Late-stage generation of (14)C/(3)H-radiolabeled lysine residues via hydroformylation of peptides.
Radiolabeled peptides just got a serious upgrade. Researchers have pulled off direct (14)C and (3)H radiolabeling of lysine residues in peptides, including complex analogs like semaglutide. This new hydroformylation-based method skips the headache of multi-step syntheses and post-synthetic tagging. For anyone working with semaglutide or other advanced research peptides, this is a big deal.
Nat Commun
by Schick A, San Jose Gracia M, Christian D Hammershøj H et al.
“Late-stage generation of (14)C/(3)H-radiolabeled lysine residues via hydroformylation of peptides. Schick A(1)(2), San Jose Gracia M(3), Christian D Hammershøj H(4), Broddefalk J(5), Martínez-Pardo P(6), Enemærke VJ(4), von Sydow L(7), Holub A(3), Gopalakrishnan R(5), Mühlfenzl KS(6), Skrydstrup T(4), Elmore CS(8). Author information: (1)Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden. anika.schick@astrazeneca.com. (2)Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Aarhus, Denmark. anika.schick@astrazeneca.com. (3)Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery, Industriepark Höchst, Frankfurt am Main, Germany. (4)Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Aarhus, Denmark. (5)Medicinal Chemistry, CVRM, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. (6)Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden. (7)Medicinal Chemistry, R&I, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. (8)Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Boston, MA, USA. chad.elmore@astrazeneca.com. Peptides constitute a well-established and rapidly expanding field in the contemporary pharmaceutical drug landscape. Studies with 14C- or 3H-radiolabeled analogs are the gold standard for drug development, yet access to 14C-peptides is costly and limited to derivatization of the native structure with tags or lengthy multi-step syntheses. In this work, we report a platform that installs 14C- or 3H-radiolabeled lysine residues directly on solid-supported peptides. The workflow constitutes a mild, peptide-compatible hydroformylation process of allylglycine residues to generate labeled allysine, followed by reductive amination that furnishes radiolabeled lysine residues directly upon cleavage from the solid support. The hydroformylation setup can be tuned for flexible isotope introduction by using 14CO from solid precursors and 3H2 from standard tritium manifolds. We show that the optimized workflow tolerates diverse sequences and enables functionalization of peptides as complex as semaglutide analogs. © 2026. The Author(s). Conflict of interest statement: Competing interests: T.S. is co-owner of SyTracks A/S, which commercializes COware® (two-chamber system and heat block), SilaCOgen, and COgen. M.S.J.G. and A.H. are Sanofi employees and may hold shares and/or stock options in the company. J.B., R.G., P.M.P., L.S., K.S.M., A.S., and C.E. are or were AstraZeneca employees and may hold shares and/or stock options in the company. The remaining authors declare no competing interests.”
Here’s the gist: the team developed a workflow that installs isotope-labeled lysine right on the solid-supported peptide. They start with allylglycine in the sequence, hit it with a mild hydroformylation, and then do reductive amination. Result: you get a radiolabeled lysine residue when you cleave the peptide from the support. No harsh conditions. No need to redesign your entire peptide just to stick a label on it.
Key points for peptide researchers:
The process uses standard radiochemistry equipment: (14)CO from solid precursors and (3)H2 from tritium manifolds.
Works on diverse peptide sequences, not just simple models.
Proven on analogs as complex as semaglutide, a heavyweight in metabolic and endocrine research.
Radiolabeled peptides are the workhorses for tracking, bioavailability studies, and metabolic research. But getting your hands on custom (14)C- or (3)H-labeled peptides used to mean big costs and long waits. This new method can speed up the workflow for academic and industry labs—and opens up access to more advanced tracer studies.
If you’re sourcing peptide building blocks or looking for a supplier who can handle custom isotopic labeling, the vendor directory is worth a look.
Bottom line: this is a practical leap forward for anyone who needs radiolabeled research peptides, especially when working with complex sequences like semaglutide.
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