Andrew V Mossine1,2, Sean S Tanzey3, Allen F Brooks1, Katarina J Makaravage4,5, Naoko Ichiishi4,6, Jason M Miller3,7, Bradford D Henderson1, Thomas Erhard8, Christian Bruetting8, Marc B Skaddan9, Melanie S Sanford10, Peter J H Scott11,12. 1. Department of Radiology, University of Michigan, Ann Arbor, MI, USA. 2. Curium Pharma, Nuclear Medicine Manufacturing, Noblesville, IN, USA. 3. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA. 4. Department of Chemistry, University of Michigan, Ann Arbor, MI, USA. 5. Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA. 6. Takeda Pharmaceuticals International Co., Process Chemistry, Boston, MA, USA. 7. Environmental Analysis Branch, US Army Corps of Engineers, Detroit, MI, USA. 8. AbbVie Deustschland GmbH & Co. KG Ludwigschafen, Ludwigshafen, Germany. 9. AbbVie Translational Imaging, North Chicago, IL, USA. 10. Department of Chemistry, University of Michigan, Ann Arbor, MI, USA. mssanfor@umich.edu. 11. Department of Radiology, University of Michigan, Ann Arbor, MI, USA. pjhscott@umich.edu. 12. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA. pjhscott@umich.edu.
Abstract
[18F]6-fluoro-L-DOPA ([18F]FDOPA) is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that is used to image Parkinson's disease, brain tumors, and focal hyperinsulinism of infancy. Despite these important applications, [18F]FDOPA PET remains underutilized because of synthetic challenges associated with accessing the radiotracer for clinical use; these stem from the need to radiofluorinate a highly electron-rich catechol ring in the presence of an amino acid. To address this longstanding challenge in the PET radiochemistry community, we have developed a one-pot, two-step synthesis of high-molar-activity [18F]FDOPA by Cu-mediated fluorination of a pinacol boronate (BPin) precursor. The method is fully automated, has been validated to work well at two separate sites (an academic facility with a cyclotron on site and an industry lab purchasing [18F]fluoride from an outside vendor), and provides [18F]FDOPA in reasonable radiochemical yield (2.44 ± 0.70 GBq, 66 ± 19 mCi, 5 ± 1%), excellent radiochemical purity (>98%) and high molar activity (76 ± 30 TBq/mmol, 2,050 ± 804 Ci/mmol), n = 26. Herein we report a detailed protocol for the synthesis of [18F]FDOPA that has been successfully implemented at two sites and validated for production of the radiotracer for human use.
[18F]6-fluoro-L-DOPA (pan> class="Chemical">[18F]FDOPA) is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that is used to image Parkinson's disease, brain tumors, and focalhyperinsulinism of infancy. Despite these important applications, [18F]FDOPA PET remains underutilized because of synthetic challenges associated with accessing the radiotracer for clinical use; these stem from the need to radiofluorinate a highly electron-rich catechol ring in the presence of an amino acid. To address this longstanding challenge in the PET radiochemistry community, we have developed a one-pot, two-step synthesis of high-molar-activity [18F]FDOPA by Cu-mediated fluorination of a pinacol boronate (BPin) precursor. The method is fully automated, has been validated to work well at two separate sites (an academic facility with a cyclotron on site and an industry lab purchasing [18F]fluoride from an outside vendor), and provides [18F]FDOPA in reasonable radiochemical yield (2.44 ± 0.70 GBq, 66 ± 19 mCi, 5 ± 1%), excellent radiochemical purity (>98%) andhigh molar activity (76 ± 30 TBq/mmol, 2,050 ± 804 Ci/mmol), n = 26. Herein we report a detailed protocol for the synthesis of [18F]FDOPA that has been successfully implemented at two sites and validated for production of the radiotracer for human use.
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