2-Methyl-6-nitrobenzenesulfonyl ester as a novel 18F-labeling precursor

n the development of an efficient 18F-labeling method for the synthesis of positron emission tomography (PET) tracers, it is important not only to improve the efficiency of [18F]fluorine incorporation into the ligand, but also to minimize non-radioactive side products from the precursor during the reaction. These side products extend the time required for purification of the target 18F-labeled compound. Sulfonyl esters prepared from strongly acidic sulfonic acids are promising precursors for 18F-nucleophilic fluorination due to their heightened reactivity towards nucleophilic substitution. However, the expected increase in labeling efficiency is often hampered by competitive degradation reactions due to coexisting bases during 18F-fluorination. In this report, we designed a 2-methyl-6-nitrobenzenesulfonyl (2-MNs) ester as a precursor for 18F-fluorination, in which the methyl group suppresses hydrolysis of the sulfonyl ester via steric hindrance. First, we compared the initial 18F-fluorination of the ethyl 2-MNs ester with that of the ethyl 2-nitrobenzenesulfonyl (Ns) ester, and found that the methyl group at the o-position did not impair the reactivity of 18F-fluorination. When the neopentyl labeling group was tested, an increase in labeling efficiency was observed for the neopentyl 2-MNs ester compared with that of the neopentyl Ns ester, and we decided this could be due to the inhibitory effect of the methyl group on hydrolysis. Ultimately, we achieved the automated synthesis of an 18F-labeled amino acid using a neopentyl labeling group that is homologous to [18F]fluoroethyl tyrosine with the 2-MNs ester as a precursor. This study thereby introduces the concept of using steric hindrance to suppress the hydrolysis of sulfonate esters as a novel strategy for designing beneficial 18F-labeled precursors.