Development of [18F]afatinib as new TKI-PET tracer for EGFR positive tumors

IntroductionAfatinib is an irreversible ErbB family blocker that was approved for the treatment of EGFR mutated non-small cell lung cancer in 2013. Positron emission tomography (PET) with fluorine-18 labeled afatinib provides a means to obtain improved understanding of afatinib tumor disposition in vivo. PET imaging with [18F]afatinib may also provide a method to select treatment responsive patients. The aim of this study was to label afatinib with fluorine-18 and evaluate its potential as TKI-PET tracer in tumor bearing mice.MethodsA radiochemically novel coupling, using peptide coupling reagent BOP, was explored and optimized to synthesize [18F]afatinib, followed by a metabolite analysis and biodistribution studies in two clinically relevant lung cancer cell lines, xenografted in nude mice.ResultsA reliable [18F]afatinib radiosynthesis was developed and the tracer could be produced in yields of 17.0 ± 2.5% calculated from [18F]F− and >98% purity. The identity of the product was confirmed by co-injection on HPLC with non-labeled afatinib. Metabolite analysis revealed a moderate rate of metabolism, with >80% intact tracer in plasma at 45 min p.i. Biodistribution studies revealed rapid tumor accumulation and good retention for a period of at least 2 hours, while background tissues showed rapid clearance of the tracer.ConclusionWe have developed a method to synthesize [18F]afatinib and related fluorine-18 labeled 4-anilinoquinazolines. [18F]Afatinib showed good stability in vivo, justifying further evaluation as a TKI-PET tracer.