Very stable copper(II) complexes of bispidines and their radiopharmaceutical behavior

The three bispidine-derived ligands L1 - L3 (bispidine = 3,7-diazabicyclo[3.3.1]-nonane) have been labeled with ⁶⁴Cu, and the radioactive copper(II) complexes have been investigated for potential radiopharmaceutical applications. The thermodynamic stability of copper(II) complexes with the 2^nd generation bispidines L2 and L3 is significantly higher than with L1 as a 1^st generation bispidine. Despite this, labeling kinetics and challenge experiments indicate that L1 has advantages as a ligand for radiocopper(II) applications over the new ligands L2 and L3. The copper(II) complexes of all three bispidine ligands were found to be rather hydrophilic (log D_o/w at pH = 7.4: ⁶⁴Cu-L1 = -2.88, ⁶⁴Cu-L2 = -1.45, ⁶⁴Cu-L3 = -1.94). In vitro experiments with rat plasma give evidence that the ⁶⁴Cu complexes of L1 – L3 are very stable.