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Investigations into the Effects of Water Exchange and the Structure of Lanthanide ChelatesPayne, Katherine Marie 05 December 2016 (has links)
Lanthanide chelates are effective agents for improving contrast in MR images. Optimizing the relaxation of inner sphere water molecules is a common focus of research in this field. However, the efforts to design an optimal contrast agent have commonly over-looked the relationship of water position and water exchange kinetics. This work explores structural conformation, the impact of very fast water exchange kinetics on hydration, and differing tumbling rates for regioisomers of a number of lanthanide chelates. We have grown crystals of LnDOTMA and obtained structural data by X-ray diffraction that provide a picture of the chelate during water exchange and demonstrate that chelate conformation is associated with water position. We observe increased population of the major isomer with increased water exchange rates in variable temperature 1H NMR studies of HoDOTMA. This suggests that water position and water exchange rates are linked. We therefore recommend that accurate water exchange data be included in the application of the SBM equations when interpreting experimental data. As further support of this recommendation, we measured water exchange kinetics with 17O NMR for the rigid GdNB-DOTMA chelates. These results were used in the fitting of 1H NMRD profiles to establish tumbling parameters. Similar results were also observed in the less rigid GdNB-DOTA, establishing the first identification of regioisomers in these chelates and their biphenyl derivatives. Binding studies of GdBP-DOTA indicate that the side isomer is a more effective agent, but it is the minor species in solution. Our work herein shows that predicting efficacy of contrast agents with SBM equations requires a more complete consideration of chelate hydration (q/r6).
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Investigation of the Structure and Dynamics of Regioisomeric Eu³⁺ and Gd³⁺ Chelates of NB-DOTMA: Implications for MRI Contrast Agent DesignWebber, Benjamin Charles 18 November 2013 (has links)
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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