Seven-Coordinate CoII FeII andSix-Coordinate NiII Amide-Appended Macrocyclic Complexesas ParaCEST Agents in Biological Media

摘要

The solution chemistry and solid-state structures of the Co^II, Fe^II, and Ni^II complexes of 7,13-bis(carbamoylmethyl)-1,4,10-trioxa-7,13-diazacyclopentadecane (>L) are reported as members of a new class of paramagnetic chemical exchange saturation transfer (paraCEST) MRI contrast agents that contain transition metal ions. Crystallographic data show that nitrogen and oxygen donor atoms of the macrocyclic ligand coordinate to the metal ions to generate complexes with distorted pentagonal bipyramidal geometry for [Co(>L)]Cl2·2H2O or [Fe(>L)](CF3SO3)2. The Ni^II complex [Ni(>L)](CF3SO3)2·H2O features a hexadentate ligand in a distorted octahedral geometry. The proton NMR spectra of all three complexes show highly dispersed and relatively sharp proton resonances. The complexes were further characterized by monitoring their dissociation under biologically relevant conditions including solutions containing phosphate and carbonate, ZnCl2, or acidic conditions. Solutions of the paraCEST agents in 20 mM N-(2-hydroxyethyl)piperazine-N′-ethanesulfonic acid (pH 7.4) and 100 mM NaCl showed highly shifted and intense CEST peaks at 59, 72, and 92 ppm away from bulk water for [Co(>L)]²⁺, [Ni(>L)]²⁺, and [Fe(>L)]²⁺, respectively at 37 °C on a 11.7 T NMR spectrometer. CEST spectra with corresponding rate constants for proton exchange are reported in 4% agarose gel (w/w), rabbit serum, egg white,or buffered solutions. CEST phantoms of 4 mM complex in buffer, 4%agarose gel (w/w), or rabbit serum on a 4.7 T MRI scanner at 37 °C,are compared. The most substantial change was observed for the reactive[Ni(>L)]²⁺, which showed reduced CEST contrastin rabbit serum and egg white. The complexes with the least highlyshifted CEST peaks ([Co(>L)]²⁺ and [Ni(>L)]²⁺) showed a reduction in CEST contrast in 4%agarose gel (w/w) compared to that in buffered solutions, while theCEST effect for [Fe(>L)]²⁺ in 4% agarose gel(w/w) was not substantially different.