Site‐Selective, Late‐Stage C−H ¹⁸F‐Fluorination on Unprotected Peptides for Positron Emission Tomography Imaging

Abstract

Peptides are often ideal ligands for diagnostic molecular imaging due to their ease of synthesis and tuneable targeting properties. However, labelling unmodified peptides with F for positron emission tomography (PET) imaging presents a number of challenges. Here we show the combination of photoactivated sodium decatungstate and [ F]-N-fluorobenzenesulfonimide effects site-selective F-fluorination at the branched position in leucine residues in unprotected and unaltered peptides. This streamlined process provides a means to directly convert native peptides into PET imaging agents under mild aqueous conditions, enabling rapid discovery and development of peptide-based molecular imaging tools.

Site‐Specific Deoxyfluorination of Small Peptides with [18F]Fluoride

“…The Groves group disclosed a method to label small organic molecules including one example of a dipeptide with [ 18 F]fluoride through direct C−H bond fluorination, but the method was not shown to be extendable to larger peptides . Direct C−H fluorination of peptides has been shown by the Britton group, however, through the use of [ 18 F]fluorine gas, which is more difficult to make and handle than [ 18 F]fluoride . The first method achieving peptide labeling without structural modifications was reported by Långström, who labeled homocysteine with [ 11 C]MeI to afford a [ 11 C]methionine residue (half‐life of 11 C: 20 min) .…”

Radical‐Based Synthesis and Modification of Amino Acids

“…Later, the groups of Britton and Schaffer partnered to expand this strategy to the synthesis of 18 F‐labeled peptides, by the C−H fluorination of Leu residues in unprotected, unmodified peptides (Scheme 28 B). [76] The selectivity of this reaction for the γ‐position of Leu, combined with the tolerance of charged, polar, and hydrophobic AAs is particularly notable.…”

Insight into the Development of PET Radiopharmaceuticals for Oncology

“…This has led to the development of reagents such as [ 18 F]NFSi [190] and [ 18 F]F-Selectfluor [191]. These methods are effective for labeling peptides that cannot tolerate nucleophilic substitution conditions [192]. However, these approaches can suffer from low molar activity and thus are better suited for radiopharmaceuticals that target transporters.…”