Stable and Inert Mn(II)-Based and pH-Responsive Contrast Agents.

Smart/intelligent contrast agent candidates for MRI based on Mn(II) ion are rare, as it usually forms labile complexes with polyaminocarboxylate-type ligands. Here, we report the first example of a Mn(II) complex that can be activated by changing the pH of its local environment. The PC2A-EA ligand with an ethylamine pendant arm was found to form a thermodynamically stable (log KMnL = 19.01, pMn = 9.27) and kinetically inert complex with Mn(II) with respect to trans-chelation with a metal ion such as Cu(II). The [MnH(PCA2-EA)] complex displays a relatively slow water exchange rate ((4.0 ± 0.2) × 107 s-1), but the pH-dependent coordination of the ethylamine moiety occurs in the pH range of 6-8 (log KMnLH = 6.88), enabling the complex to exhibit pH-sensitive relaxivity in the biologically relevant pH range.

Effect of the Nature of Donor Atoms on the Thermodynamic, Kinetic and Relaxation Properties of Mn(II) Complexes Formed With Some Trisubstituted 12-Membered Macrocyclic Ligands.

During the past few years increasing attention has been devoted to Mn(II) complexes as possible substitutes for Gd(III) complexes as contrast agents in MRI. Equilibrium (log KMnL or pMn value), kinetic parameters (rates and half-lives of dissociation) and relaxivity of the Mn(II) complexes formed with 12-membered macrocyclic ligands were studied. The ligands were selected in a way to gain information on how the ligand rigidity, the nature of the donor atoms in the macrocycle (pyridine N, amine N, and etheric O atom), the nature of the pendant arms (carboxylates, phosphonates, primary, secondary and tertiary amides) affect the physicochemical parameters of the Mn(II) complexes. As expected, decreasing the denticity of DOTA (to afford DO3A) resulted in a drop in the stability and inertness of [Mn(DO3A)]- compared to [Mn(DOTA)]2-. This decrease can be compensated partially by incorporating the fourth nitrogen atom into a pyridine ring (e.g., PCTA) or by replacement with an etheric oxygen atom (ODO3A). Moreover, the substitution of primary amides for acetates resulted in a noticeable drop in the stability constant (PC3AMH), but it increased as the primary amides (PC3AMH) were replaced by secondary (PC3AMGly) or tertiary amide (PC3AMPip) pendants. The inertness of the Mn(II) complexes behaved alike as the rates of acid catalyzed dissociation increased going from DOTA (k1 = 0.040 M-1s-1) to DO3A (k1 = 0.45 M-1s-1). However, the rates of acid catalyzed dissociation decreased from 0.112 M-1s-1 observed for the anionic Mn(II) complex of PCTA to 0.0107 M-1s-1 and 0.00458 M-1s-1 for the cationic Mn(II) complexes of PC3AMH and PC3AMPip ligands, respectively. In spite of its lower denticity (as compared to DOTA) the sterically more hindered amide complex ([Mn(PC3AMPip)]2+) displays surprisingly high conditional stability (pMn = 8.86 vs. pMn = 9.74 for [Mn(PCTA)]-) and excellent kinetic inertness. The substitution of phosphonates for the acetate pendant arms (DOTP and DO3P), however, resulted in a noticeable drop in the conditional stability as well as dissociation kinetic parameters of the corresponding Mn(II) complexes ([Mn(DOTP)]6- and [Mn(DO3P)]4-) underlining that the phosphonate pedant should not be considered as a suitable building block for further ligand design while the tertiary amide moiety will likely have some implications in this respect in the future.

Coordination Properties of GdDO3A-Based Model Compounds of Bioresponsive MRI Contrast Agents.

We report a detailed characterization of the thermodynamic stability and dissociation kinetics of Gd3+ complexes with DO3A derivatives containing a (methylethylcarbamoylmethylamino)acetic acid (L1), (methylpropylcarbamoylmethylamino)acetic acid (L2), 2-dimethylamino- N-ethylacetamide (L3), or 2-dimethylamino- N-propylacetamide (L4) group attached to the fourth nitrogen atom of the macrocyclic unit. These ligands are model systems of Ca2+- and Zn2+-responsive contrast agents (CA) for application in magnetic resonance imaging (MRI). The results of the potentiometric studies ( I = 0.15 M NaCl) provide stability constants with log KGdL values in the range 13.9-14.8. The complex speciation in solution was found to be quite complicated due to the formation of protonated species at low pH, hydroxido complexes at high pH, and stable dinuclear complexes in the case of L1,2. At neutral pH significant fractions of the complexes are protonated at the amine group of the amide side chain (log KGdL×H = 7.2-8.1). These ligands form rather weak complexes with Mg2+ and Ca2+ but very stable complexes with Cu2+ (log KCuL = 20.4-22.3) and Zn2+ (log KZnL = 15.5-17.6). Structural studies using a combination of 1H NMR and luminescence spectroscopy show that the amide group of the ligand is coordinated to the metal ion at pH ∼8.5, while protonation of the amine group provokes the decoordination of the amide O atom and a concomitant increase in the hydration number and proton relaxivity. The dissociation of the complexes occurs mainly through a rather efficient proton-assisted pathway, which results in kinetic inertness comparable to that of nonmacrocyclic ligands such as DTPA rather than DOTA-like complexes.