Investigating Cu(II) Complexes for MRI: A Comprehensive Approach Using EPR, Relaxometry, and Computational Modeling

Abstract

[Abstract] 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.