title: Development of [18F]afatinib as new TKI-PET tracer for EGFR positive tumors.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: p.slobbe@vumc.nl.
authors: Paul
authors: P
authors: Slobbe
authors: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors: Albert D
authors: AD
authors: Windhorst
authors: Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.
authors: Marijke
authors: M
authors: Stigter-van Walsum
authors: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors: Robert C
authors: RC
authors: Schuit
authors: Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands.
authors: Egbert F
authors: EF
authors: Smit
authors: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Translational Medicine and Clinical Pharmacology, Biberach a.d. Riss, Germany.
authors: Heiko G
authors: HG
authors: Niessen
authors: Boehringer Ingelheim RCV GmbH & Co. KG, Doktor-Boehringer-Gasse 5-11, A-1120, Vienna, Austria.
authors: Flavio
authors: F
authors: Solca
authors: Boehringer Ingelheim Pharma GmbH & Co. KG, Therapeutic Area Oncology, Biberach a.d. Riss, Germany.
authors: Gerd
authors: G
authors: Stehle
authors: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.
authors: Guus A M S
authors: GA
authors: van Dongen
authors: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.
authors: Alex J
authors: AJ
authors: Poot
mesh_terms: D000077716:Afatinib; D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods; D011799:Quinazolines / Q000737:chemistry / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D011799:Quinazolines; D019275:Radiopharmaceuticals; D000077716:Afatinib; C541485:EGFR protein, mouse; D066246:ErbB Receptors
keywords: Afatinib; Fluorine-18; Personalized medicine; TKI-PET; Tyrosine kinase inhibitor