The in vivo behavior of copper-64-labeled azamacrocyclic complexes

The use of copper radioisotopes in imaging and therapy applications has created a greater need for bifunctional chelates (BFCs) for complexing copper radioisotopes to biomolecules. It has been demonstrated that the charge and lipophilicity of the Cu-BFC complex has a significant effect on the in vivo behavior of the radiolabeled Cu-BFC-biomolecule conjugate. To evaluate the effects of charge, stability, and macrocyclic backbone size on the biological behavior of ⁶⁴Cu complexes, a series of macrocyclic ⁶⁴Cu complexes have been prepared, and the biodistributions of these agents were evaluated in normal Sprague-Dawley rats. Two macrocyclic backbones, dodecane and tetradecane, were evaluated; cyclen, DOTA, and DO2A were dodecane backbone derivatives, and cyclam, TETA, and et-cyclam were tetradecane backbone derivatives. The biodistributions of the ⁶⁴Cu-labeled complexes correlated with differences in the size of the macrocycle backbone and the formal charge of the complex. All compounds showed uptake and clearance through the liver and kidneys; however, the positively charged ⁶⁴Cu complexes showed significantly higher uptake in both of these organs than did the negatively charged or neutral complexes. ⁶⁴Cu-TETA, a negatively charged complex with the tetradecane backbone, had the most efficient clearance by 24 hours' postinjection. These data suggest that negatively charged complexes may have more favorable clearance properties when used as BFCs.