A convenient methodology has been developed for the synthesis of gadolinium-diethylene-triaminepentaacetic 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 (r(1)) and transverse (r(2)) relaxivities, were determined at 1.5 T at 20 degreesC. The r(1), and r(2) values increase considerably with increasing generation of Gd-DTPA-terminated dendrimer. The fifth-generation dendritic contrast agent displays the highest ionic relaxivities (per gadolinium.), r(1) = 19.7 mM(-1) s(-1) and r(2) = 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.