Modulating the Properties of Fe(III) Macrocyclic MRI Contrast Agents by Appending Sulfonate or Hydroxyl Groups.

Didar Asik,Samira M Abozeid,Travis B Mitchell,Joseph A Spernyak,Rachel Smolinski,Janet R Morrow,Steven G Turowski

doi:10.3390/molecules25102291

Abstract

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.

Highlights

40% of clinical MRI procedures use a contrast agent to produce enhanced images, and most contrast agents are Gd(III) coordination complexes
The triazacyclononane (TACN) macrocycle framework was chosen based on its propensity to bind the small Fe(III) ion
The benzyl and propane-1-sulfonate as non-coordinating pendant groups of H-L1 and H-L3 ligands, respectively, were designed to form Fe(III) complexes that bind an inner-sphere water in a six-coordinate complex

Summary

Introduction

40% of clinical MRI procedures use a contrast agent to produce enhanced images, and most contrast agents are Gd(III) coordination complexes. Gd-based contrast agents are highly successful, there are concerns about potential toxicity and retention from long-term exposure, for patients with renal insufficiency [1,2,3,4,5,6,7] These concerns have motivated research into alternatives for Gd that utilize transition metal ions. Mn(II) and Fe(III) complexes in order to capitalize on their large effective magnetic moments and long electronic relaxation times [7,8] These two metal ions are the most promising for the development of Gd-free MRI contrast agents, based on their magnetic properties and their roles as trace elements in human biology. Despite the prominent role of iron in human biology, there are significantly fewer studies on Fe(III)-based contrast agents [14,15,16,17,18,19,20]

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