Optimization of Hexadentate Bispidine Ligands as Chelators for ⁶⁴ Cu^II PET Imaging

The coordination chemistry of the hexadentate bispidine ligand L¹ with three pyridine, one pyridazine, and two tertiary amine donors with Cu^II and Zn^II is reported. The substitution of one of the two cis-disposed pyridine donors in-plane with the two tertiary amines of the bispidine backbone by a pyridazine group was predicted to substantially reduce distortion from planarity of the tetradentate subunit and therefore was assumed to lead to higher Cu^II complex stability. The X-ray single-crystal structures of the Zn^II and Cu^II complexes, which are in excellent agreement with the DFT- and MM-optimized structures, confirmed this prediction but indicated that deviation from planarity is appreciable. This also emerges from solution spectroscopy (UV/Vis/NIR and EPR of the Cu^II complex), which indicated that the in-plane ligand field is only slightly increased. The geometric parameters together with the lower basicity of pyridazine versus pyridine (pK_a =2.33 vs. 5.23) are also in agreement with an only slightly more negative redox potential of the Cu^II/I couple (E^o =-780 vs. -760 mV, MeCN, vs. Fc/Fc⁺ ), and the potentiometrically determined Cu^II stability constant with L¹ is slightly lower than that with the parent ligand L² (log K=12.7 vs. 14.5). Therefore, modification of the donor groups is a more promising approach to increasing the stabilities of these complexes and yields ⁶⁴ Cu^II chelators that outperform known hexadentate bispidine ligands.