Late-stage hydroformylation generates 14C/3H-radiolabeled lysine residues directly on solid-supported peptides

The development of new peptide therapeutics relies heavily on radiolabeled analogs for drug metabolism and pharmacokinetic (DMPK) studies. However, accessing 14C-peptides and 3H-peptides is often prohibitively costly and limited to either non-native derivatization or lengthy, multi-step synthetic routes. This gap significantly hinders the efficient and rapid progression of promising peptide drug candidates through preclinical and clinical development, necessitating a more streamlined and versatile method for site-specific isotope incorporation.

Researchers developed a mild, peptide-compatible workflow for installing radiolabeled lysine residues on solid-supported peptides. The process begins with the hydroformylation of allylglycine residues to generate labeled allysine. This is followed by a reductive amination step, which directly furnishes the desired 14C- or 3H-radiolabeled lysine residues. The hydroformylation setup was designed for flexible isotope introduction, utilizing 14CO from solid precursors and 3H2 from standard tritium manifolds, ensuring broad applicability across different labeling requirements.

The optimized workflow successfully tolerates diverse peptide sequences, demonstrating its robustness and broad utility in peptide synthesis. This method enables the efficient functionalization of peptides, including those with significant structural complexity, such as semaglutide analogs. The ability to tune the hydroformylation setup for flexible isotope introduction (using 14CO or 3H2) represents a significant advancement in radiolabeling technology. This direct, late-stage approach bypasses the need for lengthy, multi-step syntheses or non-native derivatization, streamlining the production of critical radiolabeled peptide tools. The method's compatibility with solid-phase peptide synthesis (SPPS) ensures its integration into existing synthetic pipelines.

The platform directly installs 14C- or 3H-radiolabeled lysine residues on solid-supported peptides, tolerating diverse sequences and enabling functionalization of complex semaglutide analogs.