Table Of ContentTopics in
Biological Inorganic Chemistry
Volume 2
Editorial Board:
I. Bertini· M. J. Clarke· C. D. Garner· E. Kimura
S. J. Lippard· K. N. Raymond· J. Reedijk
P. J. Sadler . A. X. Trautwein • R. Weiss
Springer
Berlin
Heidelberg
New York
Barcelona
Hong Kong
London
Milan
Paris
Singapore
Tokyo
Metallopharmaceuticals II
Diagnosis and Therapy
Editors: M.J. Clarke· P.J. Sadler
With contributions by
M. W. Brechbiel, C. 1. Hill, J. F. Kronauge,
K. Kumar, J. H. McNeill, C. Orvig, A. Packard,
P. J. Sadler, R. Schinazi, C. F. Shaw III, H. Sun,
J. T. Rhule, K. H. Thompson, M. F. Tweedle,
Z. Zheng
Springer
Volume Editors:
Professor Michael J. Clarke
Department of Chemistry
Boston College
Merkert Center
Chestnut Hill, MA 02467
USA
Professor Peter J. Sadler
Department of Chemistry
University of Edinburgh
King's Buildings
West Mains Road
Edinburgh EH9 3JJ
Scotland, GB
ISSN 1437-7993
ISBN -13: 978-3-642-64239-5 e-ISBN-13: 978-3-642-60061-6
001: 10.1007/978-3-642-60061-6
Library of Congress Cataloging-in-Publication Data
Metallopharmaceuticals II ed.: M. J. Clarke; P. J. Sadler. - Berlin;
Heidelberg; New York; Barcelona; Hong Kong; London; Milan; Paris;
Singapore; Tokyo: Springer
2. Diagnosis and therapy/with contributions by M. W. Brechbiel... - 1999
(Topics in biological inorganic chemistry; Vol. 2)
ISBN 978-3-642-64239-5
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Editorial Board of the Series
Prof. Ivano Bertini Prof. Michael J. Clarke
Department of Chemistry Merkert Chemistry Center
University of Florence Boston College
Via G. Capponi 7 Chestnut Hill, MA 02467
1-50121 Florence USA
Italy E-mail: [email protected]
E-mail: [email protected]
Prof. Eiichi Kimura
Prof. C. Dave Garner Department of Medicinal Chemistry
Department of Chemistry School of Medicine
University of Manchester Hiroshima University
Oxford Road Kasumi 1-2-3, Minami-ku
Manchester M13 9PL Hiroshima 734
U.K. Japan
E-mail: [email protected] E-mail: [email protected]
Prof. Stephen J. Lippard
Prof. Kenneth N. Raymond
Department of Chemistry
Department of Chemistry
Massachusetts Institute of Technology
University of California
77 Massachusetts Avenue
Berkeley, CA 94720-1460
Cambridge, Massachusetts 02139-4307
USA
USA
E-mail: [email protected]
E-mail: [email protected]
Prof. Jan Reedijk Prof. Peter J. Sadler
Leiden Institut of Chemistry Department of Chemistry
Gorlaeus Lab. University of Edinburg
Leiden University King's Buildings
P.O. Box 9502 West Mains Road
NL-2300 RA Leiden Edinburgh EH9 3JJ
The Netherlands UK
E-mail: [email protected] E-mail: [email protected]
Prof. Alfred X. Trautwein Prof. Raymond Weiss
Institut fUr Physik Institut Le Bel, Lab. de Christallochimie
Medizinische Universitat zu Liibeck et de Chimie Structurale
Ratzeburger Allee 160 4, rue Blaise Pascal
D-23538 Liibeck F-67070 Strasbourg Cedex
Germany France
E-mail: [email protected] E-mail: [email protected]
Preface
Inorganic chemistry is beginning to have a major impact on medicine. It offers great
potential for the design of novel therapeutic and diagnostic agents. Volume I in this
series was concerned with anticancer drugs, especially the successful platinum
complexes which target particular sites on DNA. In Volume 2, the wider scope of
inorganic medicinal chemistry is illustrated.
About one quarter of all magnetic resonance imaging (MRI) scans in the clinic
now involve administration of a contrast agent. The challenges involved in opti
mising the electronic relaxation properties of paramagnetic contrast agents through
chemical design, their formulation and dosing are described by Tweedle and Kumar.
Progress is being made with agents that can also probe biochemical functions and be
targeted to specific organs and tissues.
Packard, Kronauge and Brechbiel describe recent advances in the targeting of
radioactive compounds for diagnosis and therapy, which encompasses radio nuclide
production and processing, organic chemistry and coordination chemistry for
radiopharmaceutical synthesis, as well as associated biochemistry and molecular
pharmacology. The outstanding success of man-made 99mTc, with its rich variable
oxidation-state co-ordination chemistry, is evident.
The versatile chemistry of antiviral polyoxometallates with their variable charge
distribution, shape, acidity, hydrolytic stability and redox potentials is described by
Rhule, Hill, Zheng and Schinazi. They also speculate that the primary mode of action
of fullerenes involves inhibition of human immunodeficiency virus protease. Future
progress with improving the water solubility of fullerenes is important.
The potential of vanadium compounds as orally-administered insulin mime tics
capable of lowering blood glucose and ameliorating other diabetic symptoms is
described by Orvig, McNeill and Thompson. The main challenge is to control the
toxicity of vanadium through the choice of oxidation state, types of chelated ligands,
and amphiphilicity. A vanadium complex may well enter the clinic soon.
The chemistry and biochemistry of bismuth, the heaviest non-radioactive element
in the periodic table, is poorly understood despite its use in medicine for several
centuries. Sun and Sadler describe recent advances in understanding the structures
of bismuth antiulcer drugs and their target sites on proteins.
Although gold drugs have been in widespread use for over 60 years for the
treatment of rheumatoid arthritis (chrysotherapy), their chemistry and biochemistry
are also poorly understood. Shaw describes how both injectable and oral gold
drugs are biotransformed before they reach their biological target sites: they are pro
drugs.
VIII Preface
Could it be that the metabolite gold(I) dicyanide is an active species? This and
some other gold complexes also exhibit antiviral activity. The realisation that gold(I)
can be oxidised to gold(III) in vivo, and that this has major effects on T-cell acti
vation, is likely to lead to progress in understanding the toxic side-effects of gold
drugs.
Overall this volume will provide chemists, biochemists, molecular biologists and
pharmacologists with new insights into the mechanism of action of metallodrugs and
diagnostic agents, and inspiration for the design of novel ones.
August 1999 Peter J. Sadler
Michael J. Clarke
Contents
Magnetic Resonance Imaging (MRI) Contrast Agents
M.P. Tweedle, K. Kumar .............................. .
Metalloradiopharmaceuticals
A.B. Packard, J.P. Kronauge, M. W. Brechbiel 45
Polyoxometalates and Fullerenes as Anti-HIV Agents
J. T. Rhule, c.L. Hill, Z. Zheng, R. Schinazi .................. . 117
Vanadium-Containing Insulin Drugs
E.H. Thompson, J.H. McNeill, C. Orvig ..................... . 139
Bismuth Antiulcer Complexes
H. Sun, P./. Sadler .................................. . 159
Chrysotherapy: Gold-Drug Metabolism and Immunochemistry
c.P. Shaw III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . 187
Magnetic Resonance Imaging (MRI) Contrast Agents
Michael F. Tweedle, Krishan Kumar
Bracco Research USA, P.O. Box 5225, Princeton, NJ 08543-5225, USA
This chapter covers all current types of contrast agents (CA) for use in Magnetic Resonance Imaging
(MRI). It is intended for learning rather than exhaustive review, presenting and discussing terms and
sufficient theory to understand the original literature in the field. The emphasis is on the CA
themselves as chemical entities, rather than on the images they generate, but sufficient examples of
MRI are shown to demonstrate the observed effects. The chapter begins with an historical per
spective setting MRI agents in the context of the older X ray and radiopharmaceutical agents, which
bracket the MRI agents in tolerance and sensitivity to detection. Following a description of MRI, the
mechanisms of image contrast generation with contrast agents are introduced, including proton
water displacement, Tl enhancing agents, and T2 enhancing agents such as the iron oxides. Re
laxivity is defined, and the mechanisms of inner sphere relaxivity pertinent to paramagnetic metal
ions, particularly Gd chelates, are detailed, including the Solomon-Bloembergen Morgan theory. The
next section d'eals with the most widely used class of MRI CA, the water soluble Gd chelates.
Fundamental chemical and biological properties and their importance are described in detail, in
cluding chemical structures, dosing, formulations, relaxivity, colligative properties, in vitro and in
vivo stability, tolerance, and the mechanism by which the agents enhance CNS abnormalities.
A section on liver imaging agents follows including structures and MRI images of agents (water
soluble) for the hepatobiliary and (particulate) for the reticuloendothelial systems. A short section
follows on new agents for the near term for gastrointestinal and blood pool use (MR angiography),
including recent images. The chapter ends with a detailed discussion of the possibilities for bio
chemically targeted MRI agents that would combine the exquisite spatial detail of MRI with the
biologic specificity of the newest targeted radiopharmaceuticals.
Keywords. Magnetic resonance imaging (MRI), Contrast agents (CA), Tl and T2 enhancing agents,
Inner sphere relaxivity, Gd chelates, CNS abnormalities, Liver imaging, MR angiography, Bio
chemically targeted MRI agents
Historical Perspective 2
1.1 X-ray Contrast Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2
1.2 Radiopharmaceuticals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3
1.3 Magnetic Resonance Imaging (MRI) Contrast Agents ............. 5
2 Magnetic Resonance Imaging (MRI) and Contrast Mechanisms 6
2.1 Magnetic Resonance Imaging (MRI) . . . . . . . . . . . . . . . . . . . . . . . . .. 6
2.2 Water Proton Displacement Agents .......................... 7
2.3 Proton Relaxation Catalysis .......................... 8
2.3.1 Relaxivity....................................... 8
2.3.2 T 2-Agents ............................................. 11
2 M.F. Tweedle, K. Kumar
2.3.3 TI-Agents ............................................. 13
2.3.4 Mechanism of Inner Sphere Relaxivity of T I Agents .............. 13
2.3.5 Inner Sphere Relaxation: The SBM Equation . . . . . . . . . . . . . . . . . . .. 14
2.3.6 Correlation Times ....................................... 17
2.3.7 Outer Sphere Relaxation .................................. 19
3 Extracellular Agents with Renal Elimination
for Imaging CNS Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 20
3.1 Blood Brain Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 20
3.2 Chemistry and Biology of Gadolinium Chelates . . . . . . . . . . . . . . . . .. 21
4 Hepatobiliary Agents for Imaging Liver Pathology . . . . . . . . . . . . . .. 26
4.1 Metal Chelates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 26
4.2 Particulates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 30
5 Blood Pool Agents ...................................... 31
6 Gatrointestinal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 34
7 Future Directions ....................................... 35
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 38
1
Historical Perspective
1.1
X-ray Contrast Agents
The field of contrast agents in diagnostic medicine opened in 1895, [1] six weeks
following the discovery of X rays by Rontgen [2]. These first contrast agents were
solutions of heavy elements with greater differential absorption of X rays than tissue
and thus they cast a dark shadow on the film following intravenous administration to
cadavers. They were far from ideal, being bare metal ions, and hence quite toxic. The
concentrations required were (and still are) on the order of mM. Achieving 1-3 mM
in heavy atom concentration in vivo requires injections of tens of grams of a heavy
atom. Iodine as the sodium salt was proposed in 1918 [3], but it was not until the late
1920s that intravenously administered organoiodine agents with acceptable tolerance
were developed [4]. Three full generations of intravenous agents have evolved since
the first commercial agents, with improvements in tolerance being the driving force.
Hundreds of triiodinated benzenoids have been synthesized and tested by several
large commercial R&D groups [5]. These agents are highly water soluble and contain
hydrophilic moieties alternatively substituted with the iodine to mask the hydro
phobic iodines. The well tolerated commercial examples are renally excreted to
