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

Abstract

Introduction: Afatinib 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 [(18)F]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.

Methods: A radiochemically novel coupling, using peptide coupling reagent BOP, was explored and optimized to synthesize [(18)F]afatinib, followed by a metabolite analysis and biodistribution studies in two clinically relevant lung cancer cell lines, xenografted in nude mice.

Results: A reliable [(18)F]afatinib radiosynthesis was developed and the tracer could be produced in yields of 17.0 ± 2.5% calculated from [(18)F]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.

Conclusion: We have developed a method to synthesize [(18)F]afatinib and related fluorine-18 labeled 4-anilinoquinazolines. [(18)F]Afatinib showed good stability in vivo, justifying further evaluation as a TKI-PET tracer.

Keywords: Afatinib; Fluorine-18; Personalized medicine; TKI-PET; Tyrosine kinase inhibitor.