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

J Magn Reson Imaging. May-Jun 1998;8(3):695-702. doi: 10.1002/jmri.1880080328.


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.

Publication types

  • Comparative Study

MeSH terms

  • Chelating Agents
  • Chemical Phenomena
  • Chemistry
  • Contrast Media*
  • Gadolinium DTPA
  • Gadolinium*
  • Heterocyclic Compounds
  • Humans
  • Magnetic Resonance Imaging*
  • Organometallic Compounds
  • Peptidyl-Dipeptidase A*
  • Structure-Activity Relationship
  • Zinc*


  • Chelating Agents
  • Contrast Media
  • Heterocyclic Compounds
  • Organometallic Compounds
  • gadoteridol
  • gadodiamide
  • gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate
  • Gadolinium
  • Peptidyl-Dipeptidase A
  • Zinc
  • Gadolinium DTPA