Rousseau Julie, Zhang Zhengxing, Dias Gemma M, Zhang Chengcheng, Colpo Nadine, Bénard François, Lin Kuo-Shyan
Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Functional Imaging, BC Cancer Agency, Vancouver, BC V5Z 4E6, Canada; Department of Radiology, University of British Columbia, Vancouver, BC V5Z 4E3, Canada.
Bioorg Med Chem Lett. 2017 Feb 15;27(4):708-712. doi: 10.1016/j.bmcl.2017.01.052. Epub 2017 Jan 18.
Two compact and symmetrical bifunctional tetrahydroxamate chelators, 1 and 2, were synthesized and evaluated for labeling antibodies with Zr for imaging with positron emission tomography. Using 2,2'-iminodiacetamide as the backbone, four hydroxamate-containing moieties coupled to the diacetamide nitrogen were used for Zr labeling, while a pendant connected to the amino group provided an isothiocyanate group for coupling to the antibody. Both 1- and 2-conjugated Trastuzumab were labeled with Zr efficiently (>90% radiolabeling yield), and their Zr-labeled products maintained comparable immunoreactivity to Trastuzumab. Compared to Zr-labeled deferoxamine-conjugated Trastuzumab, Zr-1- and Zr-2-Trastuzumab showed faster demetalation in mouse plasma, and also displayed higher bone uptake in mice. Despite suboptimal stability of Zr complexes of 1 and 2, our design strategy led to tetrahydroxamate chelators for efficient Zr labeling, and could be potentially modified to provide novel chelators with improved stability.
合成了两种结构紧凑且对称的双功能四氧肟酸螯合剂1和2，并对其用锆标记抗体用于正电子发射断层扫描成像进行了评估。以2,2'-亚氨基二乙酰胺为骨架，连接到二乙酰胺氮上的四个含氧肟酸部分用于锆标记，而连接到氨基上的侧链提供了一个异硫氰酸酯基团用于与抗体偶联。1-和2-偶联的曲妥珠单抗均能高效地用锆标记（放射性标记产率>90%），并且它们的锆标记产物与曲妥珠单抗保持相当的免疫反应性。与锆标记的去铁胺偶联曲妥珠单抗相比，Zr-1-和Zr-2-曲妥珠单抗在小鼠血浆中的脱金属速度更快，并且在小鼠体内也表现出更高的骨摄取。尽管1和2的锆配合物稳定性欠佳，但我们的设计策略产生了用于高效锆标记的四氧肟酸螯合剂，并且可能经过修饰以提供稳定性更高的新型螯合剂。
