Tuning the Properties of Rigidified Acyclic DEDPA2– 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 K CuL values of 25.11(1), 22.18(1) and 20.19(1) for the complexes of CHXDEDPA2–, CpDEDPA2– and CBuDEDPA2–, 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 CHXDEDPA2– and CpDEDPA2–, 0.025 nmol for CBuDEDPA2– and 1 nmol for CBuDEDPA-NHBoc2–, with no significant differences observed at 15, 30, and 60 min. The radio-complexes are stable in PBS over a period of 24 h.