Synthesis of [18F]fluoromethyl iodide, a synthetic precursor for fluoromethylation of radiopharmaceuticals

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Abstract

[18F]fluoroiodomethane was labeled via nucleophilic substitution of diiodomethane with [18F]fluoride, and labeling conditions were optimized. The optimized labeling yield was 40±8% (decay-corrected). The synthesis and purification of [18F]fluoroiodomethane took 15 min. The reactions of [18F]fluoroiodomethane with amine, carboxylic acid, thiol and phenoxide groups produced fluoromethylated derivatives with various yields (12–95%). The results indicated that [18F]fluoroiodomethane is a valuable synthetic precursor for the introduction of an [18F]fluoromethyl group into radiopharmaceuticals.

Introduction

The development of a convenient and reliable method to prepare a synthetic precursor for [18F]fluoromethylation of radiopharmacecuticals is of interest in PET chemistry. [18F]fluoromethyliodide, the fluorine-18 analog of methyliodide, is one of the most feasible precursors for [18F]fluoromethylation. Due to the electrowithdrawing effect of fluorine, fluoroiodomethane is expected to be more reactive in SN2 reactions and less reactive in SN1 reactions. [11C]methyliodide is the precursor used to produce the majority of known carbon-11 labeled radiopharmaceuticals. It has been incorporated into a variety of compounds including amines (benzodiazepines, Maziere et al., 1980; N-methyl-l-DOPA, Horti et al., 1992; choline, Rosen et al., 1985), carboxylic acids (Dannals et al., 1985), activated carbanions Oberdorfer, 1984, Chaly and Diksic, 1988, Goethals et al., 1992 and thiols (Langstrom et al., 1976), etc. During the evaluation and application of these carbon-11 radiopharmaceuticals for PET, it is often found that carbon-11 labeled compounds have disadvantages compared to fluorine-18 labeled compounds. The longer half-life of fluorine-18 is desirable if the process to be visualized has a turn-over time longer than 1 h, or because of a need for improved specific activity, which is often higher for fluorine-18 than for carbon-11. The longer half life of the radiotracer also allows eventual distribution of the radiopharmaceuticals to camera sites located at reasonable distances from the production laboratory, such as is done commonly with [18F]FDG. Unfortunately, the methods available for no-carrier-added radiofluorination are limited and mainly restricted to nucleophilic substitution. Fluorination via small prosthetic groups is an alternative route for labeling complex, multisubstituted substrates. Fluoroethyliodide and fluoropropyliodide have been synthesized for this purpose to incorporate fluoroethyl and fluoropropyl groups into radiopharmaceuticals Shiue et al., 1987, Welch et al., 1988. Also, several attempts have been made to prepare [18F]halofluoromethanes as fluoromethylating agents. ([18F]fluoromethyl bromide (Coenen et al., 1986), chlorofluoromethanes (Palmer, 1978), fluoroalkanes, Gatley, 1982, Yagi et al., 1982). However, only poorly reproducible results were reported on functionalized fluoromethanes. Fluoromethyl iodide is the closest analog of methyl iodide which can be labeled with fluorine-18. It may be used to introduce fluorine-18 into molecules in a similar fashion as is done with methyl iodide, thereby making use of a large body of previous work done to optimize labeling methods. Therefore, we developed a method to prepare [18F]fluoromethyl iodide via nucleophilic substitution under mild conditions.

Section snippets

Experimental

Reagents and solvents were obtained from Aldrich Chemical Co. and Fisher Scientific and used without further purification unless otherwise noted. Melting points were recorded on an electrothermal melting point apparatus and are uncorrected. NMR spectroscopy was carried out on either a Varian XL-200 (200 MHz) or a Gemini-300 (300 MHz) instrument using tetramethylsilane (TMS) as internal standard and the chemical shifts are reported in parts per million (ppm) from TMS. Tetrahydrofuran (THF) was

Labeling of [18F]fluoroiodomethane

The yields of reaction of diiodomethane with [18F]fluoride under various conditions (solvent, temperature, time, kryptofix 222, K2CO3) are listed in Table 1. The reaction time for all the listed reactions were 1–10 min. The reaction time did not affect the reaction yield significantly. The listed yield for each solvent were averaged for different reaction times. In dimethylsulfoxide, we observed oxidation of diiodomethane and no fluorination (iodine color appeared and in some cases,

Conclusion

[18F]fluoroiodomethane was labeled in reproducible 40±8% yield by reaction of fluoride with diiodomethane. It was used to label a series of fluoromethylated compounds derived from various functional groups in yields of 12–95% by using methods similar to those commonly used for labeling with [11C]methyl iodide.

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