New hydroxybenzyl and hydroxypyridylmethyl substituted triazacyclononane ligands for use with gallium(III) and indium(III).

The 67Ga(III) and/or 111In(III) complexes of four new hexadentate ligands have been prepared and evaluated in vitro and in vivo. These substituted triazacyclononane ligands bind the metal ion through three tertiary ring nitrogens and three oxygens from pendant phenolic or hydroxypyridyl arms. The hydroxypyridyl moieties increase the aqueous solubility of the metal complexes while retaining a lipophilic character. As indicated by their large positive partition coefficients, the phenolic ligands proved to be significantly more lipophilic than the hydroxypyridyl ligands. Biodistribution in Sprague-Dawley rats indicated that the more lipophilic phenolic complexes cleared the body primarily through the liver, while the less lipophilic hydroxypyridyl complexes cleared rapidly, primarily through the kidney. To differentiate the clearance characteristics of these radiolabeled compounds, radiochemical purity of selected complexes in vivo was measured. The complexes were evaluated for overall charge in vitro and in vivo, in plasma samples. In addition, plasma and urine were analyzed for possible metabolites. With one exception, each complex was unmetabolized in vivo. All complexes and metabolites formed were neutral in vitro and in vivo. Extended stability in serum of selected radiometal complexes has been measured. Each complex measured was stable to exchange with transferrin, up to 72 h, as expected from the large stability constants of the complexes. The clearance characteristics of the hydroxypyridyl and phenolic ligands, however, were markedly different. The rapid hepatic clearance of the phenolic ligands indicates potential as bifunctional chelates for Ga(III) or In(III).