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

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.

Binding and Release of FeIII Complexes from Glucan Particles for the Delivery of T1 MRI Contrast Agents

“…Fe(TOD) has an effective magnetic moment in solution of 5.73, similar to that reported for Fe(TOB), Fe(TOBA) and Fe(TOT) and consistent with high spin Fe(III) complexes. 11,13 Moreover, most of the 1 H NMR resonances of these complexes are broadened into the baseline, consistent with strong relaxivity of the Fe(III) center.…”

“…The proposed form of the coordination complexes and their species at neutral pH are shown in Scheme 1. [11][12][13] These complexes are resistant towards dissociation in 100 mM acid, and in solutions containing 25 mM hydrogen carbonate and 0.4 mM hydrogen phosphate at neutral pH. 11,13 Fe(TOD), which was prepared here as a bimodal agent, has similar solution properties.…”

“…[11][12][13] These complexes are resistant towards dissociation in 100 mM acid, and in solutions containing 25 mM hydrogen carbonate and 0.4 mM hydrogen phosphate at neutral pH. 11,13 Fe(TOD), which was prepared here as a bimodal agent, has similar solution properties. Fe(TOD) contains a fluorescent dansyl group to better visualize the encapsulation of the complex in yeast cell wall particles, and for future cell uptake studies.…”

Iron(III)‐tCDTA derivatives as MRI contrast agents: Increased T1 relaxivities at higher magnetic field strength and pH sensing

“…11,12 Since then, an iron(II) complex of PyC3A, which served as a redox sensor through oxidation of low relaxivity Fe 2+ to high relaxivity Fe 3+ , 13 and a group of macrocyclic iron complexes with good relaxivities and relatively long persistence in liver and kidneys have been reported. 14,15 The purpose of this work was to produce several tCDTA derivatives by coupling amine-containing compounds to 1 carboxyl group of tCDTA and to thus obtain compounds with improved or modified contrast agent properties (Figure 1). The amines we tested were ethylenediamine and trans-1,4-diaminocyclohexane to generate tCDTA monomers that can serve for chemical coupling purposes and to generate tCDTA dimers for reduced rotational times and thus potentially increased relaxivities.…”

“…The relatively strong contrast effect in comparison to [Fe(DTPA)] 2− might be attributed to the availability of a water coordination site in [Fe( t CDTA)] − 11,12 . Since then, an iron(II) complex of PyC3A, which served as a redox sensor through oxidation of low relaxivity Fe 2+ to high relaxivity Fe 3+ , 13 and a group of macrocyclic iron complexes with good relaxivities and relatively long persistence in liver and kidneys have been reported 14,15 …”