Inner-Sphere and Outer-Sphere Water Interactions in Co(II) paraCEST Agents

Abstract

High-spin Co(II) complexes are promising for development as paraCEST agents (paraCEST = paramagnetic chemical exchange saturation transfer) for magnetic resonance imaging applications. The first examples of Co(II) paraCEST agents with bound water ligands are presented here. Four Co(II) macrocyclic complexes based on 1,4,7-triazacyclononane and containing either pendent alcohol or pendent amide groups were prepared. Two of the macrocycles encapsulate the Co(II) and contain no water ligands as shown by X-ray crystallographic studies, and two complexes have macrocycles with only five ligand donor groups to leave an open coordination site for bound water. The ionization of alcohol, water, or amide groups in the complexes was characterized by using pH potentiometry. These data show that one of the complexes has a readily deprotonated group with a pK close to 6, which is assigned as an alcohol pendent. Amide pendents deprotonate at high pH (>8), and the water ligands of the Co(II) complexes are not deprotonated at neutral pH. All complexes produce CEST peaks through either alcohol OH or amide NH proton exchange. The water ligands exchange too rapidly to produce a CEST effect as shown by variable-temperature O NMR spectroscopy studies. The complexes with available coordination sites for inner-sphere water ligands produce large paramagnetic shifts and broadening of theO resonances of bulk water, whereas the encapsulated complexes show much less shifting and broadening of O resonances. All complexes produce substantial paramagnetic shifts of theH resonances of bulk water, which is promising for the development of supramolecular CEST agents.

Nickel(II) Complexes as Paramagnetic Shift and paraCEST Agents

“…However, [Ni( L1 )] 2+ , [Ni( L2 )] 2+ and [Ni( L3 )] 2+ gave slopes that were nearly as large. This is consistent with the propensity of alcohol groups to form strong second sphere interactions with water , . In contrast, [Ni( L4 )] 2+ demonstrated the smallest effect on the shift of the protons of water.…”

“…One of these complexes has a bound water that might also produce a CEST effect, similar to Ln III complexes that have been tuned for water exchange , . Parallel to our work with analogous Co II complexes, water 17 O NMR spectroscopy studies at variable temperatures showed that the water ligand of [Ni( L5 )] 2+ exchanges too rapidly to produce a CEST effect (Scheme ). However, all Ni II complexes studied here produce a substantial hyperfine shift in the proton resonance of water, suggesting their development for supramolecular CEST applications , …”

“…In deuterated acetonitrile, an additional resonance at δ = 29 ppm is observed, which is tentatively assigned as the alcohol proton resonance. The resonances of this 1 H NMR spectrum are less well‐defined than that of the Co II complex of L1 which displays relatively sharp hyperfine‐shifted proton resonances that span 310 ppm . These broadened 1 H resonances are characteristic of paramagnetic six‐coordinate Ni II complexes , …”

“…Alcohol and amide pendent groups were chosen, in part, for their hydrogen‐bonding interactions with water. Paramagnetic Co II complexes with these pendent groups have been shown to effectively shift the proton resonances of water . One macrocycle, L5 , was designed to bind to Ni II and leave an open coordination site for water.…”

“…With the exception of [Ni( L1 )] 2+ , none of the complexes contains a group that ionizes at near neutral pH. The low p K a of [Ni( L1 )] 2+ at 6.6 mirrors that of the Co II complex of L1 which has a p K a of 5.8 . The other alcohol‐containing macrocycles, [Ni( L2 )] 2+ and [Ni( L3 )] 2+ , have p K a values of > 8.…”