2. Academic Validation
  3. "Precision on Two Wheels"─Structural Refinement of 64Cu- and 68Ga-Labeled Bicyclic Peptides Targeting Nectin-4 for Improved Tumor Imaging: From Preclinical Development to First-in-Human Application

"Precision on Two Wheels"─Structural Refinement of 64Cu- and 68Ga-Labeled Bicyclic Peptides Targeting Nectin-4 for Improved Tumor Imaging: From Preclinical Development to First-in-Human Application

  • J Med Chem. 2025 Oct 23;68(20):21962-21987. doi: 10.1021/acs.jmedchem.5c02371.
Tobias Krönke 1,  Johanna Trommer 1,  Martin Ullrich 1,  Markus Laube 1,  Reik Löser 1 2,  Jérôme Kretzschmar 3,  Marie Urbanova 4,  Sven Stadlbauer 1 2,  Florian Brandt 5,  Ivan Platzek 5,  Sebastian Hoberück 5,  Jörg Kotzerke 5,  Christian Thomas 6,  Matthias Miederer 1 7 8,  Ralph A Bundschuh 1 5 9,  Klaus Kopka 1 7 9,  Jens Pietzsch 1 2,  Robert Wodtke 1
Affiliations

Affiliations

  • 1 Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328 Dresden, Germany.
  • 2 School of Science, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, Mommsenstraße 4, 01069 Dresden, Germany.
  • 3 Institute of Resource Ecology, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328 Dresden, Germany.
  • 4 Department of Physics and Measurements, University of Chemistry and Technology, Technická 5, Prague 16628, Czech Republic.
  • 5 Klinik und Poliklinik für Nuklearmedizin, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
  • 6 Klinik und Poliklinik für Urologie, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
  • 7 National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a Partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology & Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany.
  • 8 German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 9 German Cancer Consortium (DKTK), Partner Site Dresden, 01307 Dresden, Germany.
PMID: 41081542 DOI: 10.1021/acs.jmedchem.5c02371
Abstract

The cell adhesion protein Nectin-4 emerged as a valid therapeutic target for antibody- and peptide-drug conjugates in Cancer. To support patient stratification for such targeted therapies, there is a clinical need for molecular imaging agents capable of quantifying Nectin-4 levels noninvasively in vivo. For this purpose, we developed 64Cu- and 68Ga-labeled ligands derived from bicyclic peptide-drug conjugate BT8009. A library of peptides was prepared with a major focus on the bioisosteric replacement of the original methionine residue due to its susceptibility to oxidation. The peptides were characterized for their binding behavior to Nectin-4, and radiopharmacological characterization of selected radioligands was performed using urothelial carcinoma cell lines and tumor xenograft models derived thereof. The suitability of the most promising ligand from the preclinical studies, NECT-224, for PET imaging purposes was also demonstrated in a first-in-human application using [68Ga]Ga-NECT-224. The results suggest its further clinical development, but also that of [64Cu]Cu-NECT-224.

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