Macrocyclic ligands for Fe(II) paraCEST and chemical shift MRI contrast agents

Fe(II) macrocyclic complexes are a relatively new addition to the class of MRI contrast agents that function through paraCEST (paramagnetic chemical exchange saturation transfer) or paraCSI (paramagnetic complex chemical shift imaging). Both methods require relatively narrow and highly shifted ligand proton resonances. For paraCEST, the protons are exchangeable with water (NH or OH); for paraCSI the protons are non-exchangeable and are on carbons (CH). We report on several macrocyclic ligands for Fe(II) including those based on CYCLEN (1,4,7,10-tetraazacyclododecane) and TACN (1,4,7-triazacyclononane) with attached pendent arms containing either benzimidazole, pyridine or amide donor groups. Paramagnetic proton NMR spectra and paraCEST spectra are reported for these complexes. Challenges include fluxionality of the macrocyclic complexes in solution which broadens the macrocycle proton resonances, especially for amide pendent groups. Despite this dynamic process, the exchangeable NH proton resonances of the amide pendent groups remain relatively sharp. These amide complexes are thus suitable for paraCEST but not paraCSI. The dynamic process is arrested in complexes containing pendent pyridine groups that lock the TACN macrocyclic Fe(II) complex into a single diastereomeric form over the temperature range of 15–45 °C to produce an Fe(II) complex that is promising for paraCSI.