Objectives: The use of the [18 F] cyclobutyl group as a potentially metabolic stable surrogate group for [18 F] fluoroalkyl groups has been notified [1-3]. The radiolabeling of a cis-1, 3-cyclobutanediol bis-toluenesulfonateprecursor and its conjugation to L-Tyrosine were reported with an overall yield of 8%±5.5 (n= 14, decay corrected). The aim of this work was to improve upon the yield by synthesizing various precursors with different sulfonate leaving groups and evaluating them for their ability to incorporate [18 F] fluoride to form the 3-[18 F] fluorocyclobutan-1-ol sulfonate 2. Furthermore the effect of these leaving groups on the conjugation reaction of 2 with L-Tyrosine to give the 3-[18 F] fluorocyclobutyl-L-tyrosine ([18 F] FCBT) should be assessed.Methods: Various symmetrical cis-1, 3-cyclobutanediol bis-sulfonates 1 were synthesized with the different commonly-used sulfonate leaving groups, ie tosylate, mesylate, triflate, nosylate and 3, 4-dibromobenzenesulfonate. These precursors were subjected to nca nucleophilic radiofluorination. The 18 F-labeled intermediates 2 were purified and the alkylation reaction with L-Tyrosine under standard conditions was tested to assess their conversion to [18 F] FBCT.Results: The cis-1, 3-cyclobutanediol bis-sulfonates 1 were synthesized from the cis-1, 3-cyclobutanediol using standard methodologies [3]. The triflate derivative was found to be unstable on storage and was eliminated from further evaluation. The radiofluorination of the tosylate (65%) and 3, 4-dibromobenzenesulfonate (58%) precursors resulted in better [18 F] fluoride incorporation than mesylate (30%) and nosylate (5%). The subsequent …