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

• DOI: 10.1016/j.nucmedbio.2014.06.005
• Publication Date: 2014-06-24T20:17:01Z
• Authors: Paul Slobbe; Albert D. Windhorst; Marijke Stigter-v...; Robert C. Schuit; Egbert F. Smit; Heiko G. Niessen; Flavio Solca; Gerd Stehle; Guus A.M.S. van D...; Alex J. Poot
• Keywords: 0301 basic medicine; Fluorine Radioisotopes; Mice, Inbred BALB C; Metabolic Clearance Rate; Mice, Nude; Reproducibility of Results; Neoplasms, Experimental; Afatinib; Sensitivity and Specificity; 3. Good health; ErbB Receptors; Mice; 03 medical and health sciences; Organ Specificity; Cell Line, Tumor; Isotope Labeling; Positron-Emission Tomography; Quinazolines; Animals; Tissue Distribution; Radiopharmaceuticals

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.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.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.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.