SYNTHESIS OF NONIONIC GADOLINIUM CHELATES USEFUL AS CONTRAST AGENTS FOR MAGNETIC-RESONANCE-IMAGING - 1,4,7-TRIS(CARBOXYMETHYL)-10-SUBSTITUTED-1,4,7,10-TETRAAZACYCLODODECANES AND THEIR CORRESPONDING GADOLINIUM CHELATES

The synthesis of a new and synthetically useful ligand, 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, DO3A (2), was achieved through a variety of synthetic approaches 1. These routes included (1) the partial carboxymethylation of unprotected cyclen, 1,4,7,10-tetraazacyclododecane (1), with chloroacetic acid followed by ion-exchange chromatography (Scheme I), (2) reductive debenzylation (Pd/C, H-2) of 1,4,7-tris(carboxymethyl)-10-(phenylmethyl)-1,4,7,10-tetraazacyclododecane, Bz-DO3A (7) (Scheme II), and (3) carboxymethylation of 1-formyl-1,4,7,10-tetraazacyclododecane (9) with chloroacetic acid (or tert-butyl bromoacetate) followed by removal of the protecting group(s) (Scheme III). Method III was found to be the most efficient. The novel formyl cyclen was prepared by the partial hydrolysis of the tricyclic cyclen derivative, 1,4,7,10-tetraazatricyclo[5.5.1.0]tridecane 2. The heptadentate ligand, DO3A, is a versatile intermediate, being easily derivatized to produce potentially octadentate ligands and bifunctional chelating agents. A variety of octadentate ligands and their gadolinium(III) chelates were synthesized. Many of these gadolinium chelates are neutral, stable, and highly water soluble (> 0.5 M), properties desirable in clinically useful MRI contrast media.