Dissertation/Thesis Abstract

Designing a More Effective MRI Contrast Agent: Investigation into Various Functionalization Strategies for Targeted Imaging
by Rust, Lauren Nicole, Ph.D., Portland State University, 2020, 287; 28091598
Abstract (Summary)

Magnetic resonance imaging (MRI) is a medical imaging technique that provides high-resolution images used for diagnostic medicine while maintaining a superior safety profile compared to other radiative techniques. The administration of gadolinium-based contrast agents (GBCAs) improves the diagnostic power of MRI and have been used clinically for over three decades. Although GBCAs are effective at improving the contrast in the image, their detection limits are high and require a large dose to generate an observable effect. This high dose is the consequence of the current available designs of clinical GBCAs; their structures are not tuned to generate optimal efficacy. Efficacy of GBCAs is defined as relaxivity; how effectively the agent increases the T1 relaxation rate constant of protons on water. The isoelectric structure of the f-orbitals of Gd3+ yields it an effective relaxivity agent. However, Gd3+ is toxic and insoluble in vivo, and is therefore bound as a low molecular weight hydrophilic chelate. The ligand which forms the most kinetically inert and safest GBCA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA).

Parameters defined by Solomon, Bloembergen, and Morgan (SBM) describe different factors that influence relaxivity of a GBCA. Two of which have been demonstrated to dramatically influence efficacy: chelate tumbling and water exchange rates. A drawback to current ligand systems are low molecular weight; relaxivity increases with slower tumbling chelates. Current GBCAs have a tumbling rate that is much too rapid to achieve high relaxivities. Secondly, while this value is predominating, it is difficult to ascertain the contribution of other SBM parameters. It had been originally hypothesized that to improve relaxivity, water exchange rate needs to be fast. However, research in our group has demonstrated that a chelate which exchanges water too rapidly suffers from a reduction in its hydration state. The implication of this reduction in hydration state on relaxivity has yet to be fully appreciated.

The importance of the influence of SBM parameters on relaxivity is realized when advancements in GBCA technology are applied. The non-specific nature of GBCAs means they cannot directly diagnose pathology. One promising approach to reduce detection limits by increasing specificity in vivo is through bifunctional chelators (BFCs). These ligands have two components: a metal chelating group to bind gadolinium (DOTA), and a reactive moiety that couples with a targeting vector to bind desired biological receptors. This allows for defined bioaccumulation in vivo, resulting in improved diagnostics and lower detection limits. But with several BFCs available commercially, each positioning the vector attachment differently on the DOTA scaffold, the ideal scaffold for BFC design while including the influence of SBM is yet to be established.

The three most common strategies of targeting vector attachment are off the tetraaza macrocycle, through a monoamide pendant arm, or off an α-carbon on the acetate pendant arm. A thorough investigation of these three strategies was explored herein, in which BFC precursors were synthesized, and their structures analyzed relaxometrically. It was found that the attachment strategy significantly impacted water exchange parameters and molecular tumbling, which in turn greatly influenced relaxivity. The experiments conducted herein presented compelling new evidence in the way we define water exchange and hydration state. Studies into derivatives of the macrocycle substituted chelate NB-DOTA presented the impact an extremely rapidly exchanging chelate has on hydration state and its effect on relaxivity. Synthesis and analysis of a new tetra -carbon substituted chelate, DOTFA, yielded an exceedingly high relaxivity, as well as an interesting and novel impact on water exchange; there is strong evidence that DOTFA chelates exchange water in a mechanism that is not purely dissociative. Finally, studies into amide substituted chelates provided the expected low relaxivity associated with slow water exchange. Yet, it was demonstrated that changing the type of coordinating monoamide pendant arm, water exchange can be tuned to slightly more optimal values. These systematic studies provided novel insight how the most effective targeted GBCA can be designed, synthesized, and analyzed, as well as presented new evidence into the impact functionalization strategies have on relaxometric values.

Indexing (document details)
Advisor: Woods, Mark
Commitee: Podrabsky, Jason, Strongin, Robert, Stuart, David
School: Portland State University
Department: Chemistry
School Location: United States -- Oregon
Source: DAI-B 82/6(E), Dissertation Abstracts International
Subjects: Chemistry, Medical imaging
Keywords: BFCs, Bifunctional chelators, Gadolinium based contrast agents, GBCAs, Magnetic resonance imaging, MRI
Publication Number: 28091598
ISBN: 9798557026734
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