Paul Slobbe1, Albert D Windhorst2, Marijke Stigter-van Walsum3, Robert C Schuit2, Egbert F Smit4, Heiko G Niessen5, Flavio Solca6, Gerd Stehle7, Guus A M S van Dongen8, Alex J Poot8. 1. 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. 2. Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands. 3. Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands. 4. Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands. 5. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Translational Medicine and Clinical Pharmacology, Biberach a.d. Riss, Germany. 6. Boehringer Ingelheim RCV GmbH & Co. KG, Doktor-Boehringer-Gasse 5-11, A-1120, Vienna, Austria. 7. Boehringer Ingelheim Pharma GmbH & Co. KG, Therapeutic Area Oncology, Biberach a.d. Riss, Germany. 8. 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.
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.
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 afatinibtumor 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.
Authors: Max A Kruziki; Brett A Case; Jie Y Chan; Elizabeth J Zudock; Daniel R Woldring; Douglas Yee; Benjamin J Hackel Journal: Mol Pharm Date: 2016-10-10 Impact factor: 4.939
Authors: Adriana Estrada-Bernal; Anh T Le; Andrea E Doak; Vijaya G Tirunagaru; Shevan Silva; Matthew R Bull; Jeff B Smaill; Adam V Patterson; Chul Kim; Stephen V Liu; Robert C Doebele Journal: Clin Cancer Res Date: 2020-12-22 Impact factor: 13.801
Authors: Paul Slobbe; Albert D Windhorst; Marijke Stigter-van Walsum; Egbert F Smit; Heiko G Niessen; Flavio Solca; Gerd Stehle; Guus A M S van Dongen; Alex J Poot Journal: EJNMMI Res Date: 2015-03-20 Impact factor: 3.138
Authors: Paul Slobbe; Albert D Windhorst; Kevin Adamzek; Marije Bolijn; Robert C Schuit; Daniëlle A M Heideman; Guus A M S van Dongen; Alex J Poot Journal: Oncotarget Date: 2017-06-13