Chemistry Research Laboratory, University of Oxford, Oxford, UK.
Radiobiology Research Institute, Department of Oncology, Churchill Hospital, University of Oxford, Headington, UK.
Nat Protoc. 2020 Apr;15(4):1525-1541. doi: 10.1038/s41596-020-0295-7. Epub 2020 Feb 28.
Positron emission tomography (PET) is a diagnostic nuclear imaging modality that relies on automated protocols to prepare agents labeled with a positron-emitting radionuclide (e.g., F). In recent years, new reactions have appeared for the F-labeling of agents that are difficult to access by applying traditional radiochemistry, for example those requiring F incorporation into unactivated (hetero)arenes. However, automation of these new methods for translation to the clinic has progressed slowly because extensive modification of manual protocols is typically required when implementing novel F-labeling methodologies within automated modules. Here, we describe the workflow that led to the automated radiosynthesis of the poly(ADP-ribose) polymerase (PARP) inhibitor [F]olaparib. First, we established a robust manual protocol to prepare [F]olaparib from the protected N-[2-(trimethylsilyl)ethoxy]methyl (SEM) arylboronate ester precursor in a 17% ± 5% (n = 15; synthesis time, 135 min) non-decay-corrected (NDC) activity yield, with molar activity (A) up to 34.6 GBq/µmol. Automation of the process, consisting of copper-mediated F-fluorodeboronation followed by deprotection, was achieved on an Eckert & Ziegler Modular-Lab radiosynthesis platform, affording [F]olaparib in a 6% ± 5% (n = 3; synthesis time, 120 min) NDC activity yield with A up to 319 GBq/µmol.
正电子发射断层扫描（PET）是一种依赖于自动协议来准备带有正电子发射放射性核素（例如 F）标记的试剂的诊断核成像方式。近年来，出现了新的反应，用于难以通过应用传统放射化学方法访问的试剂的 F 标记，例如需要将 F 掺入未激活的（杂）芳环中的试剂。然而，这些新方法的自动化转化为临床应用进展缓慢，因为在自动化模块中实施新的 F 标记方法时，通常需要对手动协议进行广泛修改。在这里，我们描述了导致多聚（ADP-核糖）聚合酶（PARP）抑制剂 [F]奥拉帕利自动合成的工作流程。首先，我们建立了一种从受保护的 N-[2-（三甲基甲硅烷基）乙氧基]甲基（SEM）芳基硼酸酯前体制备 [F]奥拉帕利的稳健手动协议，以 17%±5%（n=15；合成时间，135 分钟）的非衰变校正（NDC）活性产率，摩尔活性（A）高达 34.6GBq/µmol。该过程的自动化，由铜介导的 F-氟代脱硼化 followed 然后脱保护，在 Eckert & Ziegler Modular-Lab 放射性合成平台上实现，以 6%±5%（n=3；合成时间，120 分钟）的 NDC 活性产率提供 A 高达 319GBq/µmol。
