Comparative in Vivo Stability of Copper-64-Labeled Cross-Bridged and Conventional Tetraazamacrocyclic Complexes

C. Andrew Boswell, Xiankai Sun, Weijun Niu, Gary R. Weisman, Edward H. Wong, Arnold L. Rheingold, Carolyn J. Anderson

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441 Scopus citations


The increased use of copper radioisotopes in radiopharmaceutical applications has created a need for bifunctional chelators (BFCs) that form stable radiocopper complexes and allow covalent attachment to biological molecules. The chelators most commonly utilized for labeling copper radionuclides to biomolecules are analogues of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); however, recent reports have communicated the instability of the radio-Cu(II)-TETA complexes in vivo. A class of bicyclic tetraazamacrocycles, the ethylene "cross-bridged" cyclam (CB-cyclam) derivatives, form highly kinetically stable complexes with Cu(II) and therefore may be less susceptible to transchelation than their nonbridged analogues in vivo. Herein we report results on the relative biological stabilities and identification of the resulting radiolabeled metabolites of a series of 64Cu-labeled macrocyclic complexes. Metabolism studies in normal rat liver have revealed that the 64Cu complex of 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane ( 64Cu-CB-TE2A) resulted in significantly lower values of protein-associated 64CU than 64Cu-TETA [13 ± 6% vs 75 ± 9% at 4 h]. A similar trend was observed for the corresponding cyclen derivatives, with the 64CU complex of 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane ( 64Cu-CB-DO2A) undergoing less transchelation than the 64Cu complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (64Cu-DOTA) [61 ± 14% vs 90.3 ± 0.5% protein associated 64Cu at 4 h]. These data indicate that the structurally reinforcing cross-bridge enhances in vivo stability by reducing metal loss to protein in both the cyclam and cyclen cross-bridged 64Cu complexes and that 64Cu-CB-TE2A is superior to 64Cu-CB-DO2A in that regard. These findings further suggest that a bifunctional chelator derivative of CB-TE2A is a highly desirable alternative for labeling copper radionuclides to biological molecules for diagnostic imaging and targeted radiotherapy.

Original languageEnglish (US)
Pages (from-to)1465-1474
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number6
StatePublished - Mar 11 2004

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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