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18F-trifluoromethylation of unmodified peptides with 5-18F-(trifluoromethyl) dibenzothiophenium trifluoromethanesulfonate

Verhoog, Stefan, Kee, Choon Wee, Wang, Yanlan, Khotavivattana, Tanatorn, Wilson, Thomas C., Kersemans, Veerle, Smart, Sean, Tredwell, Matthew, Davis, Benjamin G. and Gouverneur, Veronique 2018. 18F-trifluoromethylation of unmodified peptides with 5-18F-(trifluoromethyl) dibenzothiophenium trifluoromethanesulfonate. Journal of the American Chemical Society 140 (5) , pp. 1572-1575. 10.1021/jacs.7b10227

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Abstract

Positron emission tomography (PET) is a molecular imaging technique that can visualize biochemical processes in vivo. In practice, these studies require molecules labeled with a positron-emitting radioisotope, for example 11C or 18F. Radiolabeled peptides are attractive candidates for PET imaging because of their favorable pharmacokinetics and high specificity targeting characteristics. Such properties have stimulated development of numerous strategies for tagging peptides with a radioactive component. Most methods require prefunctionalization of the peptide with a prosthetic group enabling attachment of the radioisotope itself, or a radiolabeled molecular entity. Alternatively, a radiolabeled prosthetic group is synthesized prior to attachment to the peptides; typically, this approach requires synthetic modification of the peptide prior to radiolabeling. Major structural modifications of the peptide target can result in alteration of their biological function, a concern that has encouraged development of innovative labeling methodologies employing unmodified peptides and minimally sized radioisotope-containing motifs. Studies have focused on the radioisotope 11C. For example, Skrydstrup and co-workers reported methyl bisphosphine–ligated complexes enable N-11C-acetylation of lysine residue of native peptides, and the direct 11CN-labeling of unprotected peptides at a cysteine residue was accomplished by Buchwald, Hooker and co-workers applying a palladium-mediated sequential cross-coupling consisting of S-arylation followed by 11C-cyanation (Figure 1a). Our objective was to demonstrate unmodified peptides are amenable to direct labeling with the longer half-life radioisotope fluorine-18 applying a method that does not require chemical manipulation of the peptide prior to 18F-incorporation, and employs a “zero-size” 18F-motif. Herein, we report radiosynthesis of a newly designed 18F-reagent and its application toward a metal-free technology to radiolabel unmodified peptides at the cysteine residue with the smallest symmetrical 18F-labeled multifluorine group possible: CF3 (Figure 1b). This approach generates the noncanonical trifluoromethylcysteine residue, a structural re-engineering operation unmatched by alternative 18F-labeling methods.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Chemical Society
ISSN: 0002-7863
Last Modified: 19 Jul 2019 12:28
URI: http://orca.cf.ac.uk/id/eprint/122231

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