N-Methylation of isoDGR Peptides: Discovery of a Selective α5β1-Integrin Ligand as a Potent Tumor Imaging Agent.

Abstract

Specific targeting of the integrin subtype α5β1 possesses high potential in cancer diagnosis and therapy. Through sequential N-methylation, we successfully converted the biselective α5β1/αvβ6 peptide c(phg- isoDGR-k) into a potent peptidic RGD binding α5β1 subtype selective ligand c(phg- isoDGR-( NMe)k). Nuclear magnetic resonance spectroscopy and molecular modeling clarified the molecular basis of its improved selectivity profile. To demonstrate its potential in vivo, c(phg- isoDGR-( NMe)k) was trimerized with the chelator TRAP and used as a positron-emission tomography tracer for monitoring α5β1 integrin expression in a M21 mouse xenograft.

• Authors: Tobias G Kapp, Francesco Saverio Di Leva, Johannes Notni, Andreas F B Räder, Maximilian Fottner, Florian Reichart, Dominik Reich, Alexander Wurzer, Katja Steiger, Ettore Novellino, Udaya Kiran Marelli, Hans-Jürgen Wester, Luciana Marinelli, Horst Kessler
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 6 Pg. 2490-2499 (03 22 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 29489355 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gallium Radioisotopes
• Integrin alpha5beta1
• Ligands
• Peptides
• Radioactive Tracers

Topics

• Animals
• Female
• Gallium Radioisotopes
• Humans
• Integrin alpha5beta1 (biosynthesis, drug effects)
• Ligands
• Magnetic Resonance Spectroscopy
• Melanoma, Experimental (diagnostic imaging)
• Methylation
• Mice
• Mice, SCID
• Models, Molecular
• Molecular Structure
• Neoplasms (diagnostic imaging)
• Peptides (chemical synthesis, pharmacology)
• Positron-Emission Tomography
• Protein Binding
• Radioactive Tracers
• Tissue Distribution
• Xenograft Model Antitumor Assays