Mn²⁺ Bispidine Complexes as Potential Magnetic Resonance Imaging Agents : Noncoordinating Peripheral Functional Groups Affect Structural, Kinetic, and Relaxation Properties

Mn 2+ bispidine complexes combine unprecedented kinetic inertness with high relaxivity and are under scrutiny as potential magnetic resonance imaging (MRI) probes. This study demonstrates that, beyond the rigid, preorganized bispidine structure and the first coordination sphere of the Mn 2+ ion, peripheral functional groups also play a role in enhancing those kinetic and relaxation properties. Three pentadentate ligands have been designed, synthesized, and their Mn 2+ complexes investigated in order to elucidate the effect of noncoordinating carboxylate and amine pendants on the bispidine scaffold. While thermodynamic stability is not influenced by these variations in the peripheral structure, kinetic inertness is increased two‐threefold when the ligand bears both carboxylate and amine functions. The synergistic effect of these groups could be related to the formation of a relatively stable dinuclear Mn L Zn complex, which can slow down transmetallation with Zn 2+ , the most important competitor of Mn 2+ in vivo. Water exchange rate on these monohydrated chelates remains unaffected by variations in the complex charge. On the other hand, the simultaneous presence of deprotonated carboxylate and protonated amine functions enhances proton relaxivity, likely via reorganization of the second sphere water shell. These insights into structure–activity relationships help fine‐tune the safety and the efficacy of MRI agents based on Mn 2+ ‐bispidines.