Comparative in Vivo Stability of Copper-64-Labeled Cross-Bridged and Conventional Tetraazamacrocyclic Complexes
Top Cited Papers
- 12 February 2004
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 47 (6), 1465-1474
- https://doi.org/10.1021/jm030383m
Abstract
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 (64)Cu-labeled macrocyclic complexes. Metabolism studies in normal rat liver have revealed that the (64)Cu complex of 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane ((64)Cu-CB-TE2A) resulted in significantly lower values of protein-associated (64)Cu than (64)Cu-TETA [13 +/- 6% vs 75 +/- 9% at 4 h]. A similar trend was observed for the corresponding cyclen derivatives, with the (64)Cu complex of 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane ((64)Cu-CB-DO2A) undergoing less transchelation than the (64)Cu complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid ((64)Cu-DOTA) [61 +/- 14% vs 90.3 +/- 0.5% protein associated (64)Cu 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 (64)Cu complexes and that (64)Cu-CB-TE2A is superior to (64)Cu-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.Keywords
This publication has 20 references indexed in Scilit:
- Synthesis, structure, and stability in acid of copper(II) and zinc(II) complexes of cross-bridged tetraazamacrocyclesInorganica Chimica Acta, 2003
- Metabolism of Radiometal-Labeled Proteins and Peptides: What are the Real Radiopharmaceuticals in vivo?Cancer Biotherapy & Radiopharmaceuticals, 2001
- Radiopharmaceuticals for targeted radiotherapy of cancerExpert Opinion on Therapeutic Patents, 2000
- Physical Parameters and Biological Stability of Yttrium(III) Diethylenetriaminepentaacetic Acid Derivative ConjugatesJournal of Medicinal Chemistry, 1998
- Catalysis by a Multiprotein IκB Kinase ComplexScience, 1997
- Efficient production of high specific activity 64Cu using a biomedical cyclotronNuclear Medicine and Biology, 1997
- Comparison of Four Bifunctional Chelates for Radiolabeling Monoclonal Antibodies with Copper Radioisotopes: Biodistribution and MetabolismBioconjugate Chemistry, 1996
- Evaluation of copper-labeled bifunctional chelate-albumin conjugates for blood pool imagingNuclear Medicine and Biology, 1993
- The stability of the metal complexes of cyclic tetra-aza tetra-acetic acidsTalanta, 1992
- Cross-bridged cyclam. Protonation and lithium cation (Li+) complexation in a diamond-lattice cleftJournal of the American Chemical Society, 1990