Seven-Coordinate Co^II, Fe^II and Six-Coordinate Ni^II Amide-Appended Macrocyclic Complexes as ParaCEST Agents in Biological Media

Abstract

The solution chemistry and solid-state structures of the CoII, FeII, and NiII 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 NiII 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 contrast in rabbit serum and egg white. The complexes with the least highly shifted 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 the CEST effect for [Fe(L)]2+ in 4% agarose gel (w/w) was not substantially different.

Six, Seven or Eight Coordinate FeII, CoII or NiII Complexes of Amide‐Appended Tetraazamacrocycles for ParaCEST Thermometry

“…This assignment is based on the lack of water ligands or other exchangeable groups, and the pH dependence of the CEST effect which is characteristic of amide proton exchange 2c,e. 9 The number of CEST peaks corresponds to the number of inequivalent amide protons which have exchange rate constants suitable for CEST and are shifted sufficiently far from the bulk water peak to be resolved. Notably, the two inequivalent protons on a single amide pendent give rise to resonances that are separated by a 50–70 ppm chemical shift difference.…”

“…For example, ligand donor groups used for transition metal ion paraCEST agents to date include aminopyridines,2c alcohols,7a benzimidazoles,2d, 8 pyrazoles2a and amides 2b,e. 9 These ligands all contain OH or NH protons that exchange with water protons to produce the CEST effect. In addition to providing exchangeable protons, macrocyclic ligands for these metal ions must produce complexes with a large degree of kinetic inertness for in vivo studies 10.…”

Enhancing magnetic resonance imaging with contrast agents for ultra-high field strengths

“…82 Complexes 64–66 were reported for their pH sensitive CEST effects between pH 6.5 and 7.7. 83 Complexes 64–66 displayed CEST signals at 72, 59, and 92 ppm, respectively, with CEST effects ranging from 25 to 39%. 83 …”

“…83 Complexes 64–66 displayed CEST signals at 72, 59, and 92 ppm, respectively, with CEST effects ranging from 25 to 39%. 83 …”

Proton Chemical Exchange Saturation Transfer (CEST) MRS and MRI

“…Three recent dedicated CEST workshops (3rd, 4th, and 5th international CEST workshops in Annapolis, 2012, Torino, 2014, and Philadelphia 2016) drew about 90-200 registrants. The last decade has shown major developments for paraCEST agents, 14,15,20,89,90,119,[135][136][137][138][139][140][141][142][143][144][145][146][147][148] diaCEST agents, 12,13,17,42,43,68,72,88,102,116,125,128,[149][150][151][152][153][154][155][156][157][158][159][160] and even hyperpolarized (hyperCEST) agents. 161,162 This is not surprising in view of the number of potential applications including pH imaging, metabolite detection, ion detection, cellular protein and peptide imaging, cell labeling, temperature i...…”