Automated radiosynthesis of two 18F-labeled tracers containing 3-fluoro-2-hydroxypropyl moiety, [18F]FMISO and [18F]PM-PBB3, via [18F]epifluorohydrin

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

doi:10.1186/s41181-021-00138-9

Abstract

Background[18F]Fluoromisonidazole ([18F]FMISO) and 1-[18F]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 ([18F]PM-PBB3 or [18F]APN-1607) are clinically used radiotracers for imaging hypoxia and tau pathology, respectively. Both radiotracers were produced by direct 18F-fluorination using the corresponding tosylate precursors 1 or 2 and [18F]F−, followed by the removal of protecting groups. In this study, we synthesized [18F]FMISO and [18F]PM-PBB3 by 18F-fluoroalkylation using [18F]epifluorohydrin ([18F]5) for clinical applications.ResultsFirst, [18F]5 was synthesized by the reaction of 1,2-epoxypropyl tosylate (8) with [18F]F− and was purified by distillation. Subsequently, [18F]5 was reacted with 2-nitroimidazole (6) or PBB3 (7) as a precursor for 18F-labeling, and each reaction mixture was purified by preparative high-performance liquid chromatography and formulated to obtain the [18F]FMISO or [18F]PM-PBB3 injection. All synthetic sequences were performed using an automated 18F-labeling synthesizer. The obtained [18F]FMISO showed sufficient radioactivity (0.83 ± 0.20 GBq at the end of synthesis (EOS); n = 8) with appropriate radiochemical yield based on [18F]F− (26 ± 7.5 % at EOS, decay-corrected; n = 8). The obtained [18F]PM-PBB3 also showed sufficient radioactivity (0.79 ± 0.10 GBq at EOS; n = 11) with appropriate radiochemical yield based on [18F]F− (16 ± 3.2 % at EOS, decay-corrected; n = 11).ConclusionsBoth [18F]FMISO and [18F]PM-PBB3 injections were successfully synthesized with sufficient radioactivity by 18F-fluoroalkylation using [18F]5.

Highlights

Fluorine-18 (T1/2 = 109.8 min) is indispensable for the development of positron emission tomography (PET) tracers because its decay characteristic is better than that of carbon-11 (T1/2 = 20.1 min)
We have synthesized 18F-fluoroalkyl agents, such as [18F]fluoro-methyl, ethyl, and propyl bromide ([18F]F(CH2)nBr, n = 1–3) (Yanamoto et al 2009; Yui et al 2010; Zhang et al 2002, 2003, 2004; Zhang and Suzuki 2007), deuterium-substituted [18F]fluoromethyl bromide ([18F]FCD2Br), and its triflate ([18F]FCD2OTf) using an automated 18F-labeling synthesizer (Arakawa et al 2008; Mori et al 2019). Using these 18F-fluoroalkyl agents, we synthesized dozens of 18F-fluoroalkylated tracers starting from the precursors of phenols, carboxylic acids, amines, and amides for PET imaging of receptors, enzymes, and transporters in the brain (Zhang and Suzuki 2007)
With an increase in the amount of 6 from 0.5 to 4 mg, the radiochemical yield of [18F]FMISO gradually increased to 36 % from 0.5 to 2 mg, and marginally increased up to 42 % from 2 to 4 mg [Fig. 4(A)]

Summary

Introduction

We have synthesized 18F-fluoroalkyl agents, such as [18F]fluoro-methyl, ethyl, and propyl bromide ([18F]F(CH2)nBr, n = 1–3) (Yanamoto et al 2009; Yui et al 2010; Zhang et al 2002, 2003, 2004; Zhang and Suzuki 2007), deuterium-substituted [18F]fluoromethyl bromide ([18F]FCD2Br), and its triflate ([18F]FCD2OTf) using an automated 18F-labeling synthesizer (Arakawa et al 2008; Mori et al 2019) Using these 18F-fluoroalkyl agents, we synthesized dozens of 18F-fluoroalkylated tracers starting from the precursors of phenols, carboxylic acids, amines, and amides for PET imaging of receptors, enzymes, and transporters in the brain (Zhang and Suzuki 2007).

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Discussion

Conclusion