Synthesis and in vivo evaluation of new contrast agents for cardiac MRI

Nada H. Saab-Ismail, Tamás Simor, Balázs Gaszner, Tamás Lóránd, Márta Szöllösy, Gabriel A. Elgavish

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Analogues 2-6 of N3,N6-bis(2'-myristoyloxyethyl)-1,8- dioxotriethylenetetraamine-N,N,N',N'-tetraacetic acid (BME-DTTA) (1), which like 1 are also based on the DTTA structure but contain shorter fatty acyl chains, were synthesized to improve the water solubility of the corresponding gadolinium complexes. The gadolinium complexes of 1 and 3-5 have very low solubility in water. Thus liposomal preparations are necessary for their in vivo MRI application. These liposomal preparations retain high in vitro relaxivities (27.1, 21.57, 20.32, 23.1 s-1 mM-1, respectively) and induce sustained MRI signal intensity enhancements (67.2, 38.4, 52.1, 41.7 in arbitrary units, respectively). The gadolinium complex of 2 is quite soluble in water. Its lifetime in the blood stream, however, is short. The gadolinium complex of analogue 6, N-(2-butyryloxyethyl)-N'- (2-ethyloxyethyl)-N -N'- bis[ N,N-bis(carboxymethyl)acetamido]-1,2-ethanediamine (ABE-DTTA), has demonstrated its potential as a water-soluble, cardiac-specific, MRI contrast agent. It is completely soluble in water at a 25 mM concentration, allowing the preparation of an injectable dose. The in vitro relaxivity of the complex is 16.24 s-1 mM-1. The agent shows a specific accumulation in the heart tissue reaching its maximum within 15 min after administration, inducing a sustained MRI signal intensity enhancement of 43.6%. This enhancement lasts for at least 3 h, thus indicating a reasonably long lifetime of this contrast agent in the myocardium without deleterious effects on heart function parameters.

Original languageEnglish
Pages (from-to)2852-2861
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number15
Publication statusPublished - Jul 29 1999


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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