A novel series of complexones with bis- or biazole structure as mixed ligands of paramagnetic contrast agents for MRI.
We describe the syntheses, physicochemical properties and biological evaluation of a novel series of complexones containing bis- or biazoles moieties and two iminodiacetic acid units as novel ligands for paramagnetic lanthanides. The complexones were prepared by reaction of the corresponding 1,1'-bishaloethylbi- or bispyrazoles with methyl iminodiacetate and subsequent NaOH hydrolysis. 1,1'-Bisbromoethyl precursors were obtained by direct alkylation with an excess of 1,2-dibromoethane, or by heating the corresponding alcohol in HCl. Sigmoidal binding isotherms and MO calculations supported as most stable structures in solution, those containing two Gd(III) atoms bound per molecule of complexone with half saturation values S(0.5) (M(-1), 22 degrees C, pH 7.2) in the range 6.5 10(-6)<S(0.5)<36.1 10(-6). Relaxivity properties [r(1), r(2), s(-1) mM(-1) Gd(III)] determined at 1.5 Tesla gave values (12.0<r(1)<17.7, 12.2<r(2)<20), improving significantly the relaxivities of reference compounds such as Gd(III)EDTA (5.2, 5.6) or Gd(III)DTPA (4.30, 4.30). These improvements involve mainly increased hydration and slower rotational motions. In vitro toxicity experiments are reported.
Mayoral
Elena P
EP
Departamento Qui;mica Orgánica y Biologi;a, Facultad de Ciencias, UNED, Senda del Rey 9, 28040 Madrid, Spain.
García-Amo
María
M
López
Pilar
P
Soriano
Elena
E
Cerdán
Sebastián
S
Ballesteros
Paloma
P
D000818:Animals; D001393:Azoles / Q000737:chemistry*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D003287:Contrast Media; D004492:Edetic Acid / Q000737:chemistry; D005682:Gadolinium / Q000737:chemistry; D019786:Gadolinium DTPA / Q000737:chemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D028581:Lanthanoid Series Elements / Q000737:chemistry; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry
D001393:Azoles; D002614:Chelating Agents; D003287:Contrast Media; D028581:Lanthanoid Series Elements; D008024:Ligands; D009942:Organometallic Compounds; C041365:gadolinium EDTA; D004492:Edetic Acid; D005682:Gadolinium; D007770:L-Lactate Dehydrogenase; D019786:Gadolinium DTPA