Zn(II)-Responsive MRI Probe Based on an Fe(III) Macrocyclic Complex

Abstract

The development of responsive MRI contrast agents to detect fluctuations in Zn(II) is a growing area of research. Here we describe a high-spin Fe(III) coordination complex, Fe(ADAPT), as one of the first examples of an Fe(III) MRI probe that is responsive to Zn(II). The six-coordinate Fe(ADAPT) contains a phenolate-appended 1,4,7-triazacyclononane (TACN) ligand framework, with the phenolate groups linked to a Zn(II) binding moiety. Fe(ADAPT) lacks an exchangeable inner-sphere water and thus relies on second- and outer-sphere water interactions for proton relaxation. Fe(ADAPT) is highly kinetically inert under physiological conditions at pH 7.4 and 37 °C and to excess Zn(II) over 72 h. In the presence of 2 equiv of Zn(II) with a 200 μM Fe(III) probe, an increase in relaxivity of ∼80% is observed. A ternary complex among Fe(ADAPT), Zn(II), and human serum albumin leads to a nearly 200% increase in relaxivity.

Figure 1.

ITC binding isotherm of 0.050 mM Fe(ADAPT) with Zn(II) in 0.10 M NaCl and 50 mM HEPES at pH 7.4.

Figure 2.

(A) Plot of 1/T₁ of Fe(ADAPT) as a function of the probe concentration to give r₁. (B) r₁ with variable Zn(II) titrated into 0.20 mM Fe(ADAPT). (C) r₁ in the presence of Zn(II), Cu(II), Fe(II), Ca(II), and Mg(II) with 0.20 mM Fe(ADAPT). All solutions contained 0.10 M NaCl and 50 mM HEPES at pH 7.4 and 33 °C. (D) Zn(II) titration into 0.20 mM Fe(ADAPT) containing 0.60 mM HSA.

Scheme 1.. MRI Probes Based on Gd(III) or Fe(III)

Scheme 2.. Model for Zn(II)-Responsive Probe: (A) Zn(II), HSA Binding and (B) Probe and Zn(II) to Give a Zn–Probe–HSA Complex