title: Structure-activity relationship of macrocyclic and linear gadolinium chelates: investigation of transmetallation effect on the zinc-dependent metallopeptidase angiotensin-converting enzyme.
abstract: 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.
authors.affiliation: Biochemistry Department, Laboratoire Guerbet, Aulnay Sous Bois, France.
authors.forename: C
authors.initials: C
authors.lastname: Corot
authors.forename: J M
authors.initials: JM
authors.lastname: Idee
authors.forename: A M
authors.initials: AM
authors.lastname: Hentsch
authors.forename: R
authors.initials: R
authors.lastname: Santus
authors.forename: C
authors.initials: C
authors.lastname: Mallet
authors.forename: V
authors.initials: V
authors.lastname: Goulas
authors.forename: B
authors.initials: B
authors.lastname: Bonnemain
authors.forename: D
authors.initials: D
authors.lastname: Meyer
mesh_terms: D002614:Chelating Agents; D055598:Chemical Phenomena; D002621:Chemistry; D003287:Contrast Media; D005682:Gadolinium; D019786:Gadolinium DTPA; D006571:Heterocyclic Compounds; D006801:Humans; D008279:Magnetic Resonance Imaging; D009942:Organometallic Compounds; D007703:Peptidyl-Dipeptidase A; D013329:Structure-Activity Relationship; D015032:Zinc
chemical_list: D002614:Chelating Agents; D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C062402:gadoteridol; C064925:gadodiamide; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D005682:Gadolinium; D007703:Peptidyl-Dipeptidase A; D015032:Zinc; D019786:Gadolinium DTPA