PRECLINICAL EVALUATION OF MNDPDP - NEW PARAMAGNETIC HEPATOBILIARY CONTRAST AGENT FOR MR IMAGING

Manganese (II)-N,N'-dipyridoxy-lethylenediamine-N,N'-diacetate-5,5'-bis(phosphate) (MnDPDP) is a paramagnetic complex designed for use as a hepatobiliary agent. The T1 relaxivity of MnDPDP (2.8 [mmol/L]-1. sec-1 in aqueous solution) was similar to that of gadolinium diethylenetriaminepentaacetic acid (DTPA) (4.5 [mmol/L]-1. sec-1) and gadolinium tetraazocyclodecanetetraacetic acid (DOTA) (3.8[mmol/L]-1.sec-1). However, in liver tissue the T1 relaxivity of MnDPDP (21.7 [mmol/L]-1.sec-1) was threefold higher than that reported for Gd-DOTA (6.7 [mmol/L]-1.sec-1). Maximum liver T1 relaxation enhancement occurred 30 minutes after injection of MnDPDP, at which time (MnDPDP)-Mn-54 biodistribution studies indicated that 13% of total body activity was in the liver. Enhanced (MnDPDP,50-mu-mol/kg) MR images showed a fivefold increase in tumor-liver contrast-to-noise ratio over baseline unenhanced images. Results of the authors' acute and subchronic toxicity studies suggest that MnDPDP will be safe at the doses necessary for clinical imaging; at 10-mu-mol/kg, the safe factor (LD50/effective dose) for MnDPDP is 540, significantly greater than the safety factor of Gd-DTPA (ie,60-100).