Thiophenes as phenyl bio-isosteres: application in radiopharmaceutical design--I. Dopamine uptake antagonists

Possible applications of thiophenes in radiopharmaceutical chemistry have been explored. Thiophene for benzene ring substitution was applied to the synthesis of thienyl-[18F]GBR 13119, an analog of the potent and selective dopamine uptake inhibitor [18F]GBR 13119. In vivo regional brain distribution in mice shows essentially identical results for the thienyl and phenyl compounds (striatum/cerebellum ratios of greater than 4 at 60 min), suggesting successful substitution by the thiophene ring. The extension of this concept to the synthesis of no-carrier-added, high specific activity [18F]fluorothiophenes was examined: 5-[18F]fluoro-2-2-thiophene carboxaldehyde was prepared in 10-20% yields by an unprecedented [18F]fluoride-for-bromo substitution of 5-bromo-2-thiophenecarboxaldehyde. The possible advantages of thiophenes (lower log P, altered metabolism) in radiopharmaceutical chemistry are discussed.