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

Vanasschen, Christian and Molnár, Enikő and Tircsó, Gyula and Kálmán, Ferenc K. and Tóth, Éva and Brandt, Marie and Coenen, Heinz H. and Neumaier, Bernd (2017) Novel CDTA-based, Bifunctional Chelators for Stable and Inert MnII Complexation: Synthesis and Physicochemical Characterization. INORGANIC CHEMISTRY, 56. pp. 7746-7760. ISSN 0020-1669

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Abstract

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 KMnL = 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– (k1 = 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 (t1/2 = 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– (r1 = 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 (τR298 = 105 ps). Additionally, the fast water exchange of the complex correlates well with the value reported for [Mn(CDTA)]2– (kex298 = 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).

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