Syntheses of fluorine-18 labelled compounds and radiopharmaceuticals by electrophilic fluorination

Previously, the fate of 5-fluoro-L-DOPA in the human brain was unknown because an efficient method for the synthesis of [18F]5-fluoro- L-DOPA in mCi quantities was not available. In the present work, a method for the synthesis of [18F]5-fluoro-L-DOPA in mCi quantities was developed by studying the reactivity and selectivity of fluorine during the electrophilic fluorination of L-DOPA in acidic solvents. As a result of this work, the present study has reported the first clinical study, using positron emission tomography (PET), that compared the in vivo behaviour of [18F]2-, [ 18F]5- and [18F]6-fluoro-L-DOPA, in the living human brain.; The site-specific fluorination method developed in the present work was extended to develop a high-yield synthesis of [18F]3-fluoro- L-α-methyltyrosine, which is a tumour imaging agent. Direct fluorination of L-α-methyltyrosine with [18F]F ₂ in HF solvent produced the 3 fluoro isomer as the major product in 30% radiochemical yield (RCY) with respect to [18F]F₂ , the highest RCY to date. These studies also revealed that a previous report had incorrectly characterized [18F]3,5-difluoro- L-α-methyltyrosine as [18F]₂-fluoro- L-α-methyltyrosine. This methodology was further extended to develop a new PET tracer, [18F]5-fluoro-3-nitro-L-tyrosine, in order to trace “reactive nitrogen species”, which are responsible for tissue damage in vivo.; A recent study has claimed that XeF₂ exchanges with [2,2,2-crypt-M][ 18F] (M = K or Cs) to produce [18F]XeF₂ at room temperature in CH₂Cl₂ solvent and that exchange between F− and XeF₂ cannot occur in CH ₃CN solvent. Contrary to the previous work, the present study showed that both XeF₂ and F− react with CH₂ Cl₂ at room temperature and that XeF₂ fluorinates 2,2,2-crypt under rigorously anhydrous conditions. The major products resulting from these reactions include several hydrochlorofluorocarbons and large amounts of HF and HF₂−. Thus, the exchange between XeF₂ and 18F− reported in the prior work arises from exchange between XeF₂ and HF/HF₂ −, and does not involve fluoride ion. Furthermore, two-dimensional EXSY and single selective inversion NMR spectroscopic studies in the present work have shown that anhydrous [N(CH₃)₄][F] exchanges with XeF₂ in CH₃CN solvent. The exchange between XeF ₂ and F− is postulated to proceed by the formation of the trifluoroxenate(II) anion, XeF₃−, a novel VSEPR system (i.e., the first AX₃E₃ arrangement), as the exchange intermediate.