The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging

Andre S. Merbach, Lothar Helm, Éva Tóth

• Publisher: Wiley
• Year: 2013
• Print ISBN: 9781119991762
• eBook ISBN: 9781118503676
• Edition: 2
• Topic: Physical Sciences
• Subtopic: Spectroscopy & Spectrum Analysis

Magnetic Resonance Imaging (MRI) is one of the most important tools in clinical diagnostics and biomedical research. The number of MRI scanners operating around the world is estimated to be approximately 20,000, and the development of contrast agents, currently used in about a third of the 50 million clinical MRI examinations performed every year, has largely contributed to this significant achievement.

This completely revised and extended second edition: 

• Includes new chapters on targeted, responsive, PARACEST and nanoparticle MRI contrast agents.
• Covers the basic chemistries, MR physics and the most important techniques used by chemists in the characterization of MRI agents from every angle from synthesis to safety considerations.
• Is written for all of those involved in the development and application of contrast agents in MRI.
• Presented in colour, it provides readers with true representation and easy interpretation of the images. 

A word from the Authors:

Twelve years after the first edition published, we are convinced that the chemistry of MRI agents has a bright future. By assembling all important information on the design principles and functioning of magnetic resonance imaging probes, this book intends to be a useful tool for both experts and newcomers in the field. We hope that it helps inspire further work in order to create more efficient and specific imaging probes that will allow materializing the dream of seeing even deeper and better inside the living organisms.

Reviews of the First Edition:

"...attempts, for the first time, to review the whole spectrum of involved chemical disciplines in this technique..."—Journal of the American Chemical Society

"...well balanced in its scope and attention to detail...a valuable addition to the library of MR scientists..."—NMR in Biomedicine

Chapter 1

General Principles of MRI

Bich-Thuy Doan,¹ Sandra Meme,² and Jean-Claude Beloeil³

¹CNRS, Chimie-Paristech, Université Paris Descartes, Paris, France

²Centre de Biophysique Moléculaire, CNRS, Orléans, France

1.1 Introduction

Magnetic Resonance Imaging (MRI) derives directly from the phenomenon of Nuclear Magnetic Resonance (NMR [1–4]), which is widely used by chemists to determine molecular structure. The word “nuclear” was dropped in the switch to imaging to avoid alarming patients as NMR has nothing to do with radioactivity. This book is intended mainly for chemists, who are generally familiar with the NMR spectra. After a brief overview of the technique explaining the notion of relaxation time and saturation transfer used in MRI, we will describe localization techniques, which are less well-known in chemistry. The purpose of this short chapter is not to provide a complete theory of MRI [5–8], but to understand the rest of the book concerning the action of contrast agents. We will not go into the theoretical background of the phenomena, and while it is important to have some understanding of quantum mechanics, it is not our purpose to develop this aspect. This is a “nuts and bolts” description of MRI. Whenever possible, we refer to chemists' knowledge of NMR (for example, “2D NMR”).

1.2 Theoretical basis of NMR

1.2.1 Short description of NMR

In most cases, MRI focuses on one type of atomic nucleus, that of hydrogen in H₂O. We will therefore only use this nucleus, termed the “¹H proton.”

The physical phenomenon of NMR lies at the boundary between “conventional” and “quantum” treatment due to the small transition energies involved. Traditionally, the ¹H proton can be considered as a charged sphere rotating with a magnetic moment and collinear angular momentum (in quantum mechanics, these two entities are quantified as magnetic quantum number and spin quantum number (or spin)). Like a spinning top precessing in the Earth's gravitational field, the nucleus ¹H precesses in the static magnetic field B₀ of the spectrometer magnet. This precession will occur at a frequency (ν₀) dictated by the nature of the nucleus and the strength of the magnetic field of the magnet (ν₀ = −(γ/2π)B₀) (Larmor frequency). There are two possible precessions (parallel and antiparallel to B₀) corresponding to two energy states in the presence of a strong magnetic field. According to the Boltzmann equation, there are more ¹H protons in the lower level (parallel to B₀) than in the upper level. There will be total magnetization (M₀) of the sample, parallel to B₀ (by definition, the z axis) (Figure 1.1). The whole process of obtaining a spectrum is summarized in Figure 1.1.

Figure 1.1 NMR experiment: (a) net magnetization M₀ at equilibrium when the spins are placed in a permanent magnetic field B₀; (b) a radio frequency (RF) pulse, induced by a perpendicular B₁ magnetic field created by an RF coil, flips the magnetization into the xy plane; (c) the magnetization M precesses around the z axis and the signal decreases in the xy plane; for example, the magnetization is recorded from the y axis and converted by an analog-to-digital converter to an FID (Free Induction Decay); (d) FID: the recorded signal is a damped sinusoid; (e) NMR spectrum produced by a Fourier transform.

In an NMR experiment, the sample is subjected to the action of an oscillating electromagnetic field (B₁) (frequency: ν₁) perpendicular to B₀ (Figure 1.1); if we place ourselves within a rotating frame around the z axis at frequency ν₁ (ν₁ close to ν₀), it is as if the magnetization M₀ precesses around the magnetic field B₁, which is stationary within this frame. The duration of the B₁ field (pulse) is calculated for a M₀ tilt of 90°, or, more generally, of a flip angle α. At the end of the RF pulse, the system then returns to equilibrium, the magnetization in the xy plane decreases exponentially with time constant T₂, and the magnetization rises exponentially on axis z with a time constant T₁ (T₂ < T₁) (Figure 1.2). If we put a receiver coil in the xy plane, an electric current is induced in the coil and a signal is obtained after analog/digital conversion into a damped sinusoid called Free Induction Decay (FID).

Figure 1.2 (a) Return to equilibrium of the magnetization, (b) return to equilibrium on the z axis: (M_z = M₀ (1-exp^−t/T1)), (c) return to equilibrium in the xy plane (My = M₀ exp^−t/T2).

This signal corresponds to a temporal frequency. The Fourier transform (FT) of this signal (Figure 1.1) provides a spectrum of frequencies contained in the signal; in this case just one because we are only interested in H₂O. The signal intensity is proportional to the quantity of ¹H protons and therefore the amount of H₂O in the sample. In NMR, it is observed that we have a temporal frequency (FID) and that the FID and spectrum are a Fourier pair (Scheme 1.1).

Scheme 1.1

1.2.2 Relaxation times

Unlike other spectroscopic techniques, the energy difference between the excited state and steady state is too low to allow spontaneous relaxation, and therefore relaxation needs to be stimulated. The longitudinal relaxation time T₁ (Figure 1.2b) is characteristic of the return to equilibrium of the magnetization (Figure 1.2a) along z (M_z = M₀ (1−e^−t/T1)); this phenomenon corresponds to the enthalpic interaction of the excited nucleus with its environment, and in particular with the magnetic active agents of this environment (¹H protons, unpaired electrons e⁻). The movement of nuclear magnetic moments of other molecules (or unpaired e⁻) creates a distribution of frequencies within which one can find the resonance frequency of the excited nucleus, and a stimulated relaxation may then occur. Therefore, for this mechanism to work, there must be a movement of the molecules (Brownian motion). T₁ relaxation time will depend on the mobility of these entities and therefore on the viscosity of the environment.

The T₂ transversal relaxation time is characteristic of the disappearance of the signal in the xy plane (Figure 1.2c). It is an entropy phenomenon that corresponds to spin dephasing in the xy plane. T₂ is always below T₁. A parameter often used in MRI is the relaxation time T₂*, which contains both T₂ and the contribution of all magnetic field inhomogeneities and therefore those that are characteristic of the sample. T₂* is thus linked to specific properties of the tissue under study and is very useful in medical MRI.

1.2.3 Saturation transfer

The saturation phenomenon is used in NMR to identify hydrogens in conformational or chemical exchange. It is easy to obtain saturati...

Table of contents

• Cover
• Title Page
• Copyright
• List of Contributors
• Preface
• Chapter 1: General Principles of MRI
• Chapter 2: Relaxivity of Gadolinium(III) Complexes: Theory and Mechanism
• Chapter 3: Synthesis and Characterization of Ligands and their Gadolinium(III) Complexes
• Chapter 4: Stability and Toxicity of Contrast Agents
• Chapter 5: Structure, Dynamics, and Computational Studies of Lanthanide-Based Contrast Agents
• Chapter 6: Electronic Spin Relaxation and Outer-Sphere Dynamics of Gadolinium-Based Contrast Agents
• Chapter 7: Targeted MRI Contrast Agents
• Chapter 8: Responsive Probes
• Chapter 9: Paramagnetic CEST MRI Contrast Agents
• Chapter 10: Superparamagnetic Iron Oxide Nanoparticles for MRI
• Chapter 11: Gd-Containing Nanoparticles as MRI Contrast Agents
• Index