The development of Gd-free MRI contrast agents requires a detailed understanding of the structural and electronic factors governing paramagnetic relaxation in first-row transition-metal complexes. In this work, we integrate EPR spectroscopy, Q-band ENDOR, variable-temperature 17O NMR, field-dependent 1H relaxometry, and DFT calculations to dissect the structure-relaxivity relationships of two prototypical Cu(II) systems: Cu(TACN)2+ and Cu(TREN)2+. These complexes differ markedly in geometry, hydration state, and electronic ground state, offering a controlled platform to probe how the coordination environment modulates dipolar and scalar relaxation pathways. EPR and ENDOR measurements yield rotational correlation times and metal-proton hyperfine couplings in close agreement with theoretical predictions, enabling a quantitative description of water and proton exchange dynamics. 1H relaxometric analysis reveals distinct regimes. Cu(TACN)2+ exhibits fast water exchange driven by a dynamic Jahn-Teller effect, whereas five-coordinate Cu(TREN)2+ shows much slower exchange and a significant scalar contribution under basic conditions, where OH- replaces inner-sphere water. Collectively, these results highlight the sensitivity of Cu(II) relaxivity to subtle structural perturbations and demonstrate that targeted control of geometry and hydration can modulate inner-sphere and prototropic exchange pathways. The integrated methodology presented here provides a robust experimental-computational framework for the rational design of Cu(II)-based MRI contrast agents.
Pagliero et al. (Tue,) studied this question.