Radiosynthesis of 8-Fluoro-3-(4-[18F]Fluorophenyl)-3,4-Dihydro-1-Isoquinolinamine ([18F]FFDI), a Potential PET Radiotracer for the Inducible Nitric Oxide Synthase

Abstract

A selective and potent iNOS inhibitor, 8-fluoro-3-(4-fluorophenyl)-3,4-dihydro-1-isoquinolinamine (IC50 =0.16 μM) has been developed recently [8]. Based on that inhibitor, a novel PET imaging tracer intended for in vivo assessment of the iNOS, the F-18 labeled 8-fluoro-3-(4-[18F]fluorophenyl)-3,4-dihydro-1-isoquinolinamine ([18F]FFDI) was synthesized. [18F]FFDI was first prepared with radiochemical yield of 12-28% (with decay correction to EOS), low specific radioactivity, and low chemical purity by the direct aromatic nucleophilic substitution of 8-fluoro-3-(4-nitrophenyl)-3,4-dihydro-1-isoquinolinamine. Here an alternate two step synthesis is reported, in which nucleophilic [18F]fluoride substitution of 4-nitro-benzaldehyde and 4-N,N,N-trimethylammoniumbenzaldehyde triflate yielded 4-[18F]fluorobenzaldehyde, which was then converted to N-Trimethylsilyl-4-[18F]fluorobenzaldimine. N-Trimethylsilyl-4-[18F]fluorobenzaldimine reacted with the 2-fluoro-6-methyl-benzonitrile to form [18F]FFDI. The total synthesis took 115-128 min and the isolated yield was in the range of 15-26% (with decay correction to EOS), the radiochemical purity of the final product was higher than 99% and the specific radioactivity at the end of synthesis was typically 1212 ± 870 Ci/mmol (n=3). The final product was prepared as a sterile saline solution suitable for in vivo use on animals.