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Routine Production of [18F]Flumazenil from Iodonium Tosylate Using a Sample Pretreatment Method: a 2.5-Year Production Report

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Abstract

Purpose

[18F]Flumazenil, which has the advantage of a longer half-life than [11C]flumazenil, is well known for determining of the central benzodiazepine receptor concentrations. However, [18F]flumazenil has not been widely used because fluctuating and relatively low yields render automatic production insufficient for routine and multicenter clinical trials. Here, we describe the results of a 2.5-year production study of [18F]flumazenil using an iodonium tosylate precursor, which allowed us to overcome the limitations of low and fluctuating radiochemical yields.

Procedures

We developed a clinically applicable production system by modifying a commercial synthesizer for the reliable and reproducible production of [18F]flumazenil for routine clinical studies. [18F]Flumazenil was prepared at 150 °C for 5 min in the presence of 4-methylphenyl-mazenil iodonium tosylate (4 mg), a radical scavenger (TEMPO, 1 mg), and [18F]KF/kryptofix 2.2.2 complex in N,N-dimethylformamide (1 ml). In the purification step, the final mixture was pretreated using different cartridges before performing high-performance liquid chromatography (HPLC) separation. Finally, we measured the radiochemical yield and performed quality-control assays on 94 batches.

Results

After carrying out additional purification before HPLC separation using a C18 plus Sep-Pak cartridge, the radiochemical yield of [18F]flumazenil increased from 34.4 ± 9.7 % (without the pretreatment, n = 24) to 53.4 ± 9.0 % (n = 94), and the lifetime of the semi-preparative column was five times that of the column without the C18 plus Sep-Pak cartridge. The mean-specific activity of [18F]flumazenil was 572 ± 116 GBq/μmol at the end of synthesis, and the radiochemical purity was more than 99 %, as determined by analytical HPLC and radio-TLC. [18F]Flumazenil prepared using this method satisfied all quality-control test standards and was highly stable for up to 6 h after preparation.

Conclusions

The results of the 2.5-year production study using an iodonium tosylate precursor indicate that [18F]flumazenil has commercial and routine clinical applicability.

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Acknowledgments

This study was supported by grants (HI09C-1444-010013, 20090078370, HI12C-0035-030013, and 2012R1A1A2005887) from the government of South Korea. In addition, this study was supported by grant no. 11-2012-003 from the SNUBH research fund. We would like to give a special thank to Bio Imaging Korea Co., Ltd., which had provided the necessary iodonium tosylate precursors.

Conflict of Interest

The authors have no conflicts of interest.

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Correspondence to Byung Chul Lee.

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Moon, B.S., Park, J.H., Lee, H.J. et al. Routine Production of [18F]Flumazenil from Iodonium Tosylate Using a Sample Pretreatment Method: a 2.5-Year Production Report. Mol Imaging Biol 16, 619–625 (2014). https://doi.org/10.1007/s11307-014-0738-z

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Key words

  • [18F]Flumazenil
  • Iodonium salt
  • Aromatic [18F]fluorination
  • Central benzodiazepine receptor