Synthesis and in Vivo Evaluation of New Contrast Agents for Cardiac MRI

• Published in: Journal of medicinal chemistry Vol. 42; no. 15; pp. 2852 - 2861
• Main Authors: Saab-Ismail, Nada H, Simor, Tamás, Gaszner, Balázs, Lóránd, Tamás, Szöllösy, Márta, Elgavish, Gabriel A
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 29-07-1999
• Subjects: Animals; Biological and medical sciences; Cardiovascular system; Contrast Media - administration & dosage; Contrast Media - chemical synthesis; Contrast Media - chemistry; Ferrets; Heart - anatomy & histology; Investigative techniques, diagnostic techniques (general aspects); Magnetic Resonance Imaging; Medical sciences; Organometallic Compounds - administration & dosage; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Pentetic Acid - administration & dosage; Pentetic Acid - analogs & derivatives; Pentetic Acid - chemical synthesis; Pentetic Acid - chemistry; Radiodiagnosis. Nmr imagery. Nmr spectrometry; Solubility; Structure-Activity Relationship; Heart; Fissipedia; Carnivora; Spin lattice relaxation; Paramagnetic contrast agent; Organic ligand; Gadolinium Complexes; Nuclear magnetic resonance imaging; Vertebrata; Mammalia; Carboxylic acid; Animal; Ferret; Water solubility; Myocardium; Lanthanide Complexes; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980454v

Analogues 2 − 6 of N 3,N 6-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.