to predict whether EGFR will undergo secondary mutation is extremely important. We synthesized a novel radiofluorinated 4-(anilino)pyrido[3,4-d]pyrimidine derivative ([18F]APP-1) and evaluated its potential as a positron emission tomography (PET) imaging probe to discriminate the difference in mutations of tumors. EGFR inhibition assay, cell uptake, and biodistribution study showed that [18F]APP-1 binds specifically to the L858R mutant EGFR but not to the L858R/T790M mutant. Finally, on PET imaging study using [18F]APP-1 with tumor-bearing mice, the H3255 tumor (L858R mutant) was more clearly visualized than the H1975 tumor (L858R/T790M mutant).