Nickel(II) Complexes as Paramagnetic Shift and paraCEST Agents

Abstract

Five NiII 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 NiII complexes. The complexes are characterized by pH‐potentiometric titrations to determine the pKa values of the bound amide or alcohol pendents or water ligand. Variable temperature 17O NMR studies are consistent with a water ligand in [Ni(L5)]2+ with an exchange rate constant of 4 × 104 s–1. All NiII 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.