Enzyme-aided synthesis of a radiofluorinated dissacharide sugar

Objectives Although radiofluorinated sugar analogues have proven valuable tools in nuclear medicine, the chemical synthesis of novel precursors with radiofluorine in defined positions in the molecule is complicated by the similar chemical reactivity of multiple hydroxyl groups in the sugar molecule. This in turn results in complex multi-step protection strategies for generating suitable precursors for radiofluorination. In the current study we examined the use of an approach that employed industrial enzymes to aid synthesis of specific radiofluorination precursors.

Methods A fluorinated and radiofluorinated analogue of the dissacharide sugar, trehalose, was prepared by regioselective mono-deacylation of trehalose octabutyrate using the industrial enzyme, Candida rugosa lipase. The action of this enzyme gave a heptabutyrate product with a free hydroxyl in the 6 position on the molecule. This free hydroxyl was then converted to the corresponding tosylate or triflate.

Results Reaction of the tosylate precursor with tetrabutylammonium fluoride, followed by base hydrolysis to remove the butyrate groups, gave 6-fluoro-6-deoxytrehalose. Similarly reaction of the trilate precusor with potassium [18F]fluoride followed by base hydrolysis gave 6-[18F]fluoro-6-deoxytrehalose, the latter in approximately 10 % overall radiochemical yield.

Conclusions Using the unique regioselectivity of industrial enzymes to monodeacylate fully protected sugars simplifies the production of suitable precursors for radiofluorination, avoiding the need for a complex classical carbohydrate protection strategy.

Research Support U. S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-98CH10886