Tuning the Properties of Rigidified Acyclic DEDPA^2– Derivatives for Application in PET Using Copper-64

We present a detailed investigation of the coordination chemistry toward [^natCu/⁶⁴Cu]copper of a series of H₂DEDPA derivatives (H₂DEDPA = 6,6'-((ethane-1,2-diylbis(azanediyl))bis(methylene))dipicolinic acid) containing cyclohexyl (H₂CHXDEDPA), cyclopentyl (H₂CpDEDPA) or cyclobutyl (H₂CBuDEDPA) spacers. Furthermore, we also developed a strategy that allowed the synthesis of a H₂CBuDEDPA analogue containing an additional NHBoc group at the cyclobutyl ring, which can be used for conjugation to targeting units. The X-ray structures of the Cu(II) complexes evidence distorted octahedral coordination around the metal ion in all cases. Cyclic voltammetry experiments (0.15 M NaCl) evidence quasi-reversible reduction waves associated with the reduction of Cu(II) to Cu(I). The complexes show a high thermodynamic stability, with log <i>K</i>_CuL values of 25.11(1), 22.18(1) and 20.19(1) for the complexes of CHXDEDPA^2-, CpDEDPA^2- and CBuDEDPA^2-, respectively (25 °C, 1 M NaCl). Dissociation kinetics experiments reveal that both the spontaneous- and proton-assisted pathways operate at physiological pH. Quantitative labeling with ⁶⁴CuCl₂ was observed at 0.1 nmol for CHXDEDPA^2- and CpDEDPA^2-, 0.025 nmol for CBuDEDPA^2- and 1 nmol for CBuDEDPA-NHBoc^2-, with no significant differences observed at 15, 30, and 60 min. The radio-complexes are stable in PBS over a period of 24 h.