Complexation of Mn(II) by Rigid Pyclen Diacetates: Equilibrium, Kinetic, Relaxometric, Density Functional Theory, and Superoxide Dismutase Activity Studies

Abstract

We report the Mn(II) complexes with two pyclen-based ligands (pyclen = 3,6,9,15tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with acetate pendant arms either at positions 3,6 (3,6-PC2A) or 3,9 (3,9-PC2A) of the macrocyclic fragment. The 3,6-PC2A ligand was synthesized in five steps from pyclenoxalate by protecting one of the secondary amine groups of pyclen using Alloc protecting chemistry. The complex with 3,9-PC2A is characterized by a higher thermodynamic stability (logKMnL = 17.09(2) than the 3,6-PC2A analogue (logKMnL = 15.53(1), 0.15 M NaCl). Both complexes contain a water molecule coordinated to the metal ion, which results in relatively high 1 H relaxivities (r1p = 2.72 and 2.91 mM -1 s -1 for the complexes with 3,6-and 3,9-PC2A, respectively, 25 ºC, 0.49 T). The coordinated water molecule displays fast exchange kinetics with the bulk in both cases; the rates (kex 298 ) are 14010 6 and 12610 6 s -1 for [Mn(3,6-PC2A)(H2O)] and [Mn(3,9-PC2A)(H2O)], respectively. The two complexes were found to be remarkably inert with respect to their dissociation, with half-lives of 63 and 21 h, respectively, at pH 7.4 in the presence of excess Cu(II). The r1p values recorded in blood serum remain constant at least over a period of 120 h. Cyclic voltammetry experiments show irreversible oxidation features shifted to higher potentials with respect to [Mn(EDTA)(H2O)] 2and [Mn(PhDTA)(H2O)] 2-, indicating that the PC2A complexes reported here have a lower tendency to stabilize Mn(III). The superoxide dismutase activity of the Mn(II) complexes was tested using the xanthine/xanthine oxidase/NBT assay at pH 7.8. The Mn(II) complexes of 3,6-PC2A and 3,9-PC2A are capable to assist the decomposition of superoxide anion radical. The kinetic rate constant of the complex of 3,9-PC2A is smaller by one order of magnitude than that of 3,6-PC2A.

Expanding the Ligand Classes Used for Mn(II) Complexation: Oxa-aza Macrocycles Make the Difference

“…The protonation constants of the tO2DO2A 2− and tO2DO2AM Pip ligands were determined by pH-potentiometric titrations with an ionic strength fixed at I = 0.15 M NaCl. The results are compared in Table 2 with the equilibrium constants reported for tDO2A 2− [17,18] and tPC2A 2− [19,48] as well as those measured previously for tO2DO2A 2− using 0.1 M Me 4 NNO 3 as the background electrolyte [49]. Both tO2DO2A 2− and tO2DO2AM Pip present two protonation constants with logK H values > 6.0, associated to the protonation of the amine N atoms of the ligand.…”

“…The cyclen derivatives cDO2A 2− and tDO2A 2− (Scheme 1) form relatively stable complexes with Mn(II), but only the complex with cDO2A 2− contains a coordinated water molecule [16][17][18]. The incorporation of a rigid pyridyl unit to the macrocyclic unit afforded Mn(II) complexes with a coordinated water molecule, regardless of the arrangement of the acetate groups (cPC2A 2− or tPC2A 2− , Scheme 1) [19,20]. The latter ligands form rather stable and inert complexes with Mn(II) and can be considered promising building blocks for the preparation of contrast agent candidates [21,22].…”

A New Oxygen Containing Pyclen-Type Ligand as a Manganese(II) Binder for MRI and 52Mn PET Applications: Equilibrium, Kinetic, Relaxometric, Structural and Radiochemical Studies

“…The given value is similar to that of macrocyclic Mn(II) complexes possessing 0.9 [(Mn(1,4-DO2A)]), i.e., one coordinated water molecule (q = 1) in their inner coordination sphere (i.g. [Mn(3,6-PC2A)], [Mn(3,9-PC2A)], or [Mn(1,7-O2DO2A]), and they were higher than the relaxivity of complexes with q = 0 (typically 1.4-1.6 mM −1 s −1 as observed for [Mn(DO3A)] − or [Mn(PCTA)] − [12,16,20,21]. Lowering the pH below pH = 4.0, resulted in a sharp relaxivity increase, reaching the r 1p value of 6.51 mM −1 s −1 (at 1.41 T and 25 • C) near pH = 1.8.…”

“…The ligand used by the authors is based on a rigid bispidine platform, and the monoaquated Mn(II) complex formed by their ligand possesses an inertness similar to that of [Mn(DOTA)] 2− [15]. Our approach to Mn(II)-based MRI CA candidates is based on the rigid pyclen derivative H 2 3,9-PC2A ligand (H 2 3,9-PC2A = pyclen-3,9-diacetate), as it forms a stable monoaquated complex with Mn(II) [16]. However, its inertness requires further improvement as [Mn(3,9-PC2A)] is readily protonated, favoring an efficient dissociation via the proton-assisted mechanism (as confirmed by the calculation of the electrostatic potential using DFT methods).…”

Semi-Rigid (Aminomethyl) Piperidine-Based Pentadentate Ligands for Mn(II) Complexation

“…However, such an agent was recently withdrawn by both the European and US markets because of poor clinical performance and toxicity concerns. Since then, several alternatives have been reported, among which, the Mn-complexes of cis -1,4-DO2A and its derivatives (1,4-DO2A = 1,4,7,10-tetraazacyclododecane-1,4-diacetic acid) [ 9 , 10 ], PC2A derivatives (PC2A = tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,9-triacetic acid) [ 11 , 12 ], trans -CDTA ( trans -1,2-diaminocyclohexane- N , N , N ′, N ′-tetraacetic acid, Figure 1 ) [ 13 ] and PyC3A ( N -picolyl- N , N ′, N ′- trans -1,2-cyclohexylenediaminetriacetate, Figure 1 ) [ 14 ] seem to be the most promising for general MRI applications.…”