Kinetic Inertness of the Mn²⁺ Complexes Formed with AAZTA and Some Open-Chain EDTA Derivatives

The results of systematic equilibrium, kinetic, and relaxometric investigations carried out on the Mn²⁺ complexes of open-chain and AAZTA ligands indicate that the [Mn­(CDTA)]^2– complex has satisfactorily high kinetic inertness (<i>t</i>_1/2 = 12 h at pH = 7.4), which, in turn, may allow its use as a contrast agent in the field of magnetic resonance imaging (as a replacement for Gd³⁺-based agents)

Equilibrium and NMR Relaxometric Studies on the <i>s</i>-Triazine-Based Heptadentate Ligand PTDITA Showing High Selectivity for Gd³⁺ Ions

A complete potentiometric and NMR relaxometric solution study on the heptadentate 2,2′,2″,2′″-[(6-piperidinyl-1,3,5-triazine-2,4-diyl)­dihydrazin-2-yl-1-ylidene]­tetraacetic acid (PTDITA) ligand has been carried out. This ligand is based on the 1,3,5-triazine ring with two hydrazine-<i>N</i>,<i>N</i>-diacetate groups in positions 2 and 4 and a piperidine moiety in position 6. The introduction of the triazine ring into the ligand backbone is expected to modify its flexibility and then to affect the stability of the corresponding complexes with transition-metal and lanthanide ions. Thermodynamic stabilities have been determined by pH potentiometry, UV spectrophotometry, and ¹H NMR spectroscopy for formation of the complexes with Mg²⁺, Ca²⁺, Cu²⁺, Zn²⁺, La³⁺, Gd³⁺, and Lu³⁺ ions. PTDITA shows a good binding affinity for Gd³⁺ (log<i>K</i> = 18.49, pGd = 18.6) and an optimal selectivity for Gd³⁺ over the endogenous Ca²⁺, Zn²⁺, and Cu²⁺ (<i>K</i>_sel = 6.78 × 10⁷), which is 3 orders of magnitude higher that that reported for Gd­(DTPA) (<i>K</i>_sel = 2.85 × 10⁴). This is mainly due to the lower stability of the Cu^II- and Zn^II(PTDITA) complexes compared to the corresponding DTPA complexes, which suggests an important role of the triazine ring on the selectivity for the Gd³⁺ ion. The relaxometric properties of Gd­(PTDITA) have been investigated in aqueous solution by measuring the ¹H relaxivity as a function of the pH, temperature, and magnetic field strength (nuclear magnetic relaxation dispersion profile). Variable-temperature ¹⁷O NMR data have provided direct information on the kinetic parameters for exchange of the coordinated water molecules. A simultaneous fit of the data suggests that the high relaxivity value (<i>r</i>₁ = 10.2 mM^–1 s^–1) is a result of the presence of two inner-sphere water molecules along with the occurrence of relatively slow rotation and electronic relaxation. The water residence lifetime, ²⁹⁸τ_M = 299 ns, is quite comparable to that of clinically approved magnetic resonance imaging contrast agents. The displacement of the inner-sphere water molecules by bidentate endogeneous anions (citrate, phosphate, and carbonate) has also been evaluated by ¹H relaxometry. In general, the binding interaction is markedly weak, and only in the case of citrate, a ca. 35% decrease in relaxivity was observed in the presence of 60 equiv of the anion. Phosphate and carbonate also interact with the paramagnetic ion, likely as monodentate ligands, but formation of the ternary complex is accompanied by a modest increase of <i>r</i>₁ due to the contribution of second-sphere water molecules

Novel CDTA-based, Bifunctional Chelators for Stable and Inert Mn^II Complexation: Synthesis and Physicochemical Characterization

In the search for Mn^II MR and PET/MR imaging agents with optimal balance between thermodynamic stability, kinetic inertness, and relaxivity, two novel bifunctional Mn^II chelators (BFMnCs) based on CDTA (<i>trans</i>-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid) were synthesized. A six-step synthesis, involving the buildup of a functionalized <i>trans</i>-1,2-diaminocyclohexane core, provided CuAAC-reactive <b>6a</b> and <b>6b</b> bearing an alkyne or azide substituent on the cyclohexane ring, respectively (CuAAC = Cu^I-catalyzed azide–alkyne 1,3-dipolar cycloaddition). Thermodynamic, kinetic, and relaxometric studies were performed with 4-HET-CDTA (<b>8a</b>) as a “model chelator,” synthesized in two steps from <b>6a</b>. The protonation constants revealed that <b>8a</b> is slightly less basic than CDTA and forms a Mn^II complex of marginally lower thermodynamic stability (log <i>K</i>_MnL = 13.80 vs 14.32, respectively), while the conditional stability constant is almost identical for both chelates (pMn = 8.62 vs 8.68, respectively). Kinetic assessment of the Cu^II-mediated transmetalation of [Mn­(4-HET-CDTA)]^2– showed that proton-assisted complex dissociation is slightly slower than for [Mn­(CDTA)]^2– (<i>k</i>₁ = 297 vs 400 M^–1 s^–1, respectively). Importantly, the dissociation half-life near physiological conditions (pH 7.4, 25 °C) underlined that [Mn­(4-HET-CDTA)]^2– is ∼35% more inert (<i>t</i>_1/2 = 16.2 vs 12.1 h, respectively). Those findings may be accounted for by a combination of reduced basicity and increased rigidity of the ligand. Analysis of the ¹⁷O NMR and ¹H NMRD data attributed the high relaxivity of [Mn­(4-HET-CDTA)]^2– (<i>r</i>₁ = 4.56 mM^–1 s^–1 vs 3.65 mM^–1 s^–1 for [Mn­(CDTA)]^2–; 20 MHz, 25 °C) to slower rotational dynamics (τ_R²⁹⁸ = 105 ps). Additionally, the fast water exchange of the complex correlates well with the value reported for [Mn­(CDTA)]^2– (<i>k</i>_ex²⁹⁸ = 17.6 × 10⁷ vs 14.0 × 10⁷ s^–1, respectively). Given the exquisite compromise between thermodynamic stability, kinetic inertness, and relaxivity achieved by [Mn­(4-HET-CDTA)]^2–, appropriately designed CuAAC-conjugates of <b>6a</b>/<b>6b</b> are promising precursors for the preparation of targeted, bioresponsive, or high relaxivity manganese-based PET/MR tracers (^{52<i>g</i>/55} Mn^II) and MR contrast agents (Mn^II)

Picolinate-Containing Macrocyclic Mn²⁺ Complexes as Potential MRI Contrast Agents

We report the synthesis of the ligand Hnompa (6-((1,4,7-triaza­cyclononan-1-yl)­methyl)­picolinic acid) and a detailed characterization of the Mn²⁺ complexes formed by this ligand and the related ligands Hdompa (6-((1,4,7,10-tetra­azacyclo­dodecan-1-yl)­methyl)­picolinic acid) and Htempa (6-((1,4,8,11-tetra­azacyclo­tetradecan-1-yl)­methyl)­picolinic acid). These ligands form thermodynamically stable complexes in aqueous solution with stability constants of log<i>K</i>_MnL = 10.28(1) (nompa), 14.48(1) (dompa), and 12.53(1) (tempa). A detailed study of the dissociation kinetics of these Mn²⁺ complexes indicates that the decomplexation reaction at about neutral pH occurs mainly following a spontaneous dissociation mechanism. The X-ray structure of [Mn₂(nompa)₂(H₂O)₂]­(ClO₄)₂ shows that the Mn²⁺ ion is seven-coordinate in the solid state, being directly bound to five donor atoms of the ligand, the oxygen atom of a coordinated water molecule and an oxygen atom of a neighboring nompa^– ligand acting as a bridging bidentate carboxylate group (μ–η¹-carboxylate). Nuclear magnetic relaxation dispersion (¹H NMRD) profiles and ¹⁷O NMR chemical shifts and transverse relaxation rates of aqueous solutions of [Mn­(nompa)]⁺ indicate that the Mn²⁺ ion is six-coordinate in solution by the pentadentate ligand and one inner-sphere water molecule. The analysis of the ¹H NMRD and ¹⁷O NMR data provides a very high water exchange rate of the inner-sphere water molecule (<i>k</i>_ex²⁹⁸ = 2.8 × 10⁹ s^–1) and an unusually high value of the ¹⁷O hyperfine coupling constant of the coordinated water molecule (<i>A</i>_O/ℏ = 73.3 ± 0.6 rad s^–1). DFT calculations performed on the [Mn­(nompa)­(H₂O)]⁺·2H₂O system (TPSSh model) provide a <i>A</i>_O/ℏ value in excellent agreement with the one obtained experimentally

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 (<b>L</b>^<b>1</b>), (methylpropylcarbamoylmethylamino)­acetic acid (<b>L</b>^<b>2</b>), 2-dimethylamino-<i>N</i>-ethylacetamide (<b>L</b>^<b>3</b>), or 2-dimethylamino-<i>N</i>-propylacetamide (<b>L</b>^<b>4</b>) 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>I</i> = 0.15 M NaCl) provide stability constants with log <i>K</i>_GdL 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 <b>L</b>^<b>1,2</b>. At neutral pH significant fractions of the complexes are protonated at the amine group of the amide side chain (log <i>K</i>_GdL×H = 7.2–8.1). These ligands form rather weak complexes with Mg²⁺ and Ca²⁺ but very stable complexes with Cu²⁺ (log <i>K</i>_CuL = 20.4–22.3) and Zn²⁺ (log <i>K</i>_ZnL = 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