Mn²⁺Bispidine Complex Combining Exceptional Stability, Inertness, and MRI Efficiency

Abstract

As an essential metal ion and an efficient relaxation agent, Mn2+ holds a great promise to replace Gd3+ in magnetic resonance imaging (MRI) contrast agent applications, if its stable and inert complexation can be achieved. Toward this goal, four pyridine and one carboxylate pendants have been introduced in coordinating positions on the bispidine platform to yield ligand L3. Thanks to its rigid and preorganized structure and perfect size match for Mn2+, L3 provides remarkably high thermodynamic stability (log K MnL = 19.47), selectivity over the major biological competitor Zn2+ (log(K MnL/K ZnL) = 4.4), and kinetic inertness. Solid-state X-ray data show that [MnL3(MeOH)](OTf)2 has an unusual eight-coordinate structure with a coordinated solvent molecule, in contrast to the six-coordinate structure of [ZnL3](OTf), underlining that the coordination cavity is perfectly adapted for Mn2+, while it is too large for Zn2+. In aqueous solution, 17O NMR data evidence one inner sphere water and dissociatively activated water exchange (k ex 298 = 13.5 × 107 s–1) for MnL3. Its water proton relaxivity (r 1 = 4.44 mM–1 s–1 at 25 °C, 20 MHz) is about 30% higher than values for typical monohydrated Mn2+ complexes, which is related to its larger molecular size; its relaxation efficiency is similar to that of clinically used Gd3+-based agents. In vivo MRI experiments realized in control mice at 0.02 mmol/kg injected dose indicate good signal enhancement in the kidneys and fast renal clearance. Taken together, MnL3 is the first chelate that combines such excellent stability, selectivity, inertness and relaxation properties, all of primary importance for MRI use.

Magnetic Resonance Diagnosis of Early Triple-Negative Breast Cancer Based on the Ionic Covalent Organic Framework with High Relaxivity and Long Retention Time

“…The capability of anti-interference with the existence of Zn 2+ is an important parameter of MRI contrast agents because Zn 2+ is the second most abundant trace metal ion in the human body and may be easier to displace more chelated Mn 2+ compared to Cu 2+ and Ca 2+ . The transmetallation experiment was performed to ascertain the chelating and kinetic stability of Mn-iCOF. , In the absence of Zn 2+ in water, the 1/ T 1 of Mn-iCOF (0.25 mM) was observed as 2.5 s –1 , while the addition of 5 molar equivalents of Zn 2+ resulted in the values with a slight decrease for 5 and 10 days, respectively (Figure I).…”

A seven-coordinate Mn(ii) complex with a pyridine-based 15-membered macrocyclic ligand containing one acetate pendant arm: structure, stability and relaxation properties

“…Few Mn( ii ) chelates were found to be inert to Zn 2+ or Cu 2+ transmetalation, 17,18 although recent examples of Mn( ii ) bispidine complexes evidence that extraordinary inertness might be possible with highly preorganized and rigid ligand structures. 19…”

Steric Effects on the Chelation of Mn2+and Zn2+by Hexadentate Polyimidazole Ligands: Modeling Metal Binding by Calprotectin Site 2

“…However, some biologically relevant transition metal ions remain difficult to coordinate selectively, including Mn 2+ . There are as yet only three (closely related) reported synthetic chelates that exhibit significant selectivity for Mn 2+ over its close biological competitor, Zn 2+ [7,8] …”

“…There are as yet only three (closely related) reported synthetic chelates that exhibit significant selectivity for Mn 2 + over its close biological competitor, Zn 2 + . [7,8] One area where nature has evolved potent strategies for strong and (in some cases) highly selective metal chelation is in metal sequestration as part of nutritional immunity, a strategy widely used by host immune systems as a defence against pathogenic virulence by starving invading pathogens of necessary trace metal nutrients. [9][10][11] In humans, the immune system protein calprotectin is a key player in this process, representing up to 60 % of soluble cytosolic protein in neutrophils.…”