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

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