First Advisor

Mark Woods

Date of Publication

Summer 8-12-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.) in Chemistry

Department

Chemistry

Language

English

Subjects

Contrast media (Diagnostic imaging) -- Research, Nuclear magnetic resonance -- Research, Diagnostic imaging

DOI

10.15760/etd.2493

Physical Description

1 online resource (xxiv, 153 pages)

Abstract

The current trend in magnetic resonance imaging (MRI) is towards higher external magnetic field strengths (B0) to take advantage of increased sensitivity and signal to noise ratio (SNR). Unfortunately, as (B0) increases the effectiveness (relaxivity) of clinical gadolinium (Gd3+)-based contrast agents (CAs) administered to enhance image contrast is significantly reduced. Excellent soft tissue contrast can be generated with current agents despite their non-optimum relaxivities but necessitates large doses. The limits of detection of a CA at high B0 fields can be lowered by recovering the lost relaxivity and is a pre-requisite to the goal of molecular imaging in which CAs are bound to biomarkers of pathology that exist at very low concentrations. Traditional methods for increasing the detectability of CAs have focused on optimizing critical parameters identified from the Solomon-Bloembergen-Morgan (SBM) theory that affect relaxivity. Gains in relaxivity with these methods to date have been modest and are far from the theoretical maximum possible. Although researchers continue to investigate novel complexes that provide improved relaxivities, any such complex would require a lengthy and costly approval process with the U.S. Food and Drug Administration (FDA). Therefore, a method that affords improved relaxivities of current clinically approved CAs, particularly at high B0 fields, that could be adopted into clinical practice rapidly, is of great interest.

Spin locking is a nuclear magnetic resonance (NMR) technique that was introduced for imaging in 1985, but has received very little attention in combination with Gd3+-based CAs. The technique employs a low power long duration radiofrequency (RF) pulse (B1) parallel to the net magnetization in the x,y-plane. This locks the magnetization into lower precessional frequencies around an "effective" field (Beff) that is reduced with respect to B0 but maintains the high field advantages required for imaging. When considered in the rotating frame, longitudinal relaxation of the magnetization against Beff exhibits shorter time constants (T1p) expected at these lower precessional frequencies. This leads to higher relaxivities, which has implications for increasing CA detectability.

The experiments described herein show that rotating frame longitudinal relaxivities (r1p) for current clinical Gd3+-based CAs are essentially independent of the strength of the spin lock pulse (yB1) as predicted by theory. This result is important because it allows the value of yB1 to be neglected when comparing r1p of Gd3+-based CAs across several B0 fields. The magnetic field dependence of r1p for all clinical agents showed that relaxivity, lost by moving to higher fields, could be "recovered" and that r1p was sensitive to the rotational correlation time constant (TR) of the agent. Using high molecular weight Nanoassembled capsules (NACs) containing a Gd3+-based CA to probe this finding further, we were able to generate relaxivities at high field up to an order of magnitude greater than clinical agents at current imaging fields. These are beyond anything previously reported, or likely to be, with current techniques. Finally, we demonstrated that by spin locking Mn2+ agents, relaxivities at high field increased by a factor of ~ 30 than without spin locking, due to their larger dependence on scalar coupling. These findings show the potential of spin locking to increase detection limits dramatically at high field and are an exciting development towards the goal of molecular imaging.

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Persistent Identifier

http://archives.pdx.edu/ds/psu/15959

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