Expanding the Family of Monosubstituted 15-Membered Pyridine-Based Macrocyclic Ligands for Mn(II) Complexation in the Context of MRI

Abstract

As Mn(II) complexes attract continuous interest as alternatives to Gd-based contrast agents (CAs) in clinical magnetic resonance imaging (MRI), we synthesized two monosubstituted derivatives of the 15-membered pyridine-based macrocycle 15-pyN₃O₂ bearing either a 2-pyridylmethyl (L2) or a 2-benzimidazolylmethyl pendant arm (L3) and characterized their Mn(II) complexes MnL2 and MnL3 in the context of MRI contrast agent development. Their X-ray molecular structures confirmed a coordination number of seven and a pentagonal bipyramidal geometry with one coordination site available for inner-sphere water. Protonation constants of L2 and L3, and stability constants with selected divalent metal ions were determined using potentiometry. MnL2 and MnL3 complexes are fully formed at pH 7.4; however, they both display low kinetic inertness due to a significant spontaneous dissociation of the nonprotonated complex. The presence of one inner-sphere water molecule in the Mn(II) complexes was confirmed by ¹⁷O NMR and ¹H NMRD measurements. The water exchange rate constants are very low (k_ex²⁹⁸ = 0.46 × 10⁷ and 0.23 × 10⁷ s^-1 for MnL2 and MnL3, respectively), but typical for Mn(II) complexes of 15-pyN₃O₂ derivatives. The relaxivities are in good agreement with monohydrated small-molecular-weight Mn(II) chelates (r₁ = 2.49 and 2.77 mM^-1 s^-1 at 20 MHz, 25 °C, for MnL2 and MnL3, respectively).

Scheme 1. Structural Formulas of Investigated Ligands L1–L3 and Other Relevant Ligands Discussed in the Text

Scheme 2. Synthetic Scheme for Ligands L2 and L3 and Atom Numbering Applied for Assignment of Signals in NMR Spectra

(i) 2-(Chloromethyl)pyridine hydrochloride, NaI, NaHCO₃, CH₃CN, RT; (ii) 2-(chloromethyl)benzimidazole, NaI, NaHCO₃, CH₃CN, RT.

Figure 1

Molecular structures of [MnL2Cl]⁺ (left) found in the crystal structure of [MnL2Cl]₂[MnCl₄]·DMF and the molecular structure of [MnL3(CN)]²⁺ found in the crystal structure of [MnL3(CN)](ClO₄)₂·(CH₃)₂CO (right). Hydrogen atoms are omitted for clarity. The thermal ellipsoids are drawn at the 50% probability level.

Figure 2

Molecular structures of the [CuL2(ClO₄)]⁺ complex (left) found in the crystal structure of [CuL2(ClO₄)](ClO₄)·2CN and molecular structure of the [CuL3(ClO₄)]²⁺ (right) complex found in the crystal structure of [CuL3(ClO₄)](ClO₄). Hydrogen atoms are omitted for clarity. Dashed lines represent semicoordination. The thermal ellipsoids are drawn at the 50% probability level.

Figure 3

Species distribution diagram of the Mn(II)-L2-H⁺ system ([Mn(II)] = [L2] = 1.5 mM; solid lines; red = [Mn(II)_free], green = [MnHL2], blue = [MnL2] and yellow = [MnL2H^–1] (left)); and species distribution diagram of the Mn(II)-L3-H⁺ system ([Mn(II)] = [L3] = 1.5 mM; solid lines; red = [Mn(II)_free], green = [MnHL3], blue = [MnL3], yellow = [MnL3H^–1] (right)); r_1p obtained as a function of pH at 1.41 T, 60 MHz (T = 25 °C and I = 0.15 M NaCl; black dots).

Figure 4

Dependence of the observed dissociation rate constants of MnL2 (1.4 mM; left) and MnL3 (1.4 mM; right) on the proton concentration at 10 (red), 20 (green), 30 (blue), and 40 (light blue) molar equivalents of Zn²⁺. The solid lines correspond to the best fit of the experimental data to eq 3, yielding the parameters in Table 5; k₂ was fixed to zero for MnL3.

Figure 5

Possible dissociation pathways of MnL2 and MnL3. The pathways having a real contribution to the overall dissociation, as indicated by the fit of the observed rate constants, are highlighted by magenta (MnL2) and blue (MnL3) dashed lines.

Figure 6

Top: Temperature dependence of the reduced ¹⁷O transverse relaxation rate for MnL2 (left) and MnL3 (right) at 9.4 T and pH 7.4. Bottom: ¹H NMRD profiles at 25 (red) and 37 °C (blue); c_MnL2 = 0.98 mM at pH = 7.22; and c_MnL3 = 0.96 mM at pH = 7.20. Full lines represent the best simultaneous fit of the ¹⁷O NMR and ¹H NMRD data.