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

Two compact and symmetrical bifunctional tetrahydroxamate chelators, 1 and 2, were synthesized and evaluated for labeling antibodies with Zr-89 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-89 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-89 efficiently (>90% radiolabeling yield), and their Zr-89-labeled products maintained comparable immunoreactivity to Trastuzumab. Compared to Zr-89-labeled deferoxamine-conjugated Trastuzumab, Zr-89-1- and Zr-89-2-Trastuzumab showed faster demetalation in mouse plasma, and also displayed higher bone uptake in mice. Despite suboptimal stability of Zr-89 complexes of 1 and 2, our design strategy led to tetrahydroxamate chelators for efficient Zr-89 labeling, and could be potentially modified to provide novel chelators with improved stability. (C) 2017 Elsevier Ltd. All rights reserved.