Optimization of Hexadentate Bispidine Ligands as Chelators for ⁶⁴CuII PET Imaging

The coordination chemistry of the hexadentate bispidine ligand L 1 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 (p K 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 L 1 is slightly lower than that with the parent ligand L 2 (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.