[18F]Fluorocyclobutyl group: sulfonate leaving group effect on the [18F]fluoride incorporation and subsequent alkylation reaction.


[18F]Fluorocyclobutyl group: sulfonate leaving group effect on the [18F]fluoride incorporation and subsequent alkylation reaction.

Graham, K.; Kniess, T.; Steinbach, J.; Friebe, M.; Dinkelborg, L. M.; Frank, D.

Objectives: The use of the [18F]cyclobutyl group as a potentially metabolic stable surrogate group for [18F]fluoroalkyl groups has been notified [1-3]. The radiolabeling of a cis-1,3-cyclobutanediol bis-toluenesulfonate
precursor 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 [18F]fluoride to form the 3-[18F]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-[18F]fluorocyclobutyl-L-tyrosine ([18F]FCBT) should be assessed.
Methods: Various symmetrical cis-1,3-cyclobutanediol bis-sulfonates 1 were synthesized with the different commonly-used sulfonate leaving groups, i.e. tosylate, mesylate, triflate, nosylate and 3,4-dibromobenzenesulfonate. These precursors were subjected to n.c.a. nucleophilic radiofluorination. The 18F-labeled intermediates 2 were purified and the alkylation reaction with L-Tyrosine under standard conditions was tested to assess their conversion to [18F]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 [18F]fluoride incorporation than mesylate (30%) and nosylate (5%). The subsequent alkylation of the purified intermediates 2 with L-Tyrosine showed the same trend with 82% yield for tosylate and 69% yield for 2,3-dibromobenzenesulfonate () whereas mesylate gave only 4% yield and nosylate failed to give product.
Conclusions: By a systematic evaluation of different sulfonate leaving groups of the symmetrical cis-1,3-cyclobutanediol bis-sulfonates 1 and the conjugation of the resulting intermediate 2 with L-Tyrosine it was clearly demonstrated that tosylate and 3,4-dibromobenzenesulfonate are more favorable than mesylate and nosylate.
Acknowledgements: We gratefully acknowledge Selahattin Ede and Mario Mandau for technical assistance.
References: [1] Franck D, et al. (2011) J Nucl Med, 52, Suppl. 1, 168P. [2] Franck D, et al. (2011) J Label Compd
Radiopharm, 54, Suppl. 1, S447. [3] Franck D, et al. (2013) Bioorg Med Chem, 21, 643-52.

  • Poster
    20th International Symposium on Radiopharmaceutical Sciences, 12.-17.05.2013, Jeju, Korea
  • Abstract in refereed journal
    Journal of Labelled Compounds and Radiopharmaceuticals (2013)56, S134
    ISSN: 0362-4803

Permalink: https://www.hzdr.de/publications/Publ-19010
Publ.-Id: 19010