First Advisor

Mark Woods

Date of Publication

Fall 11-18-2013

Document Type


Degree Name

Doctor of Philosophy (Ph.D.) in Chemistry






Contrast media (Diagnostic imaging) -- Research, Chelates -- Conformation -- Research, Magnetic resonance imaging -- Research



Physical Description

1 online resource (xx, 258 pages)


The detection of disease and abnormal pathology by magnetic resonance imaging (MRI) has been aided significantly by the use of gadolinium (Gd3+)-based contrast agents (CAs) over the past three decades. MRI and MRI CAs play a critical role in diagnosing tumors and diseases of the central nervous system. The agents used clinically have been shown to safely increase MRI contrast despite the toxicity of Gd3+, owing to the high kinetic and thermodynamic stability of these chelates. However, current CAs enhance contrast at a small fraction of what is theoretically possible. This leads to the necessity of introducing high CA doses in practice in order to afford sufficient contrast. Lanthanide (Ln3+) chelates based on 1,4,7,10–tetraazacyclododecane–1,4,7,10–tetraacetate (DOTA) have been shown to be particularly stable and effective. Chelates of DOTA exist in two interconverting coordination geometries which have varying water exchange rates. Researchers have envisioned a way to increase the per-dose efficacy both by control of the Gd3+–inner–sphere water exchange rate and via binding specificity (i.e. to tumors). The efficacy gains using these approaches have thus far been modest.

A thorough structural characterization of europium (Eu3+) chelates of a DOTA-derivative which cannot undergo conformational exchange was carried out. These studies show that a single enantiomer of the ligand (S)–2–(4-nitrobenzyl)–1,4,7,10–tetraazacyclododecane–1,4,7,10–tetra(α–methyl)acetate (NB–DOTMA) can yield chelates which are both diastereoisomeric (previously reported) and regioisomeric (not previously speculated). Molecular mechanics simulations generated from the characterization data indicate that the nitrobenzyl (NB) substituent is oriented in different directions for the two possible regioisomers. The NB group can be chemically converted to confer macromolecular binding capability, and the orientation of the NB substituent may have a significant impact on the binding and/or relaxation behavior of a prototypical CA.

The nuclear magnetic resonance (NMR) spectra of Eu–NB–DOTMA at various temperatures were compared. Unexpectedly, the chelates showed time-averaged structures which differ with a change in water exchange rate — the faster the rate, the greater the deviation from the expected structure. Consideration of the structures of Ln3+ chelates without accounting for their dynamic behavior does not yield an accurate value for the time-averaged hydration state. These observations suggest the "optimal" water exchange rate calculated using Solomon-Bloembergen-Morgan (SBM) theory may not lead to the highest-efficacy CAs. Binding and relaxometric studies of macromolecule-targeting derivatives of Gd–NB–DOTMA both by the author and in another lab showed that the coordination isomer with the slower water exchange rate should lead to more effective contrast, in direct opposition to the prevailing view of water exchange in the MRI community. Preliminary data do not indicate that regioisomeric chelates have significantly different relaxivity or macromolecular binding behavior.

The ratios between regioisomeric Ln–NB–DOTMA chelates formed were shown to be dependent on the concentration and pH of the chelation reaction, but conditions were not found which led to the production of a single regioisomer. Attempts to carry out an efficient synthesis of a Ln3+ chelate with no potential for regioisomerism were unsuccessful.


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