T₂ exchange agents: A new class of paramagnetic MRI contrast agent that shortens water T₂ by chemical exchange rather than relaxation

Exchange of water molecules between the frequency-shifted inner-sphere of a paramagnetic lanthanide ion and aqueous solvent can shorten the T₂ of bulk water protons. The magnitude of the line-broadening T₂ exchange (T_2exch) is determined by the lanthanide concentration, the chemical shift of the exchanging water molecule, and the rate of water exchange between the two pools. A large T_2exch contribution to the water linewidth was initially observed in experiments involving Eu³⁺-based paramagnetic chemical exchange saturation transfer agents in vivo at 9.4 T. Further in vitro and in vivo experiments using six different Eu³⁺ complexes having water exchange rates ranging from zero (no exchange) to 5 × 10⁶ s^-1 (fast exchange) were performed. The results showed that the exchange relaxivity (r_2exch) is small for complexes having either very fast or very slow exchange, but reaches a well-defined maximum for complexes with intermediate water exchange rates. These experimental results were verified by Bloch simulations for two site exchange. This new class of T_2exch agent could prove useful in the design of responsive MRI contrast agents for molecular imaging of biological processes.