Mn(II) MRI contrast agents supported by unsymmetric pyridinophane-picolinate ligands

Gadolinium-based contrast agents are commonly utilized in magnetic resonance imaging (MRI). However, manganese-based agents have attracted increasing interest due to their favorable relaxation properties and enhanced biocompatibility, particularly in light of concerns regarding nephrogenic systemic fibrosis associated with the administration of acyclic Gd³⁺ chelates. In this study, we developed a series of hexadentate and heptadentate chelators based on the 2,11-diaza[3.3](2,6)pyridinophane macrocycle to improve the relaxivity of the corresponding Mn(II) complexes. We evaluated how coordination number and pendant arm selection influence the efficiency of these Mn-based MRI contrast agents. Spectrophotometric titrations showed that 7-coordinate complexes are more thermodynamically stable than 6-coordinate complexes, as expected for Mn(II). However, the presence of additional chelating arms was shown to reduce the kinetic inertness of the Mn complexes by facilitating coordination with other metal ions such as Cu(II) and Zn(II), while amine methylation was found to enhance kinetic inertness and not affect relaxivity. Given its promising in vitro performance, one Mn complex was tested in mice using a 9.4 T MRI scanner, revealing that the compound was primarily cleared via the renal pathway, and low heart contrast enhancement indicated minimal albumin binding, consistent with the behavior of other promising MRI contrast agents.