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