title: Design, synthesis and evaluation of novel bifunctional tetrahydroxamate chelators for PET imaging of89Zr-labeled antibodies.
abstract: Two compact and symmetrical bifunctional tetrahydroxamate chelators, 1 and 2, were synthesized and evaluated for labeling antibodies with89Zr for imaging with positron emission tomography. Using 2,2'-iminodiacetamide as the backbone, four hydroxamate-containing moieties coupled to the diacetamide nitrogen were used for89Zr 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 with89Zr efficiently (>90% radiolabeling yield), and their89Zr-labeled products maintained comparable immunoreactivity to Trastuzumab. Compared to89Zr-labeled deferoxamine-conjugated Trastuzumab,89Zr-1- and89Zr-2-Trastuzumab showed faster demetalation in mouse plasma, and also displayed higher bone uptake in mice. Despite suboptimal stability of89Zr complexes of 1 and 2, our design strategy led to tetrahydroxamate chelators for efficient89Zr labeling, and could be potentially modified to provide novel chelators with improved stability.
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Rousseau
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Zhengxing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Gemma M
authors.initials: GM
authors.lastname: Dias
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Nadine
authors.initials: N
authors.lastname: Colpo
authors.affiliation: 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. Electronic address: fbenard@bccrc.ca.
authors.forename: François
authors.initials: F
authors.lastname: Bénard
authors.affiliation: 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. Electronic address: klin@bccrc.ca.
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry*; D003287:Contrast Media / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D003676:Deferoxamine / Q000737:chemistry; D015195:Drug Design; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D007553:Isotope Labeling; D051379:Mice; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution; D000068878:Trastuzumab / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015040:Zirconium / Q000737:chemistry*
chemical_list: D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D003287:Contrast Media; D056831:Coordination Complexes; D006877:Hydroxamic Acids; D019275:Radiopharmaceuticals; D015040:Zirconium; D003676:Deferoxamine; D000068878:Trastuzumab
keywords: Antibody; Bifunctional chelators; Molecular imaging; Positron emission tomography; Trastuzumab; Zirconium-89