High relaxivity for monomeric Gd(DOTA)-based MRI contrast agents, thanks to micellar self-organization

With the aim of obtaining a high-relaxivity MRI contrast agent, we have designed a new amphiphilic Gd-III chelate that is capable of self-organization by forming micelles in aqueous solution. The synthesis of the [GdL-(H2O)](-) complex is straightforward and offers an easy way for modification (L = 1.4,7,10-tetraazacyclododecane-1-(1'-carboxy-1'-dodecyl(methyl)amino-oxo-ethyl)-4,7,10-triacetic acid). Surface-pressure measurements have proved that the compound indeed behaves as an anionic surfactant, and the critical micellar concentration (CMC) was found to be 3.5x10(-4) M. A variable temperature O-17 NMR, EPR, and NMRD study has been performed on the [GdL(H2O)](-) complex in order to determine the different factors that influence proton relaxivity. The parameters that describe the water exchange are not affected by the micellar structure, since in the aggregates the Gd-III chelates point towards the hydrophilic exterior, and the access from the bulk water to the paramagnetic center is not limited. Hence the rate of the water exchange is identical to that of [Gd(DOTA)(H2O)](-) (k(ex)(298) = 4.8 x 10(6) s(-1)). The micellar aggregates formed in solution have a long rotational correlation time, as calculated from O-17 and H-1 longitudinal relaxation rates, which results in a high proton relaxivity (R-1 = 18.01 mM(-1) s(-1) in saline at 20 MHz proton Larmor frequency; 25 degrees C). This value is in the order of the relaxivities attained so far only with macromolecular Gd-III chelates.