Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
Curium Pharma, Nuclear Medicine Manufacturing, Noblesville, IN, USA.
Nat Protoc. 2020 May;15(5):1742-1759. doi: 10.1038/s41596-020-0305-9. Epub 2020 Apr 8.
[F]6-fluoro-L-DOPA ([F]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, [F]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 [F]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 [F]fluoride from an outside vendor), and provides [F]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 [F]FDOPA that has been successfully implemented at two sites and validated for production of the radiotracer for human use.
[F]6-氟-L-多巴 ([F]FDOPA) 是一种正电子发射断层扫描 (PET) 成像的诊断放射性药物，用于成像帕金森病、脑肿瘤和婴儿局灶性胰岛素瘤。尽管有这些重要的应用，[F]FDOPA PET 的应用仍然不足，因为与临床使用相关的放射性示踪剂获取存在合成挑战；这些源于需要在氨基酸存在下对高度富电子儿茶酚环进行放射性氟化。为了解决 PET 放射化学界长期存在的这一挑战，我们开发了一种一锅两步法，通过铜介导的频哪醇硼酸酯 (BPin) 前体的氟化来合成高摩尔活性的 [F]FDOPA。该方法完全自动化，已经在两个独立的站点（一个有现场回旋加速器的学术机构和一个从外部供应商购买 [F]氟化物的工业实验室）进行了验证，并且以合理的放射化学产率（2.44 ± 0.70 GBq，66 ± 19 mCi，5 ± 1%）提供 [F]FDOPA，放射化学纯度>98%，摩尔活性高（76 ± 30 TBq/mmol，2,050 ± 804 Ci/mmol），n = 26。本文报告了一种详细的 [F]FDOPA 合成方案，该方案已在两个站点成功实施，并验证了用于人体使用的放射性示踪剂的生产。
