Presentation Simple method for introduction of 3-[18F]fluoro-2-hydroxypropyl group and application for synthesis of 18F-labeled ligand

Fujinaga, Masayuki  ,  Ohkubo, Takayuki  ,  Yamasaki, Tomoteru  ,  Zhang, Yiding  ,  Hatori, Akiko  ,  Kumata, Katsushi  ,  Nengaki, Nobuki  ,  Ming-Rong, Zhang

2017-05-15
Description
Objectives: 18F-Fluoroalkylation is a useful method for introduction of fluorine-18 into molecules containing NH, OH, and SH-groups, analogously to the 11C-methylation with [11C]CH3I. Moreover, introduction of [18F]fluoroalkyl group could sometimes lead to significant improvement of in vitro properties and in vivo behaviors. We have developed a 18F-fluoroalkylation route with [18F]FMeOTf, [18F]FEtBr or [18F]FPrBr etc., which could be purified by simple distillation using an automated synthesis system [1]. Furthermore, we have routinely produced clinically useful 18F-ligands, such as [18F]FMeNER-d2, [18F]FEDAC and [18F]FEtPE2I by using of these agents. To further extend application of this technique, here, we developed a simple method for introducing 3-[18F]fluoro-2-hydroxypropyl group into phenol precursors with [18F]epifluorohydrin ([18F]2) and applied the method to synthesize 18F-labeled ligands.Methods: Glycidyl tosylate 1 was synthesized by reaction of glycidol and tosyl chloride with K2CO3. Unlabeled 3 and 4 were prepared by reaction of corresponding phenol derivatives and 2 in the presence of base. [18F]3 and [18F]4 was synthesized by reacting with phenol precursors with [18F]2 using a homemade automated synthesis system.Results: We used 4-phenylphenol as a model substrate. After 18F-fluorination of 1 (10 L) with [18F]fluoride ion in 1,2-dichlorobenzene at 130 oC, [18F]2 (b.p. 85-86 oC) was formed and then purified by distillation into a DMF solution containing desmethyl precursor (1 mg) and NaOH for 2 min. The radiochemical yield of [18F]2 was estimated to be 80% (based on the [18F]fluoride ion, corrected for decay). After the trapping, this reaction mixture was heated at 130 oC for 20 min. By purification for the reaction mixture using semi-preparative HPLC, [18F]3 was obtained with a synthesis time of 68 min. As application of this reagent for development of 18F-labeled ligand, [18F]4 as a new TSPO ligand was synthesized by reaction of the corresponding precursor with [18F]2. After HPLC purification and formulation, [18F]4 was obtained with 5% radiochemical yield (isolated-yield).Conclusion: We have successfully developed a convenient and reliable technique for producing [18F]2 using a home-made automated synthesis system. This reagent has been used to introduce 3-[18F]fluoro-2-hydroxypropyl group into PET ligand candidates, such as [18F]4. This novel PET ligand is now available for evaluation in mice or rat and improvement for the radiochemical yield is on progress.Acknowledgements:References: [1] Zhang M-R, et al, Curr Top Med Chem., 2007, 7(18), 1817-1828.
22nd International symposium on radiopharmaceutical science (ISRS)

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