Deoxyfluorination of phenols for chemoselective ¹⁸F-labeling of peptides

The challenge of forming C-¹⁸F bonds is often a bottleneck in the development of new ¹⁸F-labeled tracer molecules for noninvasive functional imaging studies using positron emission tomography (PET). Nucleophilic aromatic substitution is the most widely employed reaction to functionalize aromatic substrates with the radioactive fluorine-18 but its scope is restricted to arenes containing electron-withdrawing substituents. Furthermore, many protic functional groups are incompatible with basic fluoride anions. Peptide substrates, which are highly desirable targets for PET molecular imaging, are particularly challenging to label with fluorine-18 because they are densely functionalized and sensitive to high temperatures and basic conditions. To expand the utility of nucleophilic aromatic substitution with fluorine-18, we describe two complementary procedures for the radiodeoxyfluorination of bench-stable and easy-to-access phenols that ensure rapid access to densely functionalized electron-rich and electron-poor ¹⁸F-aryl fluorides. The first procedure details the synthesis of an ¹⁸F-synthon and its subsequent ligation to the cysteine residue of Arg-Gly-Asp-Cys in 10.5 h from commercially available starting materials (189-min radiosynthesis). The second procedure describes the incorporation of commercially available CpRu(Fmoc-tyrosine)OTf into a fully protected peptide Lys-Met-Glu-(CpRu-Tyr)-Leu via solid-phase peptide synthesis and subsequent ruthenium-mediated uronium deoxyfluorination with fluorine-18 followed by deprotection, accomplished within 7 d (116-min radiosynthesis). Both radiolabeling methods are highly chemoselective and have conveniently been automated using commercially available radiosynthesis equipment so that the procedures described can be employed for the synthesis of peptide-based PET probes for in vivo imaging studies according to as low as reasonably achievable (ALARA) principles.