Woods Joshua J, Rigby Alex, Wacker Jennifer N, Arino Trevor, Alvarenga Vasquez Jennifer V, Cosby Alexia, Martin Kirsten E, Abergel Rebecca J
Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States.
Department of Nuclear Engineering, University of California Berkeley, Berkeley, California 94720, United States.
J Med Chem. 2025 Jan 23;68(2):1682-1692. doi: 10.1021/acs.jmedchem.4c02423. Epub 2025 Jan 3.
Thorium-227 (Th) is an α-emitting radionuclide currently under investigation for targeted alpha therapy. Available chelators used for this isotope suffer from challenging multistep syntheses. Here, we present the synthesis and preclinical evaluation of a novel bifunctional chelator, SCN-Bn-DOTHOPO, which contains an isothiocyanate group that is suitable for conjugation to biological molecules. This bifunctional chelator was prepared with a 26% overall yield in four steps and conjugated to the human epidermal growth factor receptor 2 targeting antibody, trastuzumab. The resulting immunoconjugate was labeled with [Th]Th (pH 5.5, room temperature, 60 min) with ≥95% radiochemical yield and purity. The conjugate was also labeled with zirconium-89 (Zr), which can be used for positron emission tomography imaging. The radiometal complexes were subsequently investigated for their biological stability. The results described here provide insight into ligand design strategies and optimization of chelators for the development of the next generation of Zr and Th radiopharmaceuticals.
钍-227（Th）是一种发射α粒子的放射性核素，目前正用于靶向α治疗的研究。用于这种同位素的现有螯合剂存在多步合成困难的问题。在此，我们展示了一种新型双功能螯合剂SCN-Bn-DOTHOPO的合成及临床前评估，该螯合剂含有一个异硫氰酸酯基团，适用于与生物分子偶联。这种双功能螯合剂通过四步反应以26%的总收率制备而成，并与靶向人表皮生长因子受体2的抗体曲妥珠单抗偶联。所得免疫偶联物用[Th]Th标记（pH 5.5，室温，60分钟），放射化学产率和纯度≥95%。该偶联物还用锆-89（Zr）进行了标记，Zr可用于正电子发射断层扫描成像。随后对放射性金属配合物的生物稳定性进行了研究。本文所述结果为下一代Zr和Th放射性药物的配体设计策略及螯合剂优化提供了见解。
