Spreckelmeyer Sarah, Thomas Sophie R, Schuderer Franziska, Pinto Catarina I G, de Andrade Querino Ana Luiza, Böhm Felix A, Park Mihyun, Geppert Christopher, Gorges Christian, Mendes Filipa, Casini Angela
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.
Department of Inorganic Chemistry, University of Vienna, Währinger Straße. 42, 1090 Vienna, Austria.
J Med Chem. 2025 Aug 28;68(16):17516-17526. doi: 10.1021/acs.jmedchem.5c01073. Epub 2025 Aug 12.
The radionuclide Au, 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 Au(I) in radiopharmaceuticals. Thus, Au(I) NHC compounds featuring different scaffolds were selected for Au radiolabeling. Eventually, two compounds featuring imidazole () and theophylline () 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.
半衰期为2.7天的放射性核素金发射出对诊断目的而言理想的γ辐射，并产生适用于有效癌症放射治疗的β粒子，使其成为“诊疗一体化”的完美核素。然而，Au(I)/Au(III)配位化合物在医学上的应用受到其在体内不稳定性的限制。在此，我们探索N-杂环卡宾（NHC）有机金属化学以在放射性药物中稳定Au(I)。因此，选择了具有不同骨架的Au(I) NHC化合物用于金的放射性标记。最终，成功地对两种具有咪唑（）和茶碱（）骨架的化合物进行了放射性标记（放射化学纯度分别为92.9%和40.2%）。相反，两种能够在体外穿过血脑屏障的肽类Au(I)苯并咪唑亚基衍生物，在应用的放射性标记条件下进行了配体交换反应。所获得的概念验证结果表明，NHCs是在Au(I)配合物中实现同位素交换的合适配体。总体而言，我们的工作揭示了有机金属化学在放射性药物设计中尚未开发的潜力。
