Synthesis and in vivo evaluation of new contrast agents for cardiac MRI.
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.
Saab-Ismail
N H
NH
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Simor
T
T
Gaszner
B
B
Lóránd
T
T
Szöllösy
M
M
Elgavish
G A
GA
D000818:Animals; D003287:Contrast Media / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry; D005289:Ferrets; D006321:Heart / Q000033:anatomy & histology; D008279:Magnetic Resonance Imaging; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry; D004369:Pentetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship
D003287:Contrast Media; D009942:Organometallic Compounds; C120791:gadolinium N-(2-butyryloxyethyl)-N'-(2-ethyloxyethyl)-N,N'-bis(N'',N''-bis(carboxymethyl)acetamido)-1,2-ethanediamine; D004369:Pentetic Acid