Mn²⁺Complexes with Pyridine-Containing 15-Membered Macrocycles: Thermodynamic, Kinetic, Crystallographic, and¹H/¹⁷O Relaxation Studies

Abstract

Given its five unpaired d-electrons, long electronic relaxation time, and fast water exchange, Mn(2+) is a potential candidate for contrast agent application in medical magnetic resonance imaging. Nevertheless, the design of chelators that ensure stable Mn(2+) complexation and optimal relaxation properties remains a coordination chemistry challenge. Here, we report the synthesis of two pyridine-containing ligands L1 and L2, with 15-membered triaza-dioxa-crown and pentaaza-crown ether macrocycles, respectively, and the characterization of their Mn(2+) complexes. Protonation constants of the ligands and stability constants of various metal complexes were determined by potentiometry. The presence of the pyridine in the macrocyclic ring induces rigidity of the complexes which results in a greater thermodynamic stability with respect to the nonpyridine analogues. Solid-state structures of MnL1 and MnL2 confirmed seven-coordination of Mn(2+) with Cl(-) and H(2)O in axial positions. The dissociation kinetics of MnL2 in the presence of Zn(2+) were followed by relaxometric measurements. They proved the prime importance of the proton-assisted dissociation while the zinc(II)-assisted pathway is not important at physiological pH. For MnL1, the dissociation was too fast to be studied by conventional relaxivity measurements under pH 6. A combined (17)O NMR and (1)H NMRD study on MnL1 and MnL2 yielded the parameters that govern the relaxivity of these complexes. The water exchange rate for MnL1, k(ex)(298) = 0.38 x 10(7) s(-1), is the lowest value ever reported for a Mn(2+) complex, while a considerably higher value was obtained for MnL2 (k(ex)(298) = 6.9 x 10(7) s(-1)). Anion binding was studied by relaxometric titrations. They revealed weak interactions between MnL2 and phosphate or citrate, leading to the formation of monohydrated species. Overall, the incorporation of a pyridine into a polyaza macrocycle scaffold has several beneficial effects on the Mn(2+) chelates with respect to potential MRI contrast agent applications: (i) The thermodynamic and the kinetic stability of the complexes is increased. (ii) The rigidified ligand backbone results in higher coordination numbers of the metal ion, allowing for two inner-sphere water molecules in aqueous solution.

Stability and Toxicity of Contrast Agents

“…This suggests that incorporation of two pyridine groups in [18]-py 2 -aneN 6 results in a more highly preorganized ligand than the "flexible" [18]aneN 6 macrocycle [169]. Mn([15]-py 2 -aneN 5 ) 2+ has two Mn 2+ -bound water molecules and therefore, its relaxivity is relatively high while Mn([18]-py 2 -aneN 6 ) 2+ lacks an inner-sphere water molecule so is not terribly efficient as a CA for MRI [170].…”

“…Among the ligands that form Mn 2+ complexes that retain at least one inner-sphere water molecule, the ligands [15]-py-aneN 5 and [15]-py-aneN 3 O 2 seem to be the most promising. The improved kinetic inertness of these complexes is due to incorporation of the pyridine unit into macrocyclic backbone, which rigidifies and preorganizes the macrocycle [170]. However, even though the kinetic inertness of these macrocyclic Mn 2+ complexes are among the most favorable of the known Mn 2+ complexes, they are still less kinetically inert when compared to the open chain Gd 3+ complexes.…”

“…The kinetic inertness of Mn([15]-py-aneN 5 ) 2+ is comparable to that of Mn(DCTA) 2− . These Mn 2+ complexes also form ternary species with small bioligands such as phosphate and citrate (the presence of carbonate ions did not influence the relaxivity of complexes) so it is unlikely that they would remain intact in vivo [170]. Recently there have been some attempts to design ligands based on pyclen (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) (PCMA and PCMP, Chart 4.6) and 1-oxa-4,7-diazacyclononane (ONO2A and ONO2P, Chart 4.8) with the ultimate goal of obtaining ligands that would form thermodynamically stable and kinetically inert Mn 2+ complexes with at least one inner-sphere water molecule.…”

New Approach for Accurate QSPR Modeling of Metal Complexation: Application to Stability Constants of Complexes of Lanthanide Ions Ln3+, Ag+, Zn2+, Cd2+ and Hg2+ with Organic Ligands in Water

“…[4][5][6][7] Many efforts were done to design the ligands that selectively bind a given metal ion and allow to separate metal ions. [8][9][10][11][12][13][14] At present, a large amount of known experimental data concerning stability constants of metal-ligand complexes has been collected. [15][16][17][18][19][20][21] This opens an opportunity to develop quantitative structure -property relationships (QSPR) linking the stability constants with the structure of ligands which, in turn, can be used for computeraided design of new metal binders.…”

Complex formation of pyridine‐azacrown ether amide macrocycles with proton and heavy metal ions in aqueous solution

“…The example of divalent transition metal complexes with chiral N,O chelate Schiff-bases and heterocyclic azine ligands were early described. [11][12][13][14] In spite of forming less stable complexes than those of amine macrocyclic compounds containing pyridine, [15,16] amide macrocyclic ligands demonstrate structural rigidity to crown ether due to the presence of the pyridine-2,6-dicarbamide fragment, resulting the molecule has an open cavity and faster kinetics of formation of metal complexes. Other advantages of some properties of amide macrocycles are water solubility, easy synthetic, and purification procedures.…”