Synthesis of high-molar-activity [18F]6-fluoro-L-DOPA suitable for human use via Cu-mediated fluorination of a BPin precursor

Andrew V Mossine; Sean S Tanzey; Allen F Brooks; Katarina J Makaravage; Naoko Ichiishi; Jason M Miller; Bradford D Henderson; Thomas Erhard; Christian Bruetting; Marc B Skaddan; Melanie S Sanford; Peter J H Scott

doi:10.1038/s41596-020-0305-9

Synthesis of high-molar-activity [¹⁸F]6-fluoro-L-DOPA suitable for human use via Cu-mediated fluorination of a BPin precursor

Nat Protoc. 2020 May;15(5):1742-1759. doi: 10.1038/s41596-020-0305-9. Epub 2020 Apr 8.

Authors

Andrew V Mossine^{1

2}, Sean S Tanzey³, Allen F Brooks¹, Katarina J Makaravage^{4

5}, Naoko Ichiishi^{4

6}, Jason M Miller^{3

7}, Bradford D Henderson¹, Thomas Erhard⁸, Christian Bruetting⁸, Marc B Skaddan⁹, Melanie S Sanford¹⁰, Peter J H Scott^{11

12}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Validation Study

MeSH terms

Boronic Acids / chemistry*
Chemistry Techniques, Synthetic / methods*
Copper / chemistry*
Dihydroxyphenylalanine / analogs & derivatives*
Dihydroxyphenylalanine / chemical synthesis
Fluorine Radioisotopes
Glycols / chemistry*
Halogenation

Substances

Boronic Acids
Fluorine Radioisotopes
Glycols
pinacol
fluorodopa F 18
Dihydroxyphenylalanine
Copper

Grants and funding

R01 EB021155/EB/NIBIB NIH HHS/United States