Facile Synthesis of Rigid Binuclear Manganese Complexes for Magnetic Resonance Angiography and SLC39A14-Mediated...

Manganese(II)-based contrast agents (MBCAs) are potential candidates for gadolinium-free enhanced magnetic resonance imaging (MRI). In this work, a rigid binuclear MBCA (Mn₂-PhDTA₂) with a zero-length linker was developed via facile synthetic routes, while the other dimer (Mn₂-TPA-PhDTA₂) with a longer rigid linker was also synthesized via more complex steps. Although the molecular weight of Mn₂-PhDTA₂ is lower than that of Mn₂-TPA-PhDTA₂, their T₁ relaxivities are similar, being increased by over 71% compared to the mononuclear Mn-PhDTA. In the presence of serum albumin, the relaxivity of Mn₂-PhDTA₂ was slightly lower than that of Mn₂-TPA-PhDTA₂, possibly due to the lower affinity constant. The transmetalation reaction with copper(II) ions confirmed that Mn₂-PhDTA₂ has an ideal kinetic inertness with a dissociation half-life of approximately 10.4 h under physiological conditions. In the variable-temperature ¹⁷O NMR study, both Mn-PhDTA and Mn₂-PhDTA₂ demonstrated a similar estimated q close to 1, indicating the formation of monohydrated complexes with each manganese(II) ion. In addition, Mn₂-PhDTA₂ demonstrated a superior contrast enhancement to Mn-PhDTA in in vivo vascular and hepatic MRI and can be rapidly cleared through a dual hepatic and renal excretion pattern. The hepatic uptake mechanism of Mn₂-PhDTA₂ mediated by SLC39A14 was validated in cellular uptake studies.