The peptide way to macrocyclic bifunctional chelating agents: synthesis of 2-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid and study of its yttrium(III) complex

Abstract

Monoclonal antibody technology allows the specificity of an antibody for its antigen to be used in targeting cancer cells. The conjugation of metals/emdash/particularly radionuclides such as /sup 90/Y or /sup 67/Cu/emdash/ to monoclonal antibodies results in agents for radiommunotherapy and other medical applications. Chelators that can hold radiometals with high stability under physiological conditions are essential to avoid excessive radiation damage to nontarget cells. Macrocylic polyamines, the key precursors to macrocyclic bifunctional chelating agents, are synthesized by bimolecular cyclizations. Competition between polymerization and the desired cyclization is a common problem; the authors efforts to form a 12-membered macrocycle cyclizations gave unsatisfactory yields. They have developed a new synthetic route to these macrocycles via peptide synthesis and intramolecular tosylamide ring closure. For polyazamacrocyles with nitrogens separated by two-carbon chains, peptides made from /alpha/-amino acids are readily accessible starting materials. Treatment with borane converts peptides to linear polyamino alcohols, in which the original peptide backbone has been converted to a C-terminal alcohol, an N-terminal primary amine, and internal secondary amines (Figure 1, step 1). Treatment with p-toluenesulfonyl chloride produces a C-terminal tosyl ester, an N-terminal secondary tosylamide, and internal tertiary tosylamides. Treatment with mild base converts the N-terminal tosylamide to a nucleophliemore » which displaces the C-terminal tosyl ester and thus forms a macrocyclic ring in high yield. This intramolecular cyclication may be performed in very dilute solution, eliminating concerns about polymer formation.« less