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Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib.

Kenji MishiroRyuichi NishiiIzumi SawazakiTomoki SofukuTakeshi FuchigamiHitomi SudoNurmaya EffendiAkira MakinoYasushi KiyonoKazuhiro ShibaJunichi TakiSeigo KinuyaKazuma Ogawa
Published in: Journal of medicinal chemistry (2022)
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 vitro 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 [ 125 I]I-osimertinib and [ 77 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.
Keyphrases
  • epidermal growth factor receptor
  • small cell lung cancer
  • advanced non small cell lung cancer
  • tyrosine kinase
  • brain metastases
  • fluorescence imaging
  • single molecule
  • mass spectrometry
  • single cell