Metal Ions in Biological Systems

Volume 42: Metal Complexes in Tumor Diagnosis and as Anticancer Agents

Astrid Sigel, Helmut Sigel, Helmut Sigel

• Publisher: CRC Press
• Year: 2004
• ISBN:
  9781135483647
• Edition: 1
• Topic: Médecine
• Subtopic: Biochimie en médecine

Offering an authoritative and timely account by twenty-nine internationally recognized experts, Metal Ions in Biological Systems: Metal Complexes in Tumor Diagnosis and as Anticancer Agents is devoted solely to the vital research area concerning metal complexes in cancer diagnosis and therapy. In fourteen stimulating chapters, the book focuses on d

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Magnetic Resonance Contrast Agents for Medical and Molecular Imaging

Matthew J. Allen and Thomas J. Meade

Departments of Chemistry, Biochemistry and Molecular and Cell Biology, Neurobiology, and Physiology,
Northwestern University,
2145 Sheridan Road, Evanston, IL 60208, USA

1. INTRODUCTION

1.1. Magnetic Resonance Imaging

1.2. Classes of Contrast Agents

2. CONTRAST AGENTS FOR DIAGNOSIS

2.1. Cancer

2.1.1. Gd(III) DTPA and Its Derivatives

2.1.2. Mn(II) and Fe₂O₃ Agents

2.2. Non-Cancer Diseases

2.2.1. Blood Pool Related Diseases

2.2.2. Diseases of the Gastrointestinal Tract

2.2.3. Skeletal System Diagnosis

2.2.4. Other Diseases

3. TARGETED DELIVERY OF CONTRAST AGENTS

3.1. Contrast Agent Delivery

3.1.1. Gd(III) Containing Agents

3.1.2. Iron Oxide Agents

3.2. Penetrating the Blood Brain Barrier

4. IMAGING BIOCHEMICAL EVENTS

4.1. Enzymatically Activated Contrast Agents

4.2. Contrast Agents to Detect Biologically Significant Molecules

4.3. pH Sensitive Agents

5. CONCLUSIONS AND OUTLOOK

ACKNOWLEDGMENTS

ABBREVIATIONS

REFERENCES

1. INTRODUCTION

This chapter focuses on the wide range of chemical and biological applications that exist for magnetic resonance imaging (MRI) contrast agents. We begin with a brief introduction of how MRI and contrast agents function followed by a review of both clinical and experimental uses for MRI contrast agents. We proceed with a description of the targeted delivery of contrast agents including how they bind to and accumulate in specific biological tissues. Finally, we describe the new class of bio-activatable MR contrast agents. These agents respond to a biological phenomenon by altering the intensity of the observed signal in a conditional fashion.

1.1. Magnetic Resonance Imaging

MRI has become an extremely important tool for clinical diagnosis of disease and as a noninvasive method of acquiring threedimensional images of opaque experimental animals. MRI is based on the same principles as nuclear magnetic resonance (NMR) spectroscopy. Briefly, samples are placed in a large magnetic field and exposed to radiofrequency (rf) pulses. The relaxation times of the excited nuclei (usually protons from water) are then detected. Water proton spin density is measured, and the image is typically weighted using either the T₁ (spin-lattice relaxation time) or T₂ (spin-spin relaxation time) data. Biological samples for MRI are large and inhomogeneous (e.g. whole animals) as compared to NMR samples. In order to create an image of these heterogeneous samples, spatial information is encoded into the signal using time-varying, linear magnetic gradients that alter the magnetic field strength, which allows for mapping of spatial positions to frequencies. Mathematical transformations are performed to produce images from the spatially encoded data [1,2].

Since the development of MRI in the 1970s, technological advances have led to increases in both the speed and resolution of MRI [3]. Superconducting magnets have made higher signal-to-noise ratios and superior image resolutions possible compared with resistive or permanent magnets. Modern computers and advances in coil technology have improved image quality and decreased acquisition times. Today scans are routinely obtained in minutes (single slices in seconds) with the same spatial resolution as X-ray computed tomography (X-ray CT), approximately 1 mm [4]. Where higher fields (>10 Tesla) are employed resolution on the order of cells (~10 μm) have been reported [5]. As a result, MRI is becoming one of the primary imaging modalities in modern medicine [6]. An excellent source for a complete description of modern MRI can be found in The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging edited by Merbach and Toth [2] (see also Vol. 40 of this Series, The Lanthanides and Their Interrelations with Biosystems).

1.2. Classes of Contrast Agents

MRI can distinguish between various parts of a specimen based on differences in water concentration. However, when intrinsic contrast is low, contrast agents improve image quality similar to optical dyes. Unlike optical dyes such as fluorescent compounds, MR agents enhance image contrast as a result of their influence on nearby water protons. Paramagnetic molecules, because of their unpaired electrons, act as potent MRI contrast agents. They decrease the T₁ and T₂ relaxation times of nearby proton spins, thus enhancing the signal observed in the acquired image. The mechanism of T₁ relaxation is generally a through-space dipole-dipole interaction between the unpaired electrons of the paramagnetic metal ion and bulk water molecules (those water molecules that are not „bound“ to the metal atom). In images derived from changes in T₁, regions that are associated with a contrast agent (nearby water molecules) have increased signal intensity in a MR image compared to normal solution. The inverse is true for T₂-weighted images. Regions associated with a superparamagnetic ion (such as iron) have reduced signal intensity in an MR image compared to normal aqueous solution. Localized T₂ shortening caused by superparamagnetic particles is believed to be due to the local magnetic field inhomogenities associated with the large magnetic moments of these particles.

Many types of molecules enhance contrast in MRI. While organic and inorganic materials can be MRI contrast agents, we restrict our discussion to metal containing agents. Some paramagnetic ions decrease T₁ without causing substantial line broadening (e.g., gadolinium(III)), while others induce drastic line broadening (e.g., superparamagnetic iron oxide). The lanthanide ion Gd(III) is generally chosen as the metal atom for contrast agents because it has a high magnetic moment (μ² = 63 BM²), and a symmetric electronic ground state, (S⁸) [7]. Transition metal ions such as high spin Mn(II) and Fe(III) are candidates due to their high magnetic moments (5 unpaired electrons) [4]. Free...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Preface to the Series
• Preface to Volume 42
• Table of Contents
• Contributors
• Contents of Previous Volumes
• Chapter 1 Magnetic Resonance Contrast Agents for Medical and Molecular Imaging
• Chapter 2 Luminescent Lanthanide Probes as Diagnostic and Therapeutic Tools
• Chapter 3 Radiolanthanides in Nuclear Medicine
• Chapter 4 Radiometallo-Labeled Peptides in Tumor Diagnosis and Therapy
• Chapter 5 Cisplatin and Related Anticancer Drugs: Recent Advances and Insights
• Chapter 6 The Effect of Cytoprotective Agents in Platinum Anticancer Therapy
• Chapter 7 Antitumor Active Trans-Platinum Compounds
• Chapter 8 Polynuclear Platinum Drugs
• Chapter 9 Platinum(IV) Anticancer Complexes
• Chapter 10 Ruthenium Anticancer Drugs
• Chapter 11 Antitumor Titanium Compounds and Related Metallocenes
• Chapter 12 Gold Complexes as Antitumor Agents
• Chapter 13 Gallium and Other Main Group Metal Compounds as Antitumor Agents
• Chapter 14 Metal Ion Dependent Antibiotics in Chemotherapy
• Subject Index