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

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.

Figure 1 |

Radiosyntheses of [¹⁸F]FDOPA and motivation for this work (adapted from Ref. with permission from The Royal Society of Chemistry).

Figure 2 |

Radiosyntheses of [¹⁸F]FDOPA and the TRACERLab automated synthesis module (synthesis module schematics (Supplementary Figures 1 and 2) and timelists (Supplementary Method 1) are provided in the Supplementary Information).

Figure 3 |

Semi-preparative HPLC traces for [¹⁸F]FDOPA prepared using A: the one-pot method (Reproduced from Ref. with permission from The Royal Society of Chemistry), and B: the alternate one-pot method with HLB purification between fluorination and deprotection

Figure 3 |

Semi-preparative HPLC traces for [¹⁸F]FDOPA prepared using A: the one-pot method (Reproduced from Ref. with permission from The Royal Society of Chemistry), and B: the alternate one-pot method with HLB purification between fluorination and deprotection

Figure 4|

Analytical HPLC trace of [¹⁸F]FDOPA using a Luna NH₂ analytical column (RAD top, 282nm UV bottom). Reproduced from Ref. with permission from The Royal Society of Chemistry.

Figure 5|

Chiral HPLC trace of production [¹⁸F]FDOPA (RAD, bottom, black) 6F-D,L-DOPA reference standard (282nm, teal, middle) and 6F-L-DOPA reference standard (282nm, pink, top) using a Chirobiotic T analytical column. Reproduced from Ref. with permission from The Royal Society of Chemistry.