Jan 21, 2015 – NMR Topical Group Meeting

The North Jersey ACS NMR Topical Group proudly presents its January monthly meeting at
Rutgers CABM on Wednesday, Jan 21, 2015. [ register ]

Abstract:

Though 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, current CAs enhance contrast at a small fraction of what is theoretically possible.  We have investigated increasing per-dose CA efficacy both by control of the Gd3+-inner-sphere water exchange rate and via binding to a macromolecular target.

The Gd3+ chelate of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA), a clinically-established CA, exists as two interconverting coordination geometries which have varying water exchange rates.  A thorough structural characterization of 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 and regioisomeric.  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 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.

The NB group was 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.  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.