N-Heterocyclic Carbenes as Ligands to 198Au(I)-Radiolabeled Compounds: A New Platform for Radiopharmaceutical Design

  • J Med Chem. 2025 Aug 28;68(16):17516-17526. doi: 10.1021/acs.jmedchem.5c01073.
Sarah Spreckelmeyer  1 ,  Sophie R Thomas  2  3 ,  Franziska Schuderer  3  4 ,  Catarina I G Pinto  5 ,  Ana Luiza de Andrade Querino  3 ,  Felix A Böhm  3 ,  Mihyun Park  3 ,  Christopher Geppert  6 ,  Christian Gorges  6 ,  Filipa Mendes  5  7 ,  Angela Casini  3
Affiliations
  • 1. Department of Nuclear Medicine, Charité─Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany.
  • 2. Department of Inorganic Chemistry, University of Vienna, Währinger Straße. 42, 1090 Vienna, Austria.
  • 3. Medicinal and Bioinorganic Chemistry, Department of Chemistry, School of Natural Sciences, Technical University of Munich, Lichtenbergstraße 4, 85748 Garching bei München, Germany.
  • 4. Pharmaceutical Radiochemistry, Department of Chemistry, School of Natural Sciences, Technical University of Munich, Walther-Meißner-Str. 3, 85748 Garching bei München, Germany.
  • 5. C2TN─Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, 2695-066 Lisboa, Portugal.
  • 6. Forschungsreaktor TRIGA Mainz, Johannes Gutenberg-Universität Mainz, Fritz-Strassmann-Weg 2, 55128 Mainz, Germany.
  • 7. DECN─Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, 2695-066 Lisboa, Portugal.
PMID: 40797268 DOI: 10.1021/acs.jmedchem.5c01073
Abstract

The radionuclide 198Au, with a half-life of 2.7 days, emits γ radiation ideal for diagnostic purposes and generates β- particles suitable for effective Cancer radiotherapy, making it a perfect nuclide for "theranostics". However, the application of coordination compounds of Au(I)/Au(III) in medicine is limited by their instability in vivo. Here, we explore N-heterocyclic carbene (NHC) organometallic chemistry to stabilize 198Au(I) in radiopharmaceuticals. Thus, Au(I) NHC compounds featuring different scaffolds were selected for 198Au radiolabeling. Eventually, two compounds featuring imidazole (AuNHC-1) and theophylline (AuTMX2) scaffolds were successfully radiolabeled (radiochemical purity = 92.9% and 40.2%, respectively). Instead, two peptidic Au(I) benzimidazolylidene derivatives, capable of blood-brain barrier translocation in vitro, were subjected to ligand exchange reactions under the applied radiolabeling conditions. The obtained proof-of-concept results showed that NHCs are suitable ligands to achieve isotope exchange in Au(I) complexes. Overall, our work reveals the still untapped potential of organometallic chemistry in radiopharmaceutical design.

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