β-氟胺类化合物18F 放射性标记方法的开发

doi:10.6023/A24080235

摘要/Abstract

β-氟胺是生物活性分子中一类重要的结构, 其¹⁸F放射标记方法研究将促进β-氟胺类分子的活体可视化评估与研究. 在此次研究中, 引入新型[¹⁸F]AgF标记试剂以促进氮杂环丙烷氟化开环反应以制备了[¹⁸F]β-氟胺类衍生物. 前期条件优化结果显示标记反应不需要添加额外银盐和酸, 且反应对空气和微量的水有着良好的兼容性, 避免了繁杂的放射性除水过程. 高效液相色谱分离谱图显示标记产物放射化学转化率大于80%, 进一步对收集后的放射产物分析显示其放射收率大部分在30%以上, 关键标记产物2a比活度为15.6±2.9 GBq/μmol. 随后底物适用性筛选也表明反应对于环状融合和脂肪烃等多样的氮杂环丙烷都有着较为良好的兼容性. 总之, 该研究发展了一种针对β-氟胺较为通用的¹⁸F放射标记方法, 反应简单高效, 为β-氟胺类的相关分子可视化研究提供了新的思路.

关键词: 放射性氟化反应, β-氟胺, 正电子发射计算机断层扫描, 开环反应

β-Fluoroamines represent a crucial motif in biological and pharmaceutical sciences, largely due to the introduction of fluorine, which enhances the binding affinity, metabolic stability, and bioavailability of target molecules. This makes them highly valuable in the realm of drug discovery. Among the various radionuclides utilized in nuclear medicine imaging, fluorine-18 (¹⁸F) is the most prevalent. Its favorable physicochemical properties, including a half-life of 109.8 min, facilitate optimal target-to-background ratios in imaging processes. Additionally, ¹⁸F is advantageous for multi-step synthesis and transportation, and its decay produces oxygen-18 (¹⁸O) atoms, which are harmless to humans. Given this context, our research aims to synthesize β-fluoroamine positron emission computed tomography (PET/CT) imaging agents with significant potential applications. Developing an effective radiolabeling methodology will greatly advance the in vivo visualization and evaluation of target molecules. In this study, we employed [¹⁸F]AgF in the hydro fluorination of aziridines to achieve the radiosynthesis of [¹⁸F]β-fluoroamines. Preliminary optimizations revealed that additional silver salts and acids were unnecessary, and the labeling process does not require azeotropic drying. This method exhibits good compatibility with light, water, and oxygen, successfully circumventing the complex radioactive dehydration processes while also facilitating automatic labeling. Moreover, the reaction delivered excellent radiochemical conversion (RCC) and moderate radiochemical yield (RCY) in optimized conditions. Radioactive high performance liquid chromatography (Radio-HPLC) spectrum shows that the radiochemical conversion rate of labeled products is more than 80%. Further analysis of the collected radioactive products shows that most of the reactions have a radiation yield of more than 30%. For the key molecule 2a, we conducted a calculation of the specific activity. The higher the specific activity, the greater its potential for biological applications. After three experiments, the specific activity of 2a was determined to be 15.6±2.9 GBq/μmol. Also, the reactions have good compatibility with fused-ring and aliphatic derivatives of aziridines with various function groups. Overall, we have developed a highly efficient and easy-handling radiolabeling method for the radiosynthesis of β-fluoroamines. This solution provides greater flexibility when designing related radiopharmaceuticals.

Key words: radiofluorination, β-fluoroamine, positron emission computed tomography (PET), ring opening reaction

引用此文

殷正旭, 徐国强, 陈腾祥, 韩俊斌. β-氟胺类化合物¹⁸F 放射性标记方法的开发[J]. 化学学报, 2024, 82(11): 1120-1123.

Zhengxu Yin, Guoqiang Xu, Tengxiang Chen, Junbin Han. Radiosynthesis of β-Fluoroamines with ¹⁸F[J]. Acta Chimica Sinica, 2024, 82(11): 1120-1123.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 4

图式1. 含有β-氟胺结构的活性药物分子

Scheme 1. Selected examples of β‐fluoroamine unit in pharmaceuticals

图式2. 通过氮杂环丙烷18F标记β-氟胺类化合物的方法

Scheme 2. Various approaches to the radiosynthesis of β-fluorinated amine

Entry	Additive	Acid	Solvent	Temp./℃	RCY/%
1^b	AgOAc	HOAc	MeCN	110	0
2^b	—	HOAc	MeCN	110	0
3^c	AgOAc	—	MeCN	110	8
4^c	—	—	MeCN	110	13
5	—	—	MeCN	110	42
6	—	—	DCE	110	30
7	—	—	DMSO	110	23
8	—	—	DMF	110	18
9	—	—	MeCN	80	13
10	—	—	MeCN	50	7

表1. 放射标记条件的优化a

Table 1. Optimization of radiolabeling reaction conditions

表2. 18F放射标记底物的扩展

Table 2. Scope of radiosynthesis β-[18F]fluoroamine

参考文献 26

[1]	Gawne, P. J.; Man, F.; Blower, P. J.; Rosales, T. M. R. Chem. Rev. 2022, 122, 10266.
[2]	Schwenck, J.; Sonanini, D.; Cotton, J. M.; Rammensee, H.-G.; la Fougère, C.; Zender, L.; Pichler, B. J. Nat. Rev. Cancer. 2023, 23, 474.
[3]	McCluskey, S. P.; Plisson, C.; Rabiner, E. A.; Howes, O. Eur. J. Nucl. Med. Mol. Imaging. 2020, 47, 451.
[4]	Deng, Y.-J.; Zhu, H.; Yang, Z.; Peng, Z.-P.; Jia, J.-H. JNRC 2020, 33, 250 (in Chinese).
	(邓虞娇, 朱华, 杨志, 彭志平, 贾建华, 核化学与放射化学, 2020, 33, 250.)
[5]	Singh, S. B.; Ng, S. J.; Lau, H. C.; Khanal, K.; Bhattarai, S.; Paudyal, P.; Shrestha, B. B.; Naseer, R.; Sandhu, S.; Gokhale, S.; Raynor, W. Y. Cardiol. Ther. 2023, 12, 85.
[6]	John, P. S. J. Nucl. Med. 2023, 64, 12.
[7]	Rong, J.; Haider, A.; Jeppesen, T. E.; Josephson, L.; Liang, S. H. Nat. Commun. 2023, 14, 3257.
[8]	Inoue, M.; Sumii, Y.; Shibata, N. ACS Omega 2020, 5, 10633.
[9]	Wang, C.-Q.; Feng, C. Acta Chim. Sinica 2024, 82, 160 (in Chinese).
	(王成强, 冯超, 化学学报, 2024, 82, 160.) doi: 10.6023/A23080373
[10]	Wang, L.-B.; Liu, M.-H.; Zu, Y.-M.; Yao, H.; Wu, C.; Zhang, R.-X.; Ma, W.-N.; Lu, H.-G.; Xi, S.; Hua, L.; Wang, G.-L.; Tang, Y.-F. Eur. J. Med. Chem. 2022, 236, 11426.
[11]	Asati, V.; Mahapatra, D. K.; Bharti, S. K. Eur. J. Med. Chem. 2019, 172, 95.
[12]	Patel, H.; Pawara, R.; Ansari, A.; Surana, S. Eur. J. Med. Chem. 2017, 142, 32.
[13]	Wu, T.; Yin, G.; Liu, G.-S. J. Am. Chem. Soc. 2009, 131, 16354.
[14]	Li, Y.; Bao, J.; Zhang, Y.; Peng, X.; Yu, W.; Wang, T.; Yang, D.; Liu, Q.; Zhang, Q.; Fu, J.-K. Chem 2022, 8, 1147.
[15]	Dank, C.; Ielo, L. Org. Biomol. Chem. 2023, 21, 4553.
[16]	Fan, R.-H.; Zhou, Y.-G.; Zhang, W.-X.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 2004, 69, 335.
[17]	Kalow, J. A.; Schmitt, D. E.; Doyle, A. G. J. Org. Chem. 2012, 77, 4177.
[18]	Zhu, L.; Xiong, J.; An, J.; Chen, N.; Xue, J.; Jiang, X.-X. Org. Biomol. Chem. 2019, 17, 3797.
[19]	Okoromoba, O. E.; Li, Z.; Robertson, N.; Mashuta, M. S.; Couto, U. R.; Tormena, C. F.; Xu, B.; Hammond, G. B. Chem. Commun. 2016, 52, 13353.
[20]	Roehn, U.; Becaud, J.; Mu, L.; Srinivasan, A.; Stellfeld, T.; Fitzner, A.; Graham, K.; Dinkelborg, L.; Schubiger, A. P.; Ametamey, S. M. J. Fluorine Chem. 2009, 130, 902.
[21]	Schjoeth-Eskesen, C.; Hansen, P. R.; Kjaer, A.; Gillings, N. ChemistryOpen 2015, 4, 65. doi: 10.1002/open.201402081 pmid: 25861572
[22]	Lee, S. J.; Brooks, A. F.; Ichiishi, N.; Makaravage, K. J.; Mossine, A. V.; Sanford, M. S.; Scott, P. J. H. Chem. Commun. 2019, 55, 2976.
[23]	Thompson, S.; Lee, S. J.; Jackson, I. M.; Ichiishi, N.; Brooks, A. F.; Sanford, M. S.; Scott, P. J. H. Synthesis 2019, 51, 4401.
[24]	Zhao, Q.; Isenegger Patrick, G.; Wilson Thomas, C.; Sap Jeroen, B. I.; Guibbal, F.; Lu, L.; Gouverneur, V.; Shen, Q.-L. CCS Chem. 2020, 3, 1921.
[25]	Gao, X.-Y.; Gong, K.-H.; Wang, M.-W.; Xu, B.; Han, J.-B. Org. Lett. 2022, 24, 6438.
[26]	Gong, K.-H.; Yin, Z.-X.; Song, P.-F.; Xu, B.; Han, J.-B. Synlett 2024, 35, 1569.

β-氟胺类化合物¹⁸F 放射性标记方法的开发

Radiosynthesis of β-Fluoroamines with ¹⁸F

RichHTML

PDF

补充材料

可视化

摘要/Abstract

引用此文

分享此文

图/表 4

参考文献 26

相关文章 14

编辑推荐

相关统计

本文评价

[1]	范雪峰, 赵会君, 朱晨. 羰基兼容的氟代反应及远端氟代脂肪酮合成的近期进展[J]. 化学学报, 2015, 73(10): 979-983.
[2]	陈花磊, 李嗣锋, 徐建斌, 杨清镜, 刘珊珊, 周永云, 黄超, 樊保敏. 钯催化芳基乙炔对氧/氮杂苯并降冰片烯开环反应研究[J]. 化学学报, 2013, 71(9): 1243-1247.
[3]	钱延龙,陈斌,金军挺,黄吉玲. 钌催化降冰片烯开环移位聚合的研究[J]. 化学学报, 2000, 58(8): 1050-1052.
[4]	邵瑞链,杨光富,苗伟时,杨敏华,成俊然. 2-氯-2-氧代(硫代)-1, 3, 2-二氧磷杂环己烷的甲醇解及其开环异构化反应[J]. 化学学报, 1998, 56(9): 920-924.
[5]	梁宏,费昌沛. 1.6-缩水-2,4-二-氧-苄基-β-D-吡喃葡萄糖合成、开环及立体选择性成苷反应研究[J]. 化学学报, 1996, 54(2): 198-205.
[6]	唐作华,陈建设,孙泽民,田安民,鄢国森. 二环丁烷[1.1.0]开环反应的量子化学研究[J]. 化学学报, 1996, 54(10): 937-942.
[7]	孙华斌,刘成卜,邓从豪. 环丙基氮烯开, 闭环异构化反应理论研究[J]. 化学学报, 1994, 52(6): 556-561.
[8]	郭灿城,张尚,雷裕武. 亚碘酰苯氧化单和双(卟啉铁)反应的取代基效应研究[J]. 化学学报, 1993, 51(9): 928-932.
[9]	李玉桂,包建春. 双环笼状磷酸酯衍生物的研究Ⅵ:4-取代-2,6,7-三氧杂-1-磷杂双环[2.2.2]辛烷的反应研究[J]. 化学学报, 1993, 51(6): 602-606.
[10]	陈家碧,殷建国,徐维,来鲁华,张泽莹,邵美成. 烯烃配位的过渡金属卡宾配合物的研究XVI:四氟苯并双环[2,2,2]辛三烯三羰基铁的新奇开环反应-新型螯合双烯丙基三羰基铁配合物的合成和结构[J]. 化学学报, 1990, 48(2): 195-203.
[11]	丁新腾,葛羽,滕铸,范君瑶. 3-氯-2-烃基四氢吡喃的镁开环反应[J]. 化学学报, 1987, 45(11): 1138-1139.
[12]	许临晓,陶凤岗,于同隐. 超声波作用下丙二烯和双环丁烷衍生物的合成[J]. 化学学报, 1986, 44(11): 1134-1138.
[13]	周维善,张联,许杏祥. 青蒿素及其一类物的结构和合成XVI.青蒿戊素的合成和α-环氧青蒿酸甲酯环氧的开环反应[J]. 化学学报, 1985, 43(9): 845-851.
[14]	王积涛,谢庆兰,杨学茹. 三甲基酰氧基硅烷与环氧氯丙烷的开环反应[J]. 化学学报, 1983, 41(3): 274-278.