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

## TL;DR

This paper explores how the structure of copper complexes affects their MRI contrast properties using advanced experimental and computational methods.

## Contribution

The study introduces an integrated experimental–computational framework to rationally design Cu(II)-based MRI contrast agents.

## Key findings

- EPR and ENDOR measurements align with theoretical predictions of water and proton exchange dynamics.
- [Cu(TACN)]²+ shows fast water exchange due to a dynamic Jahn–Teller effect.
- [Cu(TREN)]²+ exhibits slower exchange and significant scalar relaxation under basic conditions.

## 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.