Structure-activity relationship of macrocyclic and linear gadolinium chelates: Investigation of transmetallation effect on the zinc-dependent metallopeptidase angiotensin-converting enzyme

Autor: Catherine Mallet, Anne-Marie Hentsch, Dominique Meyer, Robin Santus, Valérie Goulas, Claire Corot, Jean-Marc Idée, Bruno Bonnemain
Rok vydání: 1998
Předmět:
Zdroj: Journal of Magnetic Resonance Imaging. 8:695-702
ISSN: 1522-2586
1053-1807
DOI: 10.1002/jmri.1880080328
Popis: Transmetallation between commercially available solutions of gadolinium (Gd) chelates and the zinc (Zn)-dependent angiotensin-converting enzyme (ACE) was investigated. In vitro, the strongest inhibitions were observed for the linear Gd complexes, Gd diethylenetriamine pentaacetic acid (DTPA) bis-methylamide (BMA) (IC50 = .016 +/- .006 mmol/l) and Gd-DTPA (IC50 = .350 +/- .034 mmol/l). The two macrocycles Gd tetraazacyclododecane tetraacetic acid (DOTA) and Gd-HP-DO3A were similar and 400 times less active than Gd-DTPA-BMA. These effects were mainly due to the presence of free ligand for DTPA and calcium (Ca) chelate in the case of DTPA-BMA because the addition of Zn2+ in the same quantities suppresses their inhibitory effects. In vivo, these two solutions of linear Gd chelates significantly inhibited ACE activity (Gd-DTPA: (67 +/- 9% versus baseline; and Gd-DTPA-BMA: 73 +/- 2% versus baseline at the clinical dose of .1 mmol/kg), whereas no significant effect was observed for the two macrocyclic chelates Gd-DOTA and Gd-HP-DO3A. Formulating the Gd chelate solution with either an excess of free ligand or Ca chelate (to decrease Gd3+ release) in the case of linear Gd chelate may have deleterious biologic consequences.
Databáze: OpenAIRE
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