Synthesis and evaluation of bifunctional tetrahydroxamate chelators for labeling antibodies with 89Zr for imaging with positron emission tomography.
Bioorg Med Chem Lett
; 28(5): 899-905, 2018 03 01.
Article
em En
| MEDLINE
| ID: mdl-29426769
ABSTRACT
Two novel bifunctional tetrahydroxamate chelators 3 and 4 were synthesized and evaluated for labeling antibodies with 89Zr for positron emission tomography imaging. Compared to previously reported tetrahydroxamate chelators 1 and 2 with an iminodiacetamide backbone, 3 and 4 were based on an extended iminodipropionamide and dipropylenetriamine backbone, respectively. Trastuzumab conjugates of 3 and 4 were efficiently labeled with 89Zr (>95% radiochemical yield). The in vitro plasma stability of 89Zr-4-Trastuzumab and especially 89Zr-3-Trastuzumab was greatly improved over previously reported 89Zr-1-Trastuzumab and 89Zr-2-Trastuzumab, but their demetalation remained higher and faster than 89Zr-deferoxamine (DFO)-Trastuzumab. These observations were confirmed by PET imaging and biodistribution in mice, with significant higher bone uptake for 89Zr-4-Trastuzumab, followed by 89Zr-3-Trastuzumab, and to a lesser extent for 89Zr-DFO-Trastuzumab. Molecular modeling showed that 3 and 4 with an extended backbone could form eight-coordinate Zr-complexes as compared to only seven-coordinate Zr-complexes of 1 and 2. Our data suggest further elongation of linker length between hydroxamate motifs of this class of chelators is needed to reach a better Zr-coordination configuration and improve in vivo stability.
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Base de dados:
MEDLINE
Assunto principal:
Zircônio
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Quelantes
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Tomografia por Emissão de Pósitrons
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Ácidos Hidroxâmicos
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Anticorpos Monoclonais
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Neoplasias Experimentais
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article