Design, synthesis and evaluation of novel bifunctional tetrahydroxamate chelators for PET imaging of ⁸⁹Zr-labeled antibodies

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• 作者：Julie Rousseau^a ; Zhengxing Zhang^a ; Gemma M. Dias^a ; Chengcheng Zhang^a ; Nadine Colpo^a ; Franç ; ois Bé ; nard^a ; ^b ; ^c ; ^{fbenard@bccrc.ca} ; Kuo-Shyan Lin^a ; ^b ; ^c ; ^{klin@bccrc.ca}
• 关键词：Zirconium-89 ; Bifunctional chelators ; Antibody ; Trastuzumab ; Molecular imaging ; Positron emission tomography
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：27
• 期：4
• 页码：708-712
• 全文大小：1041 K
• 卷排序：27

文摘

Two compact and symmetrical bifunctional tetrahydroxamate chelators, 1 and 2, were synthesized and evaluated for labeling antibodies with 89Zr 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 89Zr 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 89Zr efficiently (>90% radiolabeling yield), and their 89Zr-labeled products maintained comparable immunoreactivity to Trastuzumab. Compared to 89Zr-labeled deferoxamine-conjugated Trastuzumab, 89Zr-1- and 89Zr-2-Trastuzumab showed faster demetalation in mouse plasma, and also displayed higher bone uptake in mice. Despite suboptimal stability of 89Zr complexes of 1 and 2, our design strategy led to tetrahydroxamate chelators for efficient 89Zr labeling, and could be potentially modified to provide novel chelators with improved stability.