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

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Synthesis of high-molar-activity [18F]6-fluoro-L-DOPA suitable for human use via Cu-mediated fluorination of a BPin precursor.
Nature Protocols ( IF 13.1 ) Pub Date : 2020-04-08 , DOI: 10.1038/s41596-020-0305-9
Andrew V Mossine _{1,

2} , Sean S Tanzey ₃ , Allen F Brooks ₁ , Katarina J Makaravage _{4,

5} , Naoko Ichiishi _{4,

6} , Jason M Miller _{3,

7} , Bradford D Henderson ₁ , Thomas Erhard ₈ , Christian Bruetting ₈ , Marc B Skaddan ₉ , Melanie S Sanford ₄ , Peter J H Scott _{1,

3}

Affiliation

[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.

中文翻译：

通过铜介导的 BPin 前体氟化合成适合人类使用的高摩尔活性 [18F]6-氟-L-DOPA。

[18F]6-氟-L-DOPA ([18F]FDOPA) 是一种用于正电子发射断层扫描 (PET) 成像的诊断放射性药物，用于对帕金森病、脑肿瘤和婴儿局灶性高胰岛素血症进行成像。尽管有这些重要的应用，但由于与临床使用放射性示踪剂相关的合成挑战，[18F]FDOPA PET 仍未得到充分利用。这些源于需要在氨基酸存在下对高度富电子的儿茶酚环进行放射性氟化。为了解决 PET 放射化学领域这一长期存在的挑战，我们开发了一种通过铜介导的硼酸频哪醇 (BPin) 前体的氟化，一锅两步合成高摩尔活性 [18F]FDOPA 的方法。该方法是完全自动化的，已被验证可以在两个不同的地点（现场设有回旋加速器的学术设施和从外部供应商购买[18F]氟化物的工业实验室）良好地工作，并以合理的放射化学产率提供[18F]FDOPA (2.44 ± 0.70 GBq, 66 ± 19 mCi, 5 ± 1%)，优异的放射化学纯度 (>98%) 和高摩尔活性 (76 ± 30 TBq/mmol, 2,050 ± 804 Ci/mmol)，n = 26。在此我们报告了合成 [18F]FDOPA 的详细方案，该方案已在两个地点成功实施，并经过验证可用于生产人类使用的放射性示踪剂。

更新日期：2020-04-08

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