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.

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Liposomes containing high-spin Fe(III) coordination complexes were prepared towards the production of T1 MRI probes with improved relaxivity. The amphiphilic Fe(III) complexes were anchored into the liposome with two alkyl...

This undergraduate laboratory experiment is designed for first-year general chemistry students with the goal of introducing the brilliant colors and magnetic properties of transition metal complexes within a bioinorganic/cell biology context. In the first laboratory period, a coordination complex formed from ferric chloride and maltol is prepared (Fe(maltol)3). The intense red color of the complex is noted, and the UV–vis spectra of the ligand and complex are compared. Yeast cells are incubated with ferric chloride and with Fe(maltol)3. In the second laboratory period, the yeast cells treated with the ferric chloride or Fe(maltol)3 are isolated and placed over ring magnets to study whether the yeast have paramagnetic properties. Yeast viability studies are done to compare the toxicity of Fe(maltol)3 and FeCl3. Students are asked to predict the magnetic properties of iron complexes of different spin and oxidation states and to consider the basis for iron uptake into yeast cells.

Liposomes containing high-spin Fe(III) coordination complexes were prepared towards the production of MRI probes with improved relaxivity and rapid pharmacokinetic clearance in mice. The amphiphilic Fe(III) complexes were anchored into the liposome with two alkyl chains to give a coordination sphere containing mixed amide hydroxypropyl pendant groups. Three types of MRI probes were prepared including those with intraliposomal Fe(III) complex (LipoA) alone, amphiphilic Fe(III) complex (LipoB) or both intraliposomal and amphiphilic complex (LipoC). Water proton relaxivities r1 and r2 were measured and compared to a small molecule macrocyclic Fe(III) complex containing similar donor groups. Liposomes with amphiphilic Fe(III) complex (LipoB) have a per particle relaxivity of 37,000 and a per iron relaxivity of 2.6 mM-1s-1 in solutions with pH 7.2, 34 C at 1.4 T. Liposomes containing both amphiphilic and intraliposomal Fe(III) complexes (lipoC) have reduced per iron relaxivity of 0.8 mM-1s-1 in solution consistent with quenching of the interior Fe(III) complex relaxivity and per particle relaxivity of 42 ,000 mM-1s-1. Liposomes containing only encapsulated Fe(III) complex have a lower relaxivity of 0.46 mM-1s-1 per iron complex. Studies show that lipoB and lipoC produce enhanced signal in the CT26 tumors of BALB/c mice. However, the biodistribution and clearance of the liposomal nanoparticles differs greatly. LipoB is a blood pool agent with a long circulation time whereas lipoC is cleared more rapidly through both renal and hepatobiliary pathways.