NCA F-18 fluoroarylketones: Useful bifunctional radiopharmaceutical intermediates

Abstract

A systematic study of parameters critical to the reproducible and high yield production of [ 18F]fluoroarylketones via the aromatic nucleophilic substitution reaction (S nAr) by NCA [ 18F]F − using enolizable substrates was undertaken. This rational approach involved investigation of the following parameters: substrate, substrate concentration, base, base concentration, and microwave irradiation time. Using this approach, optimal conditions for the production of 4-[ 18F]fluoroacetophenone (4-[ 18F]FAP) were found, as reproducible yields approaching 80% (corrected) were realized; however these or other conditions were not applicable for the production of the positional isomer 2-[ 18F]fluoroacetophenone. They were however found to be applicable with the preparation of 4-[ 18F]fluoropropiophenone (4-[ 18F]FPP). To explore the potential use of the bifunctional nature of [ 18F]FAP, the productions of 1-bromo-4′-[ 18F]fluoroacetophenone ([ 18FFAPBr), 1-(4′-[ 18F]fluorophenyl) ethanol, and methyl 4-[ 18F]fluorophenyl acetate were investigated. Optimization of the bromination of [ 18F]FAP using a variety of reaction conditions was also investigated. Using the optimized reaction conditions, the desired monobrominated product was reproducibly obtained in radiochemical yields in excess of 80% (corrected). The latter two derivatives, 1-(4′-[ 18F]fluorophenyl) ethanol and methyl 4-[ 18F]fluorophenyl acetate were obtained in high yield and in rapid reaction times with no required optimization.