Elsevier

Chemical Engineering Journal

Volume 258, 15 December 2014, Pages 62-68
Chemical Engineering Journal

Efficient microscale synthesis of [18F]-2-fluoro-2-deoxy-d-glucose

https://doi.org/10.1016/j.cej.2014.07.077Get rights and content

Highlights

  • [18F]fluorination efficiency can be enhanced by flexible aliphatic tertiary alcohols.

  • [18F]FDG was synthesized from mannose triflate on a micro-scale level with a higher radiochemical yield within shorter time.

  • Radiosynthesis of [18F]FDG was influenced by ratio of tertiary alcohols and DMSO.

  • The concentrations of mannose triflate and bases influence on the microscale substitution reaction yield.

Abstract

Microscale radiosynthesis of [18F]FDG using a miniaturized device has been reported as a promising tool for positron emission tomography. However, small scale [18F]FDG radiosynthesis on micro fluidic devices need to be studied further to evaluate its usefulness. This paper analyzes several micro-scale reactions of [18F]FDG with various reaction conditions to achieve a higher radiochemical yield of [18F]FDG. Synthesis of [18F]FDG was carried out using mannose triflate on a microchip, and the crude product was purified via cartridge purification. The reaction conditions were optimized by examining several factors including reaction solvents, bases and their concentrations, that influence microscale radio synthesis of [18F]FDG. Based on the investigation of several variables and their effects on the radio-synthetic reaction, [18F]FDG was successfully synthesized on a micro-scale level with a radiochemical yield of 71% and within shorter time frame than that of the traditional method. Moreover, purity of the product was greater than 99%. These results show that the new guideline provides a more efficient and effective method of microscale [18F]FDG radiosynthesis.

Introduction

Positron emission tomography (PET), which utilizes the detection of biomolecules with positron emitting isotopes, is a powerful and non-invasive molecular imaging technique that permits the study of molecular and biological processes associated with malfuctions of the human body [1], [2]. PET has been used for early diagnoses, metastases detection, and drug development. Furthermore, it has helped identify specific biochemical pathways that result in various illnesses. As a result, PET has become a fundamental instrument for clinical and preclinical research applications from cardiovascular perfusion to tumor monitoring for healthcare [3], [4], [5]. With this in mind, it is clear that the role of PET is expected to expand and diversify in the field of medical research [6].

2-Deoxy-2-[18F]fluoro-d-glucose ([18F]FDG), a glucose analog containing a fluoride atom on the 2-carbon of glucose, is the most widely used radiopharmaceutical substance within medical cancer imaging that uses PET [7], [8]. FDG was developed at Brookhaven National Laboratory (USA) and used for studying tumor metabolism [9]. In 1976, the first human images were obtained using FDG [10]. Since the approval of FDG by the FDA for clinical administration in 2000, it has been used for detecting cancer and monitoring a variety of malignant tumors in patients at various stages by measuring glucose uptake into their tissues [11], [12], [13]. Since then, [18F]FDG has been the radiopharmaceutical substance of choice for PET tumor imaging, As a result, the demand for [18F]FDG is expected to grow at a rate of 30% annually for the next couple years [14]. The expected increase in PET’s demand makes it highly likely that FDG suppliers install more medical cyclotron during the next several years, resulting in a larger scale production of [18F]FDG.

The mechanism of [18F]FDG uptake by the tumor cell has been previously discovered [15], [16]. As an analog of glucose, FDG is absorbed into the living cell by facilitated glucose transport, followed by phosphorylation via hexokinase. The metabolite (fluoro-2-deoxyglucose-6-phosphate) is not further processed and accumulates in the cells, in proportion to the metabolism of glucose. The accumulation of phosphorylated [18F]FDG produces a gradient between the tumor and its surrounding tissues, which allows the detection of cancer lesions. Phosphorylated [18F]FDG acts as an indicator of glucose uptake and hexokinase activity in the human tissue.

Ever since the method of [18F]FDG synthesis was first suggested by Wolf and co-workers at Brookhaven National Laboratory [17], various improvements of [18F]FDG syntheses have been made including several manual and automatic methods [18], [19], [20], [21], [22]. Until now, [18F]FDG has been produced commercially by available batch-processing synthesis modules. The problem is that these methods require manipulating large amounts of precursors in harsh reaction conditions, such as high [18F] fluorination temperature.

To prevent this issue, miniaturizing these macroscale process is necessary especially because of that fact that a small amount of chemical quantities are used during radiolabelling making PET radiochemistry amenable to miniaturization. As a result, microfabrication technology for radiosynthesis of PET probes using small-volume has been reported as an alternative technique for producing PET tracers such as [18F]FDG for imaging study [23], [24], [25], [26], [27], [28], and recently, we have reported the radiochemical synthesis of several PET tracers on an electrowetting on dielectric (EWOD), an all-electronic digital microfluidic chip [29], [30], [31], [32].

Microfluidic synthesis platforms are attractive, potential tools for PET radiochemistry applications because this technology provides several important advantages over current PET radiosynthesis methods: (1) The amount of chemical reagents, including precursors, for synthesis can be significantly reduced which can potentially save valuable chemical materials and prevent the discarding of waste. Small scale reactions will work for the synthesis of PET tracers because PET imaging requires only trace amounts of the compound (a single nanogram is enough for a human body scan). (2) The time it takes for radiosynthesis can be shortened due to a more rapid and efficient reaction in miniaturised reactors with precise control of reaction conditions such as heating, transporting and mixing of chemical reagents. This will allow for an enhanced reaction rate compared to the reaction rate using macroscale-radiosynthesis. (3) Multiple radiosynthetic reactions can be simplified via an integrated automation system. (4) Only a relatively small space will be needed to perform radiosynthetic reactions on the small chip.

Despite the increasing interest in the use of miniaturized devices for microscale reactions [33], [34], microscale radiosynthesis of [18F]FDG has yet to be extensively studied. In this study, we outline an efficient method of synthesizing [18F]FDG by investigating various reaction conditions with applications to other microscale radiosynthetic reactions.

Section snippets

Materials and instrumentations

2-Phenyl-2-butanol, 2,3-dimethyl-2-butanol, 2-methyl-2-pentanol, anhydrous dimethyl sulfoxide, potassium carbonate(K2CO3), cesium carbonate (Cs2CO3), potassium bicarbonate (KHCO3), 4,7,13,16,21,24,-hexaoxa-1,10, diazobicyclo(8.8.8) hexacosane (Kryptofix, K222), HCl, anhydrous acetonitrile (MeCN, 99.8%), hexanes, ethyl acetate, and ethanol were purchased from Sigma–Aldrich Chemical Co. (St. Louis, MO). 1,3,4,6-tetra-O-acetyl-2-O-trifluoro-methanesulfonyl-β-d-mannopyranose (mannose triflate, FDG

Microscale radiosynthesis of [18F]FDG

Based on several key advantages over macroscale reactions (low reagents usage, small space for reaction, enhanced mixing efficiency, controlled reaction condition), microscale radiolabelling using the microfluidic device indicated relative benefits of radiosynthesis over the current macroscale reaction method. Typically, radiosynthesis of [18F]FDG on miniaturized devices show low radiochemical yield in the range of 22–50% [24], [25], [27], [28]. Therefore, we investigated crucial factors which

Conclusion

In conclusion, we developed a highly efficient, microscale radiosynthetic method for [18F]FDG from mannose triflate. The fluorination efficiencies of mannose triflate on a chip were varied depending on the solvent choice. In this study, we demonstrated that the phenyl ring with its rigid steric hindrance decreased fluorination efficiency, while flexible, bulky solvents such as 2,3-dimethyl-2-butanol enhanced fluorination efficiency. Small amounts of DMSO paired with 2,3-dimethyl-2-butanol were

Acknowledgements

This work was supported by the Robert A. Welch Foundation (F-1741). We also thank C.-S. Oh for assistance in acquiring data.

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