Macrocyclic chelates of radiometals for diagnosis and therapy

C. F. Meares, M. K. Moi, H. Diril, D. L. Kukis, M. J. McCall, S. V. Deshpande, S. J. DeNardo, D. Snook, A. A. Epenetos

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

Monoclonal antibody technology allows the specificity of an antibody for its antigen to be used in targeting cancer cells. Stable attachment of metal ions to antibodies by means of 'bifunctional' chelating agents can add the nuclear, physical and chemical properties of the metallic elements to these target-selective proteins. The conjugation of metals - particularly radionuclides - 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 non-target cells. Derivatives of polyazamacrocycles (bearing a C-substituted functional group for antibody attachment) can exhibit remarkable kinetic inertness. We have developed a new synthetic route to these macrocycles via peptide synthesis and intramolecular tosylamide ring closure. Incubation of the yttrium complex of 2-p-nitrobenzyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacet ic acid (nitrobenzyl-DOTA) for 18 days in serum results in loss of so little yttrium from the complex (less than 0.5%) that the rate of loss cannot be measured under these conditions. In animal models, conjugates of this chelate with monoclonal antibodies show much lower levels of yttrium in the bone than are found with DTPA chelates prepared from the cyclic anhydride. The rates of loss of indium and cobalt from nitrobenzyl-DOTA in serum are slower than from previously studied chelates. Preliminary clinical imaging studies of 111In-labelled monoclonal antibody conjugates of DOTA show highly encouraging results.

Original languageEnglish (US)
Pages (from-to)21-26
Number of pages6
JournalBritish Journal of Cancer
Volume62
Issue numberSUPPL. X
StatePublished - 1990

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Meares, C. F., Moi, M. K., Diril, H., Kukis, D. L., McCall, M. J., Deshpande, S. V., DeNardo, S. J., Snook, D., & Epenetos, A. A. (1990). Macrocyclic chelates of radiometals for diagnosis and therapy. British Journal of Cancer, 62(SUPPL. X), 21-26.