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

  • J Med Chem. 2018 Mar 22;61(6):2490-2499. doi: 10.1021/acs.jmedchem.7b01752.
Tobias G Kapp  1 ,  Francesco Saverio Di Leva  2 ,  Johannes Notni  3 ,  Andreas F B Räder  1 ,  Maximilian Fottner  1 ,  Florian Reichart  1 ,  Dominik Reich  3 ,  Alexander Wurzer  3 ,  Katja Steiger  4 ,  Ettore Novellino  2 ,  Udaya Kiran Marelli  5 ,  Hans-Jürgen Wester  3 ,  Luciana Marinelli  2 ,  Horst Kessler  1
Affiliations
  • 1. Institute for Advanced Study and Center of Integrated Protein Science, Department Chemie , Technische Universität München , Lichtenbergstraße 4 , 85748 Garching , Germany.
  • 2. Dipartimento di Farmacia , Università degli Studi di Napoli "Federico II" , Via D. Montesano 49 , 80131 Naples , Italy.
  • 3. Lehrstuhl für Pharmazeutische Radiochemie , Technische Universität München , Walther-Meißner Straße 3 , 85748 Garching , Germany.
  • 4. Department of Pathology , Technische Universität München , Trogerstraße 18 , 81675 München , Germany.
  • 5. Central NMR Facility and Division of Organic Chemistry , CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road , 411008 Pune , India.
PMID: 29489355 DOI: 10.1021/acs.jmedchem.7b01752
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.

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