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Structure‐activity relationship of macrocyclic and linear gadolinium chelates: Investigation of transmetallation effect on the zinc‐dependent metallopeptidase angiotensin‐converting enzyme
Author(s) -
Corot Claire,
Idee JeanMarc,
Hentsch AnneMarie,
Santus Robin,
Mallet Catherine,
Goulas Valérie,
Bonnemain Bruno,
Meyer Dominique
Publication year - 1998
Publication title -
journal of magnetic resonance imaging
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.563
H-Index - 160
eISSN - 1522-2586
pISSN - 1053-1807
DOI - 10.1002/jmri.1880080328
Subject(s) - chelation , gadolinium , chemistry , transmetalation , dota , zinc , ligand (biochemistry) , enzyme , nuclear chemistry , in vitro , stereochemistry , receptor , biochemistry , inorganic chemistry , catalysis , organic chemistry
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 diethylene‐triamine pentaacetic acid (DTPA) bis‐methylamide (BMA) (IC 50 = .016 ± .006 mmol/1) and Gd‐DTPA (IC 50 = .350 ± .034 mmol/1). 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 Zn 2+ 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 Gd 3+ release) in the case of linear Gd chelate may have deleterious biologic consequences.