Complexes of Fe(III) that contain a triazacyclononane (TACN) macrocycle, two pendant hydroxyl groups, and a third ancillary pendant show promise as MRI contrast agents. The ancillary group plays an important role in tuning the solution relaxivity of the Fe(III) complex and leads to large changes in MRI contrast enhancement in mice. Two new Fe(III) complexes, one with a third coordinating hydroxypropyl pendant, Fe(L2), and one with an anionic non-coordinating sulfonate group, Fe(L1)(OH2), are compared. Both complexes have a deprotonated hydroxyl group at neutral pH and electrode potentials representative of a stabilized trivalent iron center. The r1 relaxivity of the Fe(L1)(OH2) complex is double that of the saturated complex, Fe(L2), at 4.7 T, 37 °C in buffered solutions. However, variable-temperature 17O-NMR experiments show that the inner-sphere water of Fe(L1)(OH2) does not exchange rapidly with bulk water under these conditions. The pendant sulfonate group in Fe(L1)(OH2) confers high solubility to the complex in comparison to Fe(L2) or previously studied analogues with benzyl groups. Dynamic MRI studies of the two complexes showed major differences in their pharmacokinetics clearance rates compared to an analogue containing a benzyl ancillary group. Rapid blood clearance and poor binding to serum albumin identify Fe(L1)(OH2) for development as an extracellular fluid contrast agent.

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.

Four high-spin Fe­(III) macrocyclic complexes, including three dinuclear and one mononuclear complex, were prepared toward the development of more effective iron-based magnetic resonance imaging (MRI) contrast agents. All four complexes contain a 1,4,7-triazacyclononane macrocyclic backbone with two hydroxypropyl pendant groups, an ancillary aryl or biphenyl group, and a coordination site for a water ligand. The pH potentiometric titrations support one or two deprotonations of the complexes, most likely deprotonation of hydroxypropyl groups at near-neutral pH. Variable-temperature 17O NMR studies suggest that the inner-sphere water ligand is slow to exchange with bulk water on the NMR time scale. Water proton T 1 relaxation times measured for solutions of the Fe­(III) complexes at pH 7.2 showed that the dinuclear complexes have a 2- to 3-fold increase in r 1 relaxivity in comparison to the mononuclear complex per molecule at field strengths ranging from 1.4 T to 9.4 T. The most effective agent, a dinuclear complex with macrocycles linked through para-substitution of an aryl group (Fe2(PARA)), has an r 1 of 6.7 mM–1 s–1 at 37 °C and 4.7 T or 3.3 mM–1 s–1 per iron center in the presence of serum albumin and shows enhanced blood pool and kidney contrast in mice MRI studies.

This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record.

This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record.