Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib
Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib
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DOI：
10.1021/acs.jmedchem.1c01211
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发表时间：
2022-01-11
影响因子：
7.3
通讯作者：
Ogawa，Kazuma
中科院分区：
文献类型：
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作者：
Mishiro，Kenji;Nishii，Ryuichi;Ogawa，Kazuma
奥希替尼是一种表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，获批用于治疗EGFR突变的非小细胞肺癌（NSCLC）。需要进行基因检测以检测突变，以选择可以使用奥希替尼的患者。在这里，我们报告了一种尝试，开发核成像探针，检测EGFR突变。我们设计并合成了在奥希替尼的吲哚环上带有放射性或非放射性卤素原子的I-osimertinib和Br-osimertinib，并对其进行了评价，体外试验表明I-osimertinib和Br-osimertinib对EGFR L 858 R/T790 M突变的NSCLC具有特异性高活性。在生物分布实验中，[125 I] I-奥希替尼和[77 Br] Br-奥希替尼在突变肿瘤中的蓄积显著高于血液和肌肉中的蓄积。然而，这些奥希替尼衍生物在肺中的蓄积显著高于肿瘤。因此，为了检测肺癌中的突变，需要对探针进行进一步的结构修饰。
Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for treating non-small-cell lung cancer (NSCLC) with EGFR mutations. Genetic testing is required to detect the mutation for selecting patients who can use osimertinib. Here, we report an attempt to develop nuclear imaging probes that detect the EGFR mutations. We designed and synthesized I-osimertinib and Br-osimertinib with a radioactive or nonradioactive halogen atom at an indole ring in osimertinib and evaluated them.In vitroassays suggested that both I-osimertinib and Br-osimertinib exhibit a specifically high activity toward NSCLC with EGFR L858R/T790M mutations. In biodistribution experiments, the accumulation of both [125I]I-osimertinib and [77Br]Br-osimertinib in tumors with mutations was significantly higher than that in blood and muscle. However, these osimertinib derivatives showed a significantly higher accumulation in lungs than in tumors. Therefore, for detecting the mutations in lung cancer, further structural modifications of the probes are required.