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Author Garcia, Joel
Title Studies on the physicochemical properties of Eu²⁺ cryptates [electronic resource] : implications to contrast agents for magnetic resonance imaging / by Joel Garcia.
Publication Info. 2013
Location Call No. Status Notes
 Libraries Electronic Books  Electronic Resource - WSU ETD    AVAIL. ONLINE
Description 218 p. : ill.
Note Advisor: Matthew J. Allen.
Thesis Thesis (Ph.D.) -- Wayne State University, 2013.
Summary 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.
Subject Chemistry
Added Title Wayne State University thesis (Ph.D.) : Chemistry
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