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)tetrakis(propan‐2‐ol) ( L2 ), 1,1′,1′′,1′′′‐(1,4,8,11‐tetraazacyclotetradecane‐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 p K a values of the bound amide or alcohol pendents or water ligand. Variable temperature 17 O NMR studies are consistent with a water ligand in [Ni( L5 )] 2+ with an exchange rate constant of 4 × 10 4 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.