Multivalent contrast agents based on Gd-DTPA-terminated poly (propylene imine) dendrimers for Magnetic Resonance Imaging

Abstract

A convenient methodol. has been developed for the synthesis of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-terminated poly(propylene imine) dendrimers as contrast agents for magnetic resonance imaging (MRI). In our strategy, isocyanate-activated, tert-butyl-protected DTPA analogs were coupled to different generations of poly(propylene imine) dendrimers. Deprotection of the tert-Bu esters with trifluoroacetic acid in dichloromethane and extensive dialysis afforded gadolinium-chelating poly(propylene imine) dendrimers. The corresponding Gd-DTPA-based dendritic contrast agents were prepd. from GdCl3 in either water or citrate buffer. At. force microscopy and cryogenic transmission electron microscopy expts. of the fifth-generation Gd-DTPA based dendritic contrast agent in citrate buffer demonstrated the presence of well-defined spherical particles with nanoscopic dimensions (5-6 nm), and no self-aggregation of dendrimers was obsd. The efficiencies of these dendritic contrast agents in MRI, expressed in terms of longitudinal (r1) and transverse (r2) relaxivities, were detd. at 1.5 T at 20 °C. The r1 and r2 values increase considerably with increasing generation of Gd-DTPA-terminated dendrimer. The fifth-generation dendritic contrast agent displays the highest ionic relaxivities (per gadolinium), r1 = 19.7 mM-1 s-1 and r2 = 27.8 mM-1 s-1, which are substantially higher than the ionic relaxivities of parent Gd-DTPA. Moreover, a series of combined gadolinium and yttrium complexes of the fifth-generation dendrimer are prepd., resulting in well-defined dendritic contrast agents with tunable mol. relaxivities