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Stable Bifunctional Chelates of Metals Used in Radiotherapy¹

Chemistry Department, University of California, Davis, California 95616, and Departments of Internal Medicine and Radiology, University of California, Davis, Medical Center, Sacramento, California 95817

Monoclonal antibody technology allows the specificity of an antibody for its antigen to be used in targeting cancer cells. The conjugation of metals, particularly radionuclides such as ⁹⁰Y or ⁶⁷Cu, to monoclonal antibodies results in agents for radioimmunotherapy 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. Derivatives of polyazamacrocycles (bearing a C-substituted functional group for antibody attachment) can exhibit remarkable kinetic inertness; for example, the copper complex of the 14-membered 6-(p-nitrobenzyl)-1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid is very stable in human serum under physiological conditions, and a conjugate of this complex with a monoclonal antibody has tested well in tumor-bearing mice. Desreux and coworkers [Loncin, M. F., Desreux, J. F., and Merciny, E. Inorg. Chem., 25: 2646–2648, 1986] have shown that complexes of lanthanides with 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid have formation constants that are several orders of magnitude higher than that of 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid; thus the 12-membered macrocycle is the favored target for binding trivalent yttrium. We have developed a new synthetic route to these macrocycles via peptide synthesis and intramolecular tosylamide ring closure. Incubation of the ⁸⁸Y-(III) complex of 2-p-nitrobenzyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid for 18 days in serum results in loss of so little Y(III) from the complex (less than 0.5%) that the rate of loss cannot be measured under these conditions.

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