POLYSACCHARIDES AS CARRIERS FOR MAGNETIC-RESONANCE-IMAGING CONTRAST AGENTS - SYNTHESIS AND STABILITY OF A NEW AMINO-ACID LINKER DERIVATIVE

The relative hydrolytic stability of contrast agents for magnetic reso nance imaging (MRI), consisting of paramagnetic metal chelates bound t o polysaccharides through an ester bond, has been investigated. Four p reparations of biodegradable, cross-linked starch particles were studi ed as model compounds: diethylenetriaminepentaacetic acid (DTPA)-starc h particles (1), two batches of gadolinium-DTPA (GdDTPA)-starch partic les (2a,2b) with different Gd content, and N-(2-phenylethyl)succinamoy l starch ester particles (4). In a study of hydrolytic rates in water suspension, the derivatives with GdDTPA bound directly to the particle via the carboxylic acid groups in DTPA (2a,2b) showed 74 and 86% rema ining matrix-bound GdDTPA, respectively, after 21 days. The unchelated derivative (1) showed 96% remaining matrix-bound DTPA, while for the succinamoyl-linked derivative (4), no significant hydrolysis took plac e during the same time span. To investigate the corresponding stabilit y of ester bonds in water-soluble, blood-pool agents for MRI, the degr adation rate of the macromolecular derivatives dextran-DTPAGd (5) and dextran-beta-alanine-DTPAGd (6c) were compared in artificial blood pla sma. The remaining fraction of undegraded ester bond in 6c was approxi mately 95% after 100 min, while 5 was approximately fully degraded ove r the same time span, These results indicate that the conjugate with t he p-alanine spacer may have a more suitable degradation rate for bloo d-pool MRI contrast purposes than the derivatives with GdDTPA directly ester bound. It was also shown by relaxation measurements that gadoli nium-ethylenediaminetetraacetic acid (GdEDTA) was demetalated in a tes t solution of phosphate (3 mM) at 37 degrees C. No demetalation was ob served for GdDTPA derivatives of water-soluble polysaccharides, repres ented by the dextran-GdDTPA conjugate 5 and aminoethyldextran-GdDTPA 7 , lacking an ester bond between GdDTPA and the dextran matrix. (C) 199 6 Elsevier Science Ltd.