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 Gd 3+ chelates. In this study, we developed a series of chelators based on the 2,11-diaza3.3(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, Mn(TE-2) + demonstrated greater kinetic inertness than Mn(TE-5) and Mn(TE-6) + , indicating that additional chelating arms may reduce inertness by facilitating coordination with other metal ions such as Cu(II) and Zn(II). Amine methylation was found to enhance kinetic inertness and not affect relaxivity, as Mn(TE-2) + exhibited similar relaxivity to Mn(BPPA). Given its promising in vitro performance, Mn(TE-2) + was tested in mice using a 9.4 T MRI scanner. The Mn 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.
Sayed et al. (Mon,) studied this question.