The Direct Electrophilic Fluorination of Aromatic Amino Acids and Their Role in Diagnostic Imaging

Abstract

<P> Fluorine-18 labeled 6-fluoro-3, 4-dihydroxy-phenyl-L-alanine (6-FDOPA) has been used in conjunction with Positron Emission Tomography (PET) to study the dopamine metabolism in the living human brain and also to monitor gastrointestinal carcinoid tumors. Elemental fluorination of L-DOPA in anhydrous HF (aHF) or aHF/BF3 has been shown to be an efficient method for the synthesis of 6-fluoro-L-DOPA. Utilization of aHF, however, is not desirable in a hospital environment owing to its hazardous nature. This work has consequently focused on the development of new methodologies for the direct electrophilic fluorination of aromatic amino acids, which circumvent the use of aHF. </p> <p> The present work has shown that the reactivity and selectivity of F2 towards L-DOPA in CF3S03H is comparable to that in aHF. The discovery and versatility of this new synthetic procedure has led to the production of 6-[18F]fluoro-L-DOPA, 6[18F]fluoro-D-DOPA, 4-[18F]fluoro-L-m-tyrosine (4-FMT) and 6-(8F]fluoro-L-m-tyrosine (6-FMT) in high radiochemical yields that are not only suitable for small animal imaging, but are also suitable for clinical use in human subjects. Because of the low volatility of CF3S03H, its removal from the reaction mixture was accomplished by use of an anion exchange resin in acetate form. The syntheses of2-, 4-and 6-FMT were also achieved by the direct fluorination of m-tyrosine (MT) in H20. The effect of temperature on the fluorination of MT was investigated and it was shown that, unlike CF3S03H, optimal conditions in H20 were attained at elevated reaction temperatures. </p> <p> There have been several reports relating to the formation of [18F]OF2 as a major byproduct (up to 20%) in the gas phase nuclear reaction, 180(p,n)18F. This reaction is used for the routine production of [18F]F2 which, in tum, is utilized for the syntheses of PET tracers such as radiofluorinated aromatic amino acids. Because the reactivity of OF2 has been reported to be similar to that of F2, its selectivity as a fluorinating agent towards aromatic amino acids was investigated. The effect of solvent acidity on the fluorination of MT using OF2 was studied and it was shown that, in contrast with the reactivity of F2 in superacids, OF2 is a more efficient fluorinating agent in less acidic solvent media. The use of H20 as the solvent medium for fluorination ofMT resulted in the formation of 19FFMT isomers in 4.35 ±0.04% yield. Consequently, the potential use of OF2 as a fluorinating agent for aromatic amino acids was also investigated for L-phenylalanine, 3nitro-L-tyrosine, 4-nitro-DL-phenylalanine, L-DOPA, 3-0-methyl-L-DOPA, 3,4dimethoxy-L-phenylalanine, m-, p-and a-tyrosine. In these studies, the only aromatic system fluorinated by OF2 was MT, indicating that the presence of [18F]OF2 as a byproduct resulting from the nuclear reaction, 180(p,n)18F, does not have a significant impact on the syntheses of radio fluorinated aromatic amino acids that have applications in PET imaging. </p>