NEW HYDROXYBENZYL AND HYDROXYPYRIDYLMETHYL SUBSTITUTED TRIAZACYCLONONANE LIGANDS FOR USE WITH GALLIUM(III) AND INDIUM(III)

The Ga-67(III) and/or In-111(III) complexes of four new hexadentate li gands have been prepared and evaluated in vitro and in vivo. These sub stituted triazacyclononane ligands bind the metal ion through three te rtiary ring nitrogens and three oxygens from pendant phenolic or hydro xypyridyl arms. The hydroxypyridyl moieties increase the aqueous solub ility of the metal complexes while retaining a lipophilic character. A s indicated by their large positive partition coefficients, the phenol ic ligands proved to be significantly more lipophilic than the hydroxy pyridyl ligands. Biodistribution in Sprague-Dawley rats indicated that the more lipophilic phenolic complexes cleared the body primarily thr ough the liver, while the less lipophilic hydroxypyridyl complexes cle ared rapidly, primarily through the kidney. To differentiate the clear ance characteristics of these radiolabeled compounds, radiochemical pu rity of selected complexes in vivo was measured. The complexes were ev aluated for overall charge in vitro and in vivo, in plasma samples. In addition, plasma and urine were analyzed for possible metabolites. Wi th one exception, each complex was unmetabolized in vivo. All complexe s and metabolites formed were neutral in vitro and in vivo. Extended s tability in serum of selected radiometal complexes has been measured. Each complex measured was stable to exchange with transferrin, up to 7 2 h, as expected from the large stability constants of the complexes. The clearance characteristics of the hydroxypyridyl and phenolic ligan ds, however, were markedly different. The rapid hepatic clearance of t he phenolic ligands indicates potential as bifunctional chelates for G a(III) or In(III).