Imidazole-Appended Macrocyclic Complexes of Fe(II), Co(II), and Ni(II) as ParaCEST Agents

The solution chemistry and solid state structures of the Co(II), Fe(II), and Ni(II) complexes of N,N'-bis(imidazole-2-ylmethyl)-4,10-diaza-15-crown-5 (HINO) are reported. The Co(II) and Ni(II) complexes of HINO are the first examples of paraCEST agents (paramagnetic chemical exchange saturation transfer) that feature exchangeable imidazole NH protons. The crystal structures of [Co(HINO)]CoCl₄·H₂O and [Fe(HINO)](CF₃SO₃)₂ have the metal ions coordinated to four nitrogen and three oxygen donor atoms of the macrocyclic ligand in a distorted pentagonal bipyramidal geometry. In [Ni(HINO)](CF₃SO₃)₂, the nickel ion is bound to only two of the three ether oxygens and three nitrogens to produce a complex with a distorted octahedral geometry. The ¹H NMR spectra of the three paramagnetic complexes show resonances characteristic of effective C₂ symmetry in solution. CEST peaks attributed to the imidazole NH proton of the pendent group are observed at 32 and 55 ppm away from bulk water for [Co(HINO)]²⁺ and [Ni(HINO)]²⁺, respectively, on a 11.7 or 9.4 T NMR spectrometer. For both complexes, an optimal CEST effect was observed at pH 7.2, and the rate constant for proton exchange under these conditions was 1.0 × 10³ s^-1. [Fe(HINO)]²⁺ did not produce a CEST peak due to oxidation of the complex in water at neutral pH. The CEST peak of [Co(HINO)]²⁺ or [Ni(HINO)]²⁺ is observed in the presence of human serum albumin (HSA). These complexes show enhanced kinetic inertness toward dissociation in acid or in the presence of HSA in comparison to analogous complexes with amide pendent groups.