Nickel(II) complexes as paramagnetic shift and paraCEST agents

Five Ni^II macrocyclic complexes are studied as water proton shift agents and as paraCEST agents (paraCEST = paramagnetic chemical exchange saturation transfer) for MRI applications. The five macrocycles have amide and/or alcohol pendent groups with either tetraaza-or triazamacrocycles including 1,1′,1′′-(1,4,7-triazonane-1,4,7-triyl)tris(propan-2-ol) (L1), 1,1′,1′′,1′′′-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra)tetra-kis(propan-2-ol) (L2), 1,1′,1′′,1′′′-(1,4,8,11-tetraazacyclotetra-decane-1,4,8,11-tetrayl)tetrakis(propan-2-ol) (L3), 2,2′,2′′-(1,4,7-triazonane-1,4,7-triyl)triacetamide (L4), or 2,2′-(7-benzyl-1,4,7-triazonane-1,4-diyl) diacetamide (L5). Solution magnetic moments are consistent with paramagnetic Ni^II complexes. The complexes are characterized by pH-potentiometric titrations to determine the pK_a values of the bound amide or alcohol pendents or water ligand. Variable temperature¹⁷O NMR studies are consistent with a water ligand in [Ni(L5)]²⁺ with an exchange rate constant of 4 × 10⁴ s^–1. All Ni^II complexes produce a substantial hyperfine shift of bulk water proton resonances. The smallest shifts are observed for [Ni(L4)]²⁺, which lacks alcohol pendents or bound water and the largest are observed for [Ni(L5)]²⁺ which contains a bound water molecule. The alcohol-appended complexes, [Ni(L2)]²⁺ and [Ni(L3)]²⁺ produce CEST spectra with far-shifted peaks of low intensity at 94 and 104 ppm versus bulk water, whereas [Ni(L5)]²⁺ shows a CEST peak at δ = 72 ppm.