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.

Toxicity concerns related to Gd(III)-based MRI agents prompted an intensive research towards their replacement by complexes of essential Mn(II) ion. Here, we report a macrocyclic chelate, [Mn(PC2A-BP)], which possesses high thermodynamic stability and kinetic inertness as well as remarkable relaxivity (r 1p = 23.5 mM-1 s-1 , 20 MHz, 37 °C) in the presence of human serum albumin allowing a significant MRI signal intensity increase in the vasculature even at low dose (25 mol/kg) of the complex.

The stability constants of lanthanide complexes with the potentially octadentate ligand CHX OCTAPA 4– , which contains a rigid 1,2-diaminocyclohexane scaffold functionalized with two acetate and two picolinate pendant arms, reveal the formation of stable complexes [log K LaL = 17.82(1) and log K YbL = 19.65(1)]. Luminescence studies on the Eu 3+ and Tb 3+ analogues evidenced rather high emission quantum yields of 3.4 and 11%, respectively. The emission lifetimes recorded in H 2 O and D 2 O solutions indicate the presence of a water molecule coordinated to the metal ion. 1 H nuclear magnetic relaxation dispersion profiles and 17 O NMR chemical shift and relaxation measurements point to a rather low water exchange rate of the coordinated water molecule ( k ex 298 = 1.58 × 10 6 s –1 ) and relatively high relaxivities of 5.6 and 4.5 mM –1 s –1 at 20 MHz and 25 and 37 °C, respectively. Density functional theory calculations and analysis of the paramagnetic shifts induced by Yb 3+ indicate that the complexes adopt an unprecedented cis geometry with the two picolinate groups situated on the same side of the coordination sphere. Dissociation kinetics experiments were conducted by investigating the exchange reactions of LuL occurring with Cu 2+ . The results confirmed the beneficial effect of the rigid cyclohexyl group on the inertness of the Lu 3+ complex. Complex dissociation occurs following proton- and metal-assisted pathways. The latter is relatively efficient at neutral pH, thanks to the formation of a heterodinuclear hydroxo complex.

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The discovery of the nephrogenic systemic fibrosis (NSF) and its link with the in vivo dissociation of certain Gd(III)-based contrast agents (CAs) applied in the magnetic resonance imaging (MRI) induced a still growing research to replace the compromised agents with safer alternatives. In recent years, several ligands were designed to exploit the luminescence properties of the lanthanides, containing structurally constrained aromatic moieties, which may form rigid Gd(III) complexes. One of these ligands is (1,10-phenanthroline-2,9-diyl)bis(methyliminodiacetic acid) (H 4 FENTA) designed and synthesized to sensitize Eu(III) and Tb(III) luminescence. Our results show that the conditional stability of the [Gd(FENTA)] − chelate calculated for physiological pH (pGd = 19.7) is similar to those determined for [Gd(DTPA)] 2− (pGd = 19.4) and [Gd(DOTA)] − (pGd = 20.1), routinely used in the clinical practice. The [Gd(FENTA)] − complex is remarkably inert with respect to its dissociation (t 1/2 = 872 days at pH = 7 and 25 °C); furthermore, its relaxivity values determined at different field strengths and temperatures (e.g., r 1p = 4.3 mM −1 s −1 at 60 MHz and 37 °C) are ca. one unit higher than those of [Gd(DTPA)] 2− (r 1p = 3.4 mM −1 s −1 ) and [Gd(DOTA)] − (r 1p = 3.1 mM −1 s −1 ) under the same conditions. Moreover, significant improvement on the relaxivity was observed in the presence of serum proteins (r 1p = 6.9 mM −1 s −1 at 60 MHz and 37 °C). The luminescence lifetimes recorded in H 2 O and D 2 O solutions indicate the presence of a water molecule (q = 1) in the inner sphere of the complex directly coordinated to the metal ion, possessing a relatively high water exchange rate (k ex 298 = 29(2) × 10 6 s −1 ). The acceleration of the water exchange can be explained by the steric compression around the water binding site due to the rigid structure of the complex, which was supported by DFT calculations. On the basis of these results, ligands containing a phenanthroline platform have great potential in the design of safer Gd(III) agents for MRI.