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通过[F]表氟醇实现两种含3-氟-2-羟丙基部分的F标记示踪剂[F]FMISO和[F]PM-PBB3的自动化放射性合成。

Automated radiosynthesis of two F-labeled tracers containing 3-fluoro-2-hydroxypropyl moiety, [F]FMISO and [F]PM-PBB3, via [F]epifluorohydrin.

作者信息

Ohkubo Takayuki, Kurihara Yusuke, Ogawa Masanao, Nengaki Nobuki, Fujinaga Masayuki, Mori Wakana, Kumata Katsushi, Hanyu Masayuki, Furutsuka Kenji, Hashimoto Hiroki, Kawamura Kazunori, Zhang Ming-Rong

机构信息

Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, 263-8555, Chiba, Japan.

SHI Accelerator Service Ltd, 141-0032, Tokyo, Japan.

出版信息

EJNMMI Radiopharm Chem. 2021 Jul 10;6(1):23. doi: 10.1186/s41181-021-00138-9.

DOI:10.1186/s41181-021-00138-9
PMID:34245396
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8272768/
Abstract

BACKGROUND

[F]Fluoromisonidazole ([F]FMISO) and 1-[F]fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridine-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol ([F]PM-PBB3 or [F]APN-1607) are clinically used radiotracers for imaging hypoxia and tau pathology, respectively. Both radiotracers were produced by direct F-fluorination using the corresponding tosylate precursors 1 or 2 and [F]F, followed by the removal of protecting groups. In this study, we synthesized [F]FMISO and [F]PM-PBB3 by F-fluoroalkylation using [F]epifluorohydrin ([F]5) for clinical applications.

RESULTS

First, [F]5 was synthesized by the reaction of 1,2-epoxypropyl tosylate (8) with [F]F and was purified by distillation. Subsequently, [F]5 was reacted with 2-nitroimidazole (6) or PBB3 (7) as a precursor for F-labeling, and each reaction mixture was purified by preparative high-performance liquid chromatography and formulated to obtain the [F]FMISO or [F]PM-PBB3 injection. All synthetic sequences were performed using an automated F-labeling synthesizer. The obtained [F]FMISO showed sufficient radioactivity (0.83 ± 0.20 GBq at the end of synthesis (EOS); n = 8) with appropriate radiochemical yield based on [F]F (26 ± 7.5 % at EOS, decay-corrected; n = 8). The obtained [F]PM-PBB3 also showed sufficient radioactivity (0.79 ± 0.10 GBq at EOS; n = 11) with appropriate radiochemical yield based on [F]F (16 ± 3.2 % at EOS, decay-corrected; n = 11).

CONCLUSIONS

Both [F]FMISO and [F]PM-PBB3 injections were successfully synthesized with sufficient radioactivity by F-fluoroalkylation using [F]5.

摘要

背景

[F]氟米索硝唑（[F]FMISO）和1-[F]氟-3-((2-((1E,3E)-4-(6-(甲氨基)吡啶-3-基)丁-1,3-二烯-1-基)苯并[d]噻唑-6-基)氧基)丙-2-醇（[F]PM-PBB3或[F]APN-1607）分别是临床上用于成像缺氧和tau病理的放射性示踪剂。这两种放射性示踪剂均通过使用相应的对甲苯磺酸酯前体1或2与[F]F进行直接F-氟化反应，随后去除保护基团来制备。在本研究中，我们使用[F]表氟醇（[F]5）通过F-氟烷基化反应合成了[F]FMISO和[F]PM-PBB3用于临床应用。

结果

首先，通过对甲苯磺酸1,2-环氧丙酯（8）与[F]F反应合成[F]5，并通过蒸馏进行纯化。随后，[F]5与2-硝基咪唑（6）或PBB3（7）作为F-标记前体进行反应，每个反应混合物通过制备型高效液相色谱进行纯化并配制成[F]FMISO或[F]PM-PBB3注射液。所有合成步骤均使用自动F-标记合成仪进行。所得的[F]FMISO在合成结束时显示出足够的放射性（合成结束时为0.83±0.20 GBq；n = 8），基于[F]F具有适当的放射化学产率（合成结束时经衰变校正后为26±7.5%；n = 8）。所得的[F]PM-PBB3也显示出足够的放射性（合成结束时为0.79±0.10 GBq；n = 11），基于[F]F具有适当的放射化学产率（合成结束时经衰变校正后为16±3.2%；n = 11）。

结论

使用[F]5通过F-氟烷基化反应成功合成了具有足够放射性的[F]FMISO和[F]PM-PBB3注射液。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/bef879d196b8/41181_2021_138_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/526f003f2cd2/41181_2021_138_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/72143fb157fa/41181_2021_138_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/bde694f01076/41181_2021_138_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/1ae8f0db3902/41181_2021_138_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/dabda721b449/41181_2021_138_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/bef879d196b8/41181_2021_138_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/526f003f2cd2/41181_2021_138_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/72143fb157fa/41181_2021_138_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/bde694f01076/41181_2021_138_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/1ae8f0db3902/41181_2021_138_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/dabda721b449/41181_2021_138_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7f2/8272768/bef879d196b8/41181_2021_138_Fig6_HTML.jpg

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