Access Type

Open Access Dissertation

Date of Award

January 2013

Degree Type


Degree Name




First Advisor

Matthew J. Allen


Magnetic resonance imaging (MRI) is a powerful medical imaging technique that can be enhanced using metal complexes called contrast agents. Most clinically approved contrast agents contain Gd3+. However, the efficiency (also known as relaxivity) of these Gd3+-containing complexes decreases as field strength increases, and in the ultra-high field strength regime, the relaxivity of these complexes is decreased considerably. Because of the slow water-exchange rate of most Gd3+-containing complexes (∼;106 s-1), I used Eu2+ instead of Gd3+ and adapted the ligand modification strategies that have been used for Gd3+-containing contrast agents to my Eu2+-containing complexes. Eu2+ is isoelectronic to Gd3+ and has fast water-exchange rate (∼;109 s-1); however, the propensity of Eu2+ to oxidize in aerobic conditions limits its utility. Earlier work in the Allen lab demonstrated that modified cryptands can stabilize the divalent state of Eu. Because of the favorable properties of Eu2+ and the ability of cryptands to oxidatively stabilize Eu2+, I hypothesized that Eu2+-containing cryptates could serve as good candidates for use as contrast agents for MRI. Relaxometric studies revealed higher efficacy of small Eu2+-containing cryptates compared to the clinically approved contrast agent gadolinium(III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate at ultra-high field strengths. Also, an increase in relaxivity with increasing field strength was observed for these cryptates. Further, the relaxivity of Eu2+-containing cryptates decreases as temperature increases, but is not affected by changes in pH in a physiologically relevant range.

Variable-temperature 17O NMR and electron paramagnetic resonance spectroscopy were used to understand these observations in relaxivity. Variable-temperature 17O NMR experiments revealed the presence of two inner-sphere water molecules and fast water-exchange rates (∼;107-108 s-1) for small Eu2+-containing cryptates. With the relaxivity and 17O NMR and EPR data, rotational-correlation rates for these cryptates were estimated and were found to limit relaxivity.

In addition to relaxometric studies, transmetallation experiments were performed in the presence of Ca2+, Mg2+, and Zn2+ because of their relative abundance in plasma and the affinity of these ions for ligands. The transmetallation experiments demonstrated that amine-based cryptates are stable to transmetallation in the presence of Ca2+, Mg2+, and Zn2+ and are more stable than the clinically approved gadolinium(III) diethylenetriaminepentaacetate, a promising result for their potential use for in vivo applications.

Because relaxivity of small Eu2+-containing cryptates increases with molecular weight, I also investigated the effect of albumin on the relaxivity of a biphenyl-containing cryptate. While relaxivity enhancement was observed in the presence of albumin at 1.4 T, the relaxivity of the biphenyl-based cryptate in the presence of albumin at 3, 7, 9.4, and 11.7 T was lower compared to in the absence of albumin. This decrease in relaxivity was attributed to a displacement of one inner-sphere water molecule upon protein binding.

These studies of the physicochemical properties of Eu2+-containing cryptates provide a better understanding of how relaxivity is influenced by molecular parameters including the number of inner-sphere water molecules, water-exchange rate, and rotational-correlation rate for these cryptates and pave the way for designing more efficient Eu2+-containing cryptates for use as contrast agents for MRI.

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