Multivalent Contrast Agents Based on Gadolinium−Diethylenetriaminepentaacetic Acid-Terminated Poly(propylene imine) Dendrimers for Magnetic Resonance Imaging

Abstract

A convenient methodology 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 analogues were coupled to different generations of poly(propylene imine) dendrimers. Deprotection of the tert-butyl 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 prepared from GdCl3 in either water or citrate buffer. Atomic force microscopy and cryogenic transmission electron microscopy experiments 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 observed. The efficiencies of these dendritic contrast agents in MRI, expressed in terms of longitudinal (r1) and transverse (r2) relaxivities, were determined 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 prepared, resulting in well-defined dendritic contrast agents with tunable molecular relaxivities.