Fully automated synthesis system of 3′-deoxy-3′-[18F]fluorothymidine

https://doi.org/10.1016/j.nucmedbio.2004.01.008Get rights and content

Abstract

We developed a new fully automated method for the synthesis of 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT), by modifying a commercial FDG synthesizer and its disposable fluid pathway. Optimal labeling condition was that 40 mg of precursor in acetonitrile (2 mL) was heated at 150 °C for 100 sec, followed by heating at 85 °C for 450 sec and hydrolysis with 1 N HCl at 105°C for 300 sec. Using 3.7 GBq of [18F]F as starting activity, [18F]FLT was obtained with a yield of 50.5±5.2% (n=28, decay corrected) within 60.0±5.4 min including HPLC purification. With 37.0 GBq, we obtained 48.7±5.6% (n=10). The [18F]FLT showed the good stability for 6 h. This new automated synthesis procedure combines high and reproducible yields with the benefits of a disposable cassette system.

Introduction

3′-Deoxy-3′-[18F]fluorothymidine ([18F]FLT) appears to be the one of the most promising radiopharmaceuticals because of the lack of in vivo degradation, metabolic trapping in proliferating cells, and the favorable half life for PET imaging [1]. Recent clinical studies have also demonstrated that it would be a promising tumor therapy response marker for lung and other kinds of cancer [2], [3].

Many previous papers showed new synthesis methods for [18F]FLT and its precursor but the synthesis methods were rather complicated and the yields were quite low [4], [5], [6], [7], [8]. Recently, Grierson reported the use of a new nosylate precursor [6]. Although the preparation of the precursor was complex and the [18F]FLT synthesis yield still quite low, but this publication suggested that the protection of the pyrimidine ring by NH groups and the use of leaving groups such as nosylate were key parameters to get high yields. Martin et al. also reported a new method for synthesis of [18F]FLT using a new nosylate precursor with an N-BOC-protecting group on the pyrimidine ring. The radiochemical yield obtained with this method was 19.8% (decay corrected) and the synthesis time was 85 min [9].

Our group also reported [18F]FLT synthesis in higher yield using the same precursor used by Martin et al. [10]. In this study, we obtained a radiochemical yield of 42±5.4% and we showed that reaction temperature and precursor concentration were important factors for high yields.

To use [18F]FLT in clinical studies, automation is necessary to reduce unnecessary radiation exposure for the operators and to obtain high radiochemical yield with reproducibility. Herein, we wish to report an automated production system of [18F]FLT using a commercial [18F]FDG synthesis module.

Section snippets

[18F]FLT synthesis module and disposable cassette

TracerLab Mx FDG synthesis module from GEMS Benelux SA (former Coincidence FDG synthesizer) was used for the production of [18F]FLT. The standard disposable [18F]FDG cassette was adapted to the [18F]FLT synthesis as follows: (1) the alumina N and the two C18 Sep-Pak cartridges were removed, (2) the central and right stopcock manifolds were connected together by a silicone tube, and (3) the outlet tube of the cassette was moved from position 11 to position 12 (stopcocks counted from the left to

Results

Overall radiochemical yields highly depended on the amount of precursor and [18F]fluorination temperature. Optimal labeling condition was that 40 mg of precursor in acetonitril (2 mL) at 150°C for 100 sec, followed by heating at 85°C for 450 sec (Table 2). With this condition, we obtained radiochemical yields of 50.5±5.2% (n=28) after HPLC purification (decay-corrected) from 3.7 GBq of [18F]F and radiochemical purities of 98.2±1.2%. We also had similar radiochemical yields of 48.7±5.6% (n=10)

Discussion

Fully automated [18F]FLT synthesis was performed with high radiochemical yield and high radiochemical stability. The radiochemical yield of the automated [18F]FLT synthesis was dependent mainly on the amount of precursor and on the labeling reaction temperature. These results were very similar to those obtained previously with a non-automated process [10]. Although the “precursor vial” used on the TracerLab Mx was filled with 40 mg of precursor, only 34.0±1.5 mg of precursor was really

Conclusion

We developed an automated method of [18F]FLT production using commercial FDG module and modified disposable cassette system. The preparation was simple and gave consistently high radiochemical yield. Automated synthesis of [18F]FLT with high yield and reproducibility would facilitate the clinical application of [18F]FLT.

Acknowledgements

This study was supported by a grant (2002-287) from the Asian Institute for Life Sciences, Seoul, Korea.

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