Comparison of two full automatic synthesis methods of 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine using different chemistry modules

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Abstract

We have developed synthesis methods for 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG) using two commercial automatic chemistry modules, Tracerlab MX and Explora RN, and compared radiochemical yields. Synthesis conditions and sequence programs were modified for two modules because both these modules have different mechanical structures, including heater type, vacuum system, reactor, and tubing size. Synthesis using the Tracerlab MX module showed a 21.0±3.8% yield of radiochemical, which was 98±0.9% pure; the total preparation time was 63.0±5.0 min including an HPLC purification step. In contrast, synthesis using the Explora RN module showed a 32.0±1.2% yield of radiochemical, which was 99.0±0.6% pure; the total preparation time was 38±2 min, using different HPLC purification conditions and without the HPLC solvent evaporation step.

Introduction

Non-invasive reporter gene imaging technology with PET and radiopharmaceuticals can be used to show the location and level of expression of reporter genes, as well as to monitor the success of clinical gene therapy protocols (Herschman et al., 2000; Gambhir et al., 1999a, Gambhir et al., 1999b; Tjuvajev et al., 1998). For PET imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression, [124I]/[131I]FIAU, [18F]FHBG, [18F]FHPG, [18F]FFAU, [18F]FEAU, and [18F]FMAU have been reported (Tjuvajev et al., 2002; Alauddin et al., 2004; Sun et al., 2005). Among these probes, [18F]FHBG is considered as one of the most promising radiopharmaceuticals for PET imaging of HSV1-tk expression in vivo, and the probe has been used clinically for human pharmacokinetic and dosimetry studies (Yaghoubi et al., 2001).

Several manual and robotic synthesis methods have been employed to synthesize [18F]FHBG. In the manual synthesis, there were many reports using various methods such as microwave heating to increase radiochemical yields and to have simple purification such as Sep-Pak purification of solvent and unreacted [18F]F (Chang et al., 2007; Ponde et al., 2004; Wang et al., 2003; Shiue et al., 2001; Alauddin and Conti, 1998). These reports, however, showed low radiochemical yield of<20% after HPLC purification as they used DMF or DMSO as reaction solvent. Use of these solvents has the advantage of the possibility of high temperature reaction but may cause problems in the HPLC purification procedure because of their high polarity. In the automatic synthesis results, we also found low radiochemical yields using a high polarity solvent such as DMSO (Peñuelas et al., 2002).

Fully automatic preparation of [18F]FHBG is essential for preclinical and clinical applications to reduce radiation exposure during preparation and to offer a reliable high radiochemical yield. To our knowledge, however, [18F]FHBG has not been prepared by employing commercial disposable cassette-type chemistry modules. We have therefore developed fully automatic synthesis methods using two kinds of chemistry modules, one disposable and one non-disposable cassette-type module, and optimized the synthesis conditions for each module. We also compared radiochemical yields and preparation times including HPLC purification condition.

Section snippets

Precursor and chemicals

The precursor, N2-(monomethoxytrityl)-9-[(4-tosyl)-3-(monomethoxytrityloxy)methyl]but-1-yl]guanine was purchased from FutureChem (Seoul, Korea), and solvents and reagents were purchased from Sigma-Aldrich (Seoul, Korea). [18F]Fluoride was produced by the cyclotrons IBA Cyclone 18/9(Belgium) and CTI RDS 111 (USA).

Manual synthesis of [18F]FHBG

Manual synthesis was performed according to Fig. 1 and we modified previous synthesis conditions. Briefly, [18F]fluoride (370 MBq/0.5 mL) was trapped on a QMA cartridge and eluted with a

Results

Optimal labeling condition for manual synthesis was obtained by incubating 10 mg of precursor in 0.5 mL acetonitrile at 100 °C for 10 min. As heating at 95, 100, 120, and 130 °C showed similar results (Table 1), we chose the highest labeling efficiency condition at 100 °C for the automated [18F]fluorination process. The product could be easily hydrolyzed by 1 N HCl at 85 °C for 5 min.

For the Tracerlab MX, the final radiochemical yields and purity were 21.0±3.8% and 98.0±0.9% (n=5, decay-corrected),

Discussion

We describe here the development of two fully automated methods of synthesizing [18F]FHBG, using two different commercial chemistry modules. We increased the amount of precursor to 10 mg and used CH3CN as the [18F]fluorination solvent. Because of the larger amount of precursor, our [18F]fluorination yield was higher at similar [18F]fluorination temperatures. Increasing the temperature above 100 °C, however, did not result in dramatically higher levels of [18F]fluorination, indicating that 10 mg of

Conclusion

We developed two [18F]fluorination automated methods using Tracerlab MX and Explora RN. Both systems have unique advantages and successfully led to high radiochemical yields and purity for routine clinical applications.

Acknowledgements

This work was supported by Real-time Molecular Imaging and the Mid- and Long-term Nuclear Research program from the Korea Science, Engineering Foundation (KOSEF) grant funded by the Korea government (MOST) and research grant 0710072 (KIM S-K) from the National Cancer Center, Korea.

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