Distinct Coordination Chemistry of Fe(III)-Based MRI Probes

Abstract

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.

Redox-Responsive MRI Probes Based on First-Row Transition-Metal Complexes

“…The water molecules that undergo proton relaxation may bind directly to the metal center (inner sphere, r 1IS ), indirectly through the coordination sphere (second sphere, r 1SS ), or through closely diffusing waters (outer sphere, r 1OS ). There are many studies of Gd­(III) and Mn­(II) complexes that have focused on optimizing inner-sphere interactions such as water exchange. , By contrast, many studies of six-coordinate Fe­(III) complexes have focused on second-sphere interactions given the slow rates of water exchange for these complexes . However, several seven-coordinate Fe­(III) complexes have an exchangeable inner-sphere water. − Relaxivity increases with the total electron spin quantum number of the complex, which at S = 5/2 for Mn­(II) or Fe­(III) is less than that of Gd­(III) at S = 7/2.…”

“…It has been noted that electronic relaxation times may limit the relaxivity of Fe­(III) complexes at low magnetic field strengths. There remains much to learn about the role of the coordination sphere including donor groups and geometry for optimizing the relaxivity of Fe­(III) contrast agents. , …”

“…For example, if the tissue background proton relaxation time is 1 s, reduction of the signal by 10% would require 50 μM contrast agent with a relaxivity 2.0 mM –1 s –1 . Relaxivity values for mononuclear Fe­(III) probes are often close to 2.0 mM –1 s –1 and are higher for multinuclear probes at 5.3 and 8.7 mM –1 s –1 for dinuclear and tetranuclear Fe­(III) complexes, respectively, at 4.7 T and 37 °C in buffered solution . By contrast, paraCEST agents require higher concentrations and are detectable in low millimolar concentrations in solution .…”

“…The development of paramagnetic first-row transition-metal complexes as MRI probes or contrast agents is based on a strategy to employ metal ions that are naturally present in the body. − One goal is to prepare transition-metal complexes that may serve as alternatives to the clinically important Gd­(III)-based contrast agents. In addition to the advantage of being essential elements that are also earth abundant, transition-metal complexes have certain advantages in the development of responsive probes.…”

Low-Molecular-Weight Fe(III) Complexes for MRI Contrast Agents

“…Since 2013, more clear evidences have been reported to support Gd(III) accumulation in the central nervous system after exposure to gadolinium [ 13 , 14 , 15 ]. Although the toxic effect related to Gd(III) retention has not yet been confirmed, the concerns about the long-term safety of Gd(III)-based agents have led to renewed interest in Fe(III) complexes as alternatives [ 16 , 17 , 18 ], which display a similar biodistribution and pharmacokinetic clearance to the clinically used Gd(III) agents.…”