Simulations were performed to understand the relative contributions of molecular parameters to longitudinal (r1) and transverse (r2) relaxivity as a function of field, and to obtain theoretical relaxivity maxima over a range of fields to appreciate what relaxivities can be achieved experimentally. The field dependent relaxivity of a panel of gadolinium and manganese complexes with different molecular parameters: water exchange rates, rotational correlation times, hydration state, etc were measured to confirm that measured relaxivities were consistent with theory. The design tenets previously stressed for optimizing r1 at low fields (very slow rotational motion; chelate immobilized by protein binding; optimized water exchange rate) do not apply at higher fields. At 1.5T and higher fields, an intermediate rotational correlation time is desired (0.5 – 4 ns), while water exchange rate is not as critical to achieving a high r1. For targeted applications it is recommended to tether a multimer of metal chelates to a protein-targeting group via a long flexible linker to decouple the slow motion of the protein from the water(s) bound to the metal ions. Per ion relaxivities of 80, 45, and 18 mM−1s−1 at 1.5, 3, and 9.4T respectively are feasible for Gd3+ and Mn2+ complexes.

A remarkably high relaxation enhancement of water protons has been observed for solutions containing apoferritin loaded with GdHPDO3A (see schematic representation). The entrapment of the complex within apoferritin (internal diameter: 7.5 nm, external diameter: 12.5 nm) allows an increased number of dipolar interactions with water molecules and exchangeable protons in the protein cavity.

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