Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST) Chiba, Inage-ku, Chiba 263-8555, Japan.
J Med Chem. 2022 Feb 10;65(3):1835-1847. doi: 10.1021/acs.jmedchem.1c01211. Epub 2022 Jan 11.
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. assays 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 [I]I-osimertinib and [Br]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.
奥希替尼是一种表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂，已获准用于治疗具有 EGFR 突变的非小细胞肺癌 (NSCLC)。需要进行基因检测以检测突变，从而选择可以使用奥希替尼的患者。在这里，我们报告了开发用于检测 EGFR 突变的核成像探针的尝试。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原子的 I-奥希替尼和 Br-奥希替尼，并对其进行了评估。测定表明，I-奥希替尼和 Br-奥希替尼均对具有 EGFR L858R/T790M 突变的 NSCLC 表现出特别高的活性。在分布实验中，突变肿瘤中 [I]I-奥希替尼和 [Br]Br-奥希替尼的积累明显高于血液和肌肉。然而，这些奥希替尼衍生物在肺部的积累明显高于肿瘤。因此，对于检测肺癌中的突变，需要对探针进行进一步的结构修饰。
