Metrics & MoreArticle RecommendationsCONSPECTUS: Contrast agents are used in approximately 40% of all magnetic resonance imaging (MRI) procedures to improve the quality of the images based on the distribution and dynamic clearance of the agent. To date, all clinically approved contrast agents are Gd(III) coordination complexes that serve to shorten the longitudinal (T 1 ) and transverse (T 2 ) proton relaxation times of water. Recent interest in replacing Gd with biologically relevant metal ions such as Mn or Fe has led to increased interest in the aqueous coordination chemistry of their complexes. In this Account, we focus on high-spin Fe(III) complexes that have been recently reported as MRI contrast agents or probes in our laboratory.The highly Lewis acidic Fe(III) center has distinct coordination chemistry in aqueous solutions, facilitating alternative strategies in the design of MRI probes. To illustrate this, we describe different classes of Fe(III) MRI probes with a focus on macrocyclic complexes and multinuclear complexes such as self-assembled metal organic polyhedra (MOP). Our initial efforts focused on macrocyclic complexes of Fe(III) in order to tune spin and oxidation states with the goal of stabilizing high-spin Fe(III) in reducing biological environments. Our probes feature six-coordinate Fe(III) complexes of 1,4,7-triazacyclononane with hydroxypropyl, phosphonate, or carboxylate pendant groups to produce Fe(III) complexes that shorten proton T 1 times predominantly from second-sphere or outer-sphere interactions at neutral pH. Analogues with pentadentate macrocyclic ligands have an inner-sphere water that does not exchange rapidly on the NMR time scale, yet these complexes are effective relaxation agents. Fe(III) macrocyclic complexes in this class can be modified to modulate their biodistribution and pharmacokinetic clearance in mice. The goal of these studies is for the Fe(III) agents to clear as extracellular fluid agents and produce profiles similar to those of Gd agents. Finally, studies of multimeric Fe(III) complexes are of interest to produce probes that give large proton relaxivity. In this approach the two Fe(III) centers are connected through aryl linkers as demonstrated for several macrocyclic complexes. Even more tightly connected Fe(III) centers are produced in a Fe(III) self-assembled cage with relaxivity of 21 mM −1 s −1 at 4.7 T, 37 °C in the presence of serum albumin to which it is tightly bound. This cage enhances contrast of the vasculature as a blood pool agent and accumulates in tumors. Finally, we present our perspectives on the further development of Fe(III) complexes for various applications in MRI.

A metal−organic polyhedron (MOP) with four paramagnetic Fe­(III) centers was studied as a magnetic resonance imaging (MRI) probe. The MOP was characterized in solution by using electron paramagnetic resonance (EPR), UV–visible (UV–vis) spectroscopies, Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry, and in the solid state with single-crystal X-ray diffraction. Water proton T1 relaxation properties were examined in solution and showed significant enhancement in the presence of human serum albumin (HSA). The r 1 relaxivities in the absence and presence of HSA were 8.7 mM–1 s–1 and 21 mM–1 s–1, respectively, per molecule (2.2 mM–1 s–1 and 5.3 mM–1 s–1 per Fe) at 4.7 T, 37 °C. In vivo studies of the iron MOP show strong contrast enhancement of the blood pool even at a low dose of 0.025 mmol/kg with prolonged residence in vasculature and clearance through the intestinal tract of mice. The MOP binds strongly to serum albumin and shows comparable accumulation in a murine tumor model as compared to a covalently linked Gd-HSA contrast agent.

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.

Three paramagnetic CoII macrocyclic complexes containing 2‐hydroxypropyl pendant groups, 1,1′,1′′,1′′′‐(1,4,8,11‐tetraazacyclotetradecane‐1,4,8,11‐tetrayl)tetrakis‐ (propan‐2‐ol) ([Co(L1)]2+, 1,1′‐(4,11‐dibenzyl‐1,4,8,11‐tetraazacyclotetradecane‐1,8‐diyl)bis(propan‐2‐ol) ([Co(L2)]2+), and 1,1′‐(4,11‐dibenzyl‐1,4,8,11‐tetraazacyclotetradecane‐1,8‐diyl)bis(octadecan‐2‐ol) ([Co(L3)]2+) were synthesized to prepare transition metal liposomal chemical exchange saturation transfer (lipoCEST) agents. In solution, ([Co(L1)]2+) forms two isomers as shown by 1H NMR spectroscopy. X‐ray crystallographic studies show one isomer with 1,8‐pendants in cis‐configuration and a second isomer with 1,4‐pendants in trans‐configuration. The [Co(L2)]2+ complex has 1,8‐pendants in a cis‐configuration. Remarkably, the paramagnetic‐induced shift of water 1H NMR resonances in the presence of the [Co(L1)]2+ complex is as large as that observed for one of the most effective LnIII water proton shift agents. Incorporation of [Co(L1)]2+ into the liposome aqueous core, followed by dialysis against a solution of 300 mOsm L−1 produces a CEST peak at 3.5 ppm. Incorporation of the amphiphilic [Co(L3)]2+ complex into the liposome bilayer produces a more highly shifted CEST peak at −13 ppm. Taken together, these data demonstrate the feasibility of preparing CoII lipoCEST agents.

A new method to tune solubility of ZrMOPs via node-modification.