亲核氟源参与的芳环氟-18标记反应研究进展

doi:10.6023/cjoc202010030

有机化学 ›› 2021, Vol. 41 ›› Issue (5): 1774-1788.DOI: 10.6023/cjoc202010030 上一篇下一篇

综述与进展

亲核氟源参与的芳环氟-18标记反应研究进展

朱源¹, 陈乐园¹, 侯文彬¹^,^*(), 李祎亮¹^,^*()

1 中国医学科学院北京协和医学院放射医学研究所天津市放射医学与分子核医学重点实验室天津 300192

收稿日期:2020-10-21 修回日期:2020-12-29 发布日期:2021-02-07
通讯作者: 侯文彬, 李祎亮
基金资助:
中国医学科学院医学与健康科技创新工程(2016-I2M-3-022); 中国医学科学院医学与健康科技创新工程(2017-I2M-3-019); 中央高校基本科研业务费专项资金(3332018117); 天津市科技计划(18ZXXYSY00110)

Recent Progress in Nucleophilic Fluoride Mediated Fluorine-18 Labeling of Arenes and Heteroarenes

Yuan Zhu¹, Leyuan Chen¹, Wenbin Hou¹^,^*(), Yiliang Li¹^,^*()

1 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College ＆ Chinese Academy of Medical Sciences, Tianjin 300192

Received:2020-10-21 Revised:2020-12-29 Published:2021-02-07
Contact: Wenbin Hou, Yiliang Li
About author:
* Corresponding authors. E-mail: houwenbin@irm-cams.ac.cn;
E-mail: liyiliang@irm-cams.ac.cn
Supported by:
Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2016-I2M-3-022); Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2017-I2M-3-019); Fundamental Research Funds for the Central Universities(3332018117); Science and Technology Project of Tianjin of China(18ZXXYSY00110)

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摘要/Abstract

氟18是用于临床和临床前研究的正电子发射计算机断层扫描(PET)放射性药物中最常用的放射性同位素, 至今已发现发展出多种标记方法. 亲核性¹⁸F氟源由于易于操作且具有高放射性比活度, 在氟标记反应中得到广泛应用. 同时, 引入氟原子可调节药物分子的空间构象和电性, 也能影响其极性、亲脂性和解离常数等药物代谢动力学参数. 芳香环本身代谢稳定性好, 是理想的氟标记载体. 亲核型氟源参与的芳香环氟-18标记反应为放射性药物的标记, 具有高效、操作简便、反应条件温和及原子经济性等优点, 为氟-18标记提供了一条新途径. 根据标记前体结构的不同, 综述了近年来亲核型氟源参与的芳香环氟-18标记方法领域研究进展, 同时探讨了部分反应的机理, 并对本领域未来发展进行了展望.

关键词: 氟-18, 亲核取代反应, 标记反应, 放射性药物, 正电子发射计算机断层扫描

Fluorine-18 is the most frequently used radioisotope in positron emission tomography radiopharmaceuticals for both clinical and preclinical researches. A variety of labeling methodologies have also been developed in recent years. For most purposes, nucleophilic ¹⁸F-fluoride is preferentially used for ¹⁸F-labeling because this reagent is easy to handle and made available with high specific activity. Meanwhile, fluorine substitution has also served the purpose of modulating conformational and stereoelectronic properties, and favorably influences pharmacokinetic parameters such as polarity, lipophilicity and pK_a values. Arenes and heteroarenes are privileged candidates for ¹⁸F-incorporation as they are metabolically robust and therefore widely used for ¹⁸F-labeling. Nucleophilic fluoride mediated fluorine-18 labeling reaction has emerged as a promising green and efficient synthetic tool and provides a novel approach for ¹⁸F-labeling. The recent developments in nucleophilic fluoride mediated fluorine-18 labeling of arenes and heteroarenes are summarized on the basis of different labeling precursor, including phenols, aryl iodoniums, aryl sulfoniums, aromatic metallic compounds and C(sp²)—H bond. The scope of labeling substrate, some application for radiopharmaceuticals and mechanism of several reactions are also discussed.

Key words: fluorine-18, nucleophilic substitution reaction, labeling reaction, radiopharmaceuticals, positron emission tomography

引用此文

朱源, 陈乐园, 侯文彬, 李祎亮. 亲核氟源参与的芳环氟-18标记反应研究进展[J]. 有机化学, 2021, 41(5): 1774-1788.

Yuan Zhu, Leyuan Chen, Wenbin Hou, Yiliang Li. Recent Progress in Nucleophilic Fluoride Mediated Fluorine-18 Labeling of Arenes and Heteroarenes[J]. Chinese Journal of Organic Chemistry, 2021, 41(5): 1774-1788.

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图/表 9

图1. 一些重要的放射性药物

Figure 1. Representative examples of radiopharmaceuticals

图式1. 以酚为前体的脱氧氟代氟-18标记

Scheme 1. [18F]Deoxyfluorination of phenols

图式2. 钌催化酚的氧氟代氟-18标记

Scheme 2. Ruthenium-mediated [18F]deoxyfluorination of phenols

图式3. 以酚为前体的氧化氟代氟-18标记

Scheme 3. Oxidative [18F]fluorination of phenols

图式4. 二芳基碘鎓盐氟-18标记反应的反应选择性及和机理

Scheme 4. Selectivity and mechanism in [18F]fluorination of aryl iodonium salts

图式5. 铜催化二芳基碘鎓盐氟-18标记反应可能的反应机理

Scheme 5. Possible mechanism of copper-catalyzed [18F]fluo- rination of diaryliodonium salts

图式6. 碘叶立德氟-18标记反应可能的反应机理

Scheme 6. Possible mechanism of [18F]fluorination of aryl iodonium ylides

图式7. 以有机钯复合物为前体进行氟-18标记

Scheme 7. [18F]Fluorination of palladium aryl complexes

图式8. 光催化芳香环碳-氢键氟-18化的机理研究

Scheme 8. Possible mechanism of [18F]fluorination of arene C(sp2)—H bonds via organic photoredox catalysis

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亲核氟源参与的芳环氟-18标记反应研究进展

Recent Progress in Nucleophilic Fluoride Mediated Fluorine-18 Labeling of Arenes and Heteroarenes

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