Synthesis of a new bifunctional chelating agent for radioimmunotherapy: Cyclohexyl fused tetraazacyclodo-decanetetraacetic acid

Preorganization of the coordinating groups within a chelating agent increases the stability of its metal-ligand complexes. For example, 1,2-diaminocyclo-hexanetetraacetic acid (CDTA) forms metal complexes with stability constants 1-3 orders of magnitude higher than the corresponding complexes of EDTA. Incorporation of a cyclohexyl group into a macrocyclic ligand produces a similar effect; stability constants of Cu complexes of tetrathiocyclotetradecanes are increased by 1.5 orders of magnitude by incorporating one cyclohexyl group into the macrocyclic ring and 3 orders of magnitude by incorporating two cyclohexyl moieties. In this study, we have synthesized cycohexyl DOTA (C-DOTA) in which the cyclohexyl group is fused to two carbons of the macrocyclic ring. Alkylation of disodium ethylene ditosylamide with trans-1,2-di(bromoacetamido)cyclohexane afforded the C{sub 8}N{sub 4} macrocycle. Reduction with lithium aluminum hydride not only reduced the amide moieties to amines but also removed the tosyl protecting groups affording the cyclohexylcyclen. Cyanomethylation followed by hydrolysis gave C-DOTA in an overall yield of 9.4%. C-DOTA is expected to offer improvements in the biodistribution of radiometal immunoconjugates for radioimmunotherapy, in particular with Sc-47, Y-90, and Sm-153 that have given encouraging results using the plain DOTA ligand.