Exploring Inner-Sphere Water Interactions of Fe(II) and Co(II) Complexes of 12-Membered Macrocycles To Develop CEST MRI Probes

Abstract

Several paramagnetic Co­(II) and Fe­(II) macrocyclic complexes were prepared with the goal of introducing a bound water ligand to produce paramagnetically shifted water 1H resonances and for paramagnetic chemical exchange saturation transfer (paraCEST) applications. Three 12-membered macrocycles with amide pendent groups including 1,7-bis­(carbamoylmethyl)-1,4,7,10-tetraazacyclodocane (DCMC), 4,7,10-tris­(carbamoylmethyl)-,4,7,10-triaza-12-crown-ether (N3OA), and 4,10-bis­(carbamoylmethyl)-4,10-diaza-12-crown-ether (NODA) were prepared and their Co­(II) complexes were characterized in the solid state and in solution. The crystal structure of [Co­(DCMC)]­Br2 featured a six-coordinated Co­(II) center with distorted octahedral geometry, while [Co­(NODA)­(OH2)]­Cl2 and [Co­(N3OA)]­(NO3)2 were seven-coordinated. The analogous Fe­(II) complexes of NODA and NO3A were successfully prepared, but the complex of DCMC oxidized rapidly to the Fe­(III) form. Similarly, [Fe­(NODA)]2+ oxidized over several days, forming crystals of the Fe­(III) complex isolated as the μ-O bridged dimer. Magnetic susceptibility values and paramagnetic NMR spectra of the Fe­(II) complexes of NODA and N3OA, as well as Co­(II) complexes of DCMC, NODA, and N3OA, were consistent with high spin complexes. CEST peaks ranging from 60 ppm to 70 ppm, attributed to NH groups of the amide pendents, were identified. Variable-temperature 17O NMR spectra of Co­(II) and Fe­(II) NODA complexes were consistent with rapid exchange of the water ligand with bulk water. Notably, the Co­(II) and Fe­(II) complexes presented here produced substantial paramagnetic shifts of bulk water 1H resonances, independent of having an inner-sphere water.

CoII Complexes as Liposomal CEST Agents

“…The behavior of [Co(L1)] 2+ and [Co(L2)] 2+ is characteristic of complexes with an exchangeable inner‐sphere water molecule, whereas that of [Co(L4)] 2+ is characteristic of a complex with no inner‐sphere water molecules. A Swift–Connick plot of the reduced shift ( q =1) and linewidth for [Co(L1)] 2+ and [Co(L2)] 2+ gives k ex of 4.47×10 6 s −1 and 3.54×10 6 s −1 , respectively, for an inner‐sphere water, similar to rate constants reported previously for Co II macrocyclic complexes (Figure S12 and Table S3) …”

“…Shrunken liposomes with bilayer incorporated amphiphilic and core‐loaded complexes are especially promising as they demonstrate that Co II complexes, despite having a lower effective magnetic moment than Dy III or Tm III complexes, show a pronounced lipoCEST signal. Our studies suggest ways to improve Co II ‐based lipoCEST agents including development of Co II complexes of increased kinetic inertness by modifying the macrocycle framework . The preparation of complexes with an overall neutral charge and with multiple Co II centers will further improve the liposome loading efficiency in order to produce increased CEST peak shifts .…”

“…High‐spin Co II and Fe II macrocyclic complexes are alternatives to Ln III complexes for the production of highly paramagnetically shifted water protons . Interestingly, while paramagnetic complexes with inner‐sphere water ligands produce strongly shifted water protons, so do complexes that interact with water through second‐sphere interactions .…”

Expanding the Ligand Classes Used for Mn(II) Complexation: Oxa-aza Macrocycles Make the Difference

“…From this, it can be deduced that as a result of such a donor atom exchange, the seven-coordinate Mn(II) ion becomes somewhat favored in solution (which in turn is expected to contain a coordinated water molecule). This was confirmed recently by J. R. Morrow et al for a Co(II) complex formed with a bis(amide) derivative ligand (tO2DO2AM H ) [26]. Furthermore, complexes with amide derivatives of cDO2A 2− were found to be considerably more inert than the parent ligand, in spite of the lower thermodynamic stability [27].…”

Binding and Release of FeIII Complexes from Glucan Particles for the Delivery of T1 MRI Contrast Agents

“…The maltol likely binds directly to the Fe(TOB) through displacement of water to give a seven coordinate complex (Scheme 2), analogous to a seven-coordinate Fe(III) macrocyclic complex reported recently. 23 While we do not know that exact nature of the coordination mode of maltol to Fe(TOB), it seems reasonable that the ligand would be bidentate. Consistent with this postulate, titration of Fe(TOT), a closed coordination complex, with maltol did not produce a UV-vis absorbance peak characteristic of a ternary complex (Figure S6).…”