F-Labeled Pyrido[3,4-]pyrimidine as an Effective Probe for Imaging of L858R Mutant Epidermal Growth Factor Receptor.

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-]pyrimidine derivative ([F]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 [F]APP-1 binds specifically to the L858R mutant EGFR but not to the L858R/T790M mutant. Finally, on PET imaging study using [F]APP-1 with tumor-bearing mice, the H3255 tumor (L858R mutant) was more clearly visualized than the H1975 tumor (L858R/T790M mutant).