铜介导的放射性氟化反应中的氢化副反应

IF 4.4 Q1 CHEMISTRY, INORGANIC & NUCLEAR

EJNMMI Radiopharmacy and Chemistry Pub Date : 2025-09-08 DOI:10.1186/s41181-025-00384-1

Sarandeep Kaur, Barbara Wenzel, Ramona Oehme, Claudia Wiesner, Klaus Kopka, Rareş-Petru Moldovan

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引用次数: 0

摘要

铜介导的放射性氟化（CMRF）是18F放射化学的一个突破，使18F甚至在富含电子的芳族位置融入分子。近年来，一些改进的协议被报道，以促进CMRF的应用。这些进步主要集中在改善放射化学转化、扩大衬底范围以及实现遥控放射性示踪剂生产的可扩展性。尽管有这些改进，一个主要的挑战仍然存在：原金属化。原脱金属是过渡金属介导的交叉偶联中常见的副反应，其发生机制尚未完全阐明。在18f化学中，氢化副产物（HSP）的形成会干扰所需放射性示踪剂的色谱纯化，导致复杂的放射性示踪剂生产。结果利用以-B(OH)2、-Bpin、-BEpin和-SnBu3为离去基的模型前驱体，研究了影响CMRF加氢反应速率的因素和氢的来源。虽然CMRF反应通常在无水条件下进行，但通过控制化学成分（试剂的类型和摩尔浓度）以及物理参数（时间和温度）来评估HSP的形成速度。此外，用氘化试剂和高分辨率质谱（HRMS）分析进行了实验，以确定还原消除步骤的氢来源。本研究确定了影响CMRF加氢副反应的反应参数，实现了以最小热sp形成的高RCC。最佳反应条件包括温度低、反应时间短、前驱体铜用量少、理想情况下无碱和醇类溶剂。在评价的前体中，-BEpin对HSP的形成最低，而-B (OH)2对HSP的形成最高。总的来说，本研究表明，选择合适的反应试剂和调整反应参数可以在保持最佳放射化学转化的同时大幅减少热sp的形成。图形抽象

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The hydrogenation side-reaction in copper-mediated radiofluorination

Background

Copper-mediated radiofluorination (CMRF) is a breakthrough in ¹⁸F-radiochemistry, enabling ¹⁸F incorporation into molecules even at electron-rich aromatic positions. In recent years, several improved protocols have been reported to advance the application of CMRF. These advancements primarily focus on improving radiochemical conversion, expanding substrate scope, and enabling scalability for remote-controlled radiotracer production. Despite these improvements, one major challenge remains: the protodemetallation. Protodemetallation is a common side reaction in transition metal-mediated cross-couplings that takes place by a mechanism that is not yet fully elucidated. In ¹⁸F-chemistry, the formation of the hydrogenated side product (HSP) can interfere with the chromatographic purification of the desired radiotracer, resulting in complex radiotracer production.

Results

The present work investigates the factors influencing the rate of the hydrogenation reaction as well as the source of hydrogen in the CMRF by use of model precursors bearing -B(OH)₂, -Bpin, -BEpin and -SnBu₃ as leaving groups. While the CMRF reactions are usually carried out under anhydrous conditions, the formation rate of the HSP was evaluated by controlling the chemical constituents (type and molarity of reagents) as well as the physical parameters (time and temperature). Moreover, experiments with deuterated reagents complemented by high-resolution mass spectrometry (HRMS) analysis were carried out to identify the source of hydrogen for the reductive elimination step.

Conclusion

This study identifies reaction parameters that influence hydrogenation side reactions in CMRF, enabling high RCC with minimal HSP formation. The optimal reaction conditions include low temperature, short reaction time, and minimal amount of precursor, copper, and ideally no base and alcohols as solvents. Among the evaluated precursors, –BEpin afforded the lowest HSP formation, while –B(OH)₂ afforded the highest. Overall, this study showed that the selection of proper reaction reagents and the fine-tuning of reaction parameters can substantially reduce the HSP formation while maintaining optimal radiochemical conversion.