POLYMERIC CONJUGATES OF GD3-DIETHYLENETRIAMINEPENTAACETIC ACID AND DEXTRAN - 2 - INFLUENCE OF SPACER ARM LENGTH AND CONJUGATE MOLECULAR-MASS ON THE PARAMAGNETIC PROPERTIES AND SOME BIOLOGICAL PARAMETERS()

Macromolecular conjugates of dextran 40 ((M-n) over bar = 38 kg/mol, ( M-w) over bar = 43 kg/mol) and diethylenetriaminepentaacetic acid (DTP A), capable of complexing Gd3+, were synthesized in order to obtain co ntrast agents for nuclear magnetic resonance imaging, with long intrav ascular persistence. As already reported, relaxivity of these macromol ecular complexes was greater than that of molecular complexes (2-2.5 t imes). On the other hand, as relaxivity of paramagnetic agents partial ly depends on their rotation speed, the influence of the length of the spacer arm inserted between DTPA and dextran was investigated. Variou s conjugates with spacer arms comprised of methylenic chains (-(CH2)(n )-) with varying lengths (2 less than or equal to n less than or equal to 6) were prepared. The result was that, whatever the distance betwe en DTPA and dextran, all of the Gd3+-complexed polymeric conjugates wi th similar DTPA content (0.6-0.8 mmol/g) exhibited, at 20 MHz, about t he same relaxivity values. On the other hand, in the same way, no sign ificant effect of the molecular masses ((M-n) over bar between 166 and 224 kg/mol and (M-w) over bar between 332 and 865 kg/mol) of the poly meric conjugates on relaxivity were observed. Toxicity studies carried out on mice, showed very similar LD50 values whatever the spacer arm and molecular mass of the macromolecular conjugates. Finally the urina ry excretion studied on rats (after 4 h) and on rabbits (after 24 h) w as relatively low (15-20% of the administered dose), and, as expected, the lower values were obtained with the higher molecular mass conjuga tes.