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

In the search for MnII MR and PET/MR imaging agents with optimal balance between thermodynamic stability, kinetic inertness, and relaxivity, two novel bifunctional MnII chelators (BFMnCs) based on CDTA (trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid) were synthesized. A six-step synthesis, involving the buildup of a functionalized trans-1,2-diaminocyclohexane core, provided CuAAC-reactive 6a and 6b bearing an alkyne or azide substituent on the cyclohexane ring, respectively (CuAAC = CuI-catalyzed azide–alkyne 1,3-dipolar cycloaddition). Thermodynamic, kinetic, and relaxometric studies were performed with 4-HET-CDTA (8a) as a “model chelator,” synthesized in two steps from 6a. The protonation constants revealed that 8a is slightly less basic than CDTA and forms a MnII complex of marginally lower thermodynamic stability (log K 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 CuII-mediated transmetalation of [Mn­(4-HET-CDTA)]2– showed that proton-assisted complex dissociation is slightly slower than for [Mn­(CDTA)]2– (k 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 (t 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– (r 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 (τR 298 = 105 ps). Additionally, the fast water exchange of the complex correlates well with the value reported for [Mn­(CDTA)]2– (k ex 298 = 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 6a/6b are promising precursors for the preparation of targeted, bioresponsive, or high relaxivity manganese-based PET/MR tracers (52g/55 MnII) and MR contrast agents (MnII).