| Abstract
| - The increased use of copper radioisotopes in radiopharmaceutical applications has created aneed for bifunctional chelators (BFCs) that form stable radiocopper complexes and allow covalentattachment to biological molecules. The chelators most commonly utilized for labeling copperradionuclides 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 invivo. Herein we report results on the relative biological stabilities and identification of theresulting radiolabeled metabolites of a series of 64Cu-labeled macrocyclic complexes. Metabolismstudies 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 valuesof protein-associated 64Cu than 64Cu-TETA [13 ± 6% vs 75 ± 9% at 4 h]. A similar trend wasobserved 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 thestructurally reinforcing cross-bridge enhances in vivo stability by reducing metal loss to proteinin both the cyclam and cyclen cross-bridged 64Cu complexes and that 64Cu-CB-TE2A is superiorto 64Cu-CB-DO2A in that regard. These findings further suggest that a bifunctional chelatorderivative of CB-TE2A is a highly desirable alternative for labeling copper radionuclides tobiological molecules for diagnostic imaging and targeted radiotherapy.
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