“Precision on Two Wheels”─Structural Refinement of <sup>64</sup> Cu- and <sup>68</sup> Ga-Labeled Bicyclic Peptides Targeting Nectin-4 for Improved Tumor Imaging: From Preclinical Development to First-in-Human Application
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 <sup>64</sup>Cu- and <sup>68</sup>Ga-labeled ligands derived from bicyclic peptide-drug conjugate <b>BT8009</b>. 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, <b>NECT-224</b>, for PET imaging purposes was also demonstrated in a first-in-human application using <b>[</b><sup><b>68</b></sup><b>Ga]Ga-NECT-224</b>. The results suggest its further clinical development, but also that of <b>[</b><sup><b>64</b></sup><b>Cu]Cu-NECT-224</b>.
Authors
- Reik Löser (ORCID: https://orcid.org/0000-0003-1531-7601)
- Sven Stadlbauer (ORCID: https://orcid.org/0000-0003-2276-5330)
- Matthias Miederer (ORCID: https://orcid.org/0000-0001-5075-5995)
- Ralph A. Bundschuh (ORCID: https://orcid.org/0000-0001-7291-9372)
- Robert Wodtke (ORCID: https://orcid.org/0000-0001-7462-7111)
- Marie Urbanová (ORCID: https://orcid.org/0000-0003-3402-9998)
- Klaus Kopka (ORCID: https://orcid.org/0000-0003-4846-1271)
- Sebastian Hoberück (ORCID: https://orcid.org/0000-0003-3601-0924)
- Florian Brandt (ORCID: https://orcid.org/0000-0001-7711-4805)
- Ivan Platzek (ORCID: https://orcid.org/0000-0002-5933-8108)
- Martin Ullrich (ORCID: https://orcid.org/0000-0001-6104-6676)
- Markus Laube (ORCID: https://orcid.org/0000-0003-4916-3794)
- Jens Pietzsch (ORCID: https://orcid.org/0000-0002-1610-1493)
- Jérôme Kretzschmar (ORCID: https://orcid.org/0000-0001-5042-8134)
- Johanna Trommer
- Tobias Krönke
- Christian Thomas
- Jörg Kotzerke
Institutions
- German Cancer Research Center (DE)
- Helmholtz-Zentrum Dresden-Rossendorf (DE)
- Klinik und Poliklinik für Nuklearmedizin (DE)
- National Center for Tumor Diseases (DE)
- University Hospital Carl Gustav Carus (DE)
- Klinik und Poliklinik für Psychotherapie und Psychosomatik (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Technische Universität Dresden (DE)
- University of Chemistry and Technology, Prague (CZ)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-13
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02371
- Citations
- 1
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 0.81