Biomedical imaging the chemistry of labels probes and contrast agents

RSC Drug Discovery

Edited by Martin Braddock

Biomedical Imaging
The Chemistry of Labels, Probes and Contrast Agents


Biomedical Imaging
The Chemistry of Labels, Probes and Contrast Agents


RSC Drug Discovery Series

Editor-in-Chief:
Professor David Thurston, London School of Pharmacy, UK

Series Editors:
Dr David Fox, Pfizer Global Research and Development, Sandwich, UK
Professor Salvatore Guccione, University of Catania, Italy
Professor Ana Martinez, Instituto de Quimica Medica-CSIC, Spain
Dr David Rotella, Montclair State University, USA

Advisor to the Board:
Professor Robin Ganellin, University College London, UK

Titles in the Series:
1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups: Impact
of Chemical Building Blocks on ADMET
2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1: BetaAmyloid, Tau Protein and Glucose Metabolism
3: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2: Neuronal

Plasticity, Neuronal Protection and Other Miscellaneous Strategies
4: Accounts in Drug Discovery: Case Studies in Medicinal Chemistry
5: New Frontiers in Chemical Biology: Enabling Drug Discovery
6: Animal Models for Neurodegenerative Disease
7: Neurodegeneration: Metallostasis and Proteostasis
8: G Protein-Coupled Receptors: From Structure to Function
9: Pharmaceutical Process Development: Current Chemical and Engineering
Challenges
10: Extracellular and Intracellular Signaling
11: New Synthetic Technologies in Medicinal Chemistry
12: New Horizons in Predictive Toxicology: Current Status and Application
13: Drug Design Strategies: Quantitative Approaches
14: Neglected Diseases and Drug Discovery
15: Biomedical Imaging: The Chemistry of Labels, Probes and Contrast Agents

How to obtain future titles on publication:
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Biomedical Imaging
The Chemistry of Labels, Probes and
Contrast Agents
Edited by
Martin Braddock

AstraZeneca, Loughborough, UK


RSC Drug Discovery Series No. 15
ISBN: 978-1-84973-014-3
ISSN: 2041-3203
A catalogue record for this book is available from the British Library
r Royal Society of Chemistry 2012
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Preface
The concept of medical imaging is one of the cornerstones of modern medicine. Although its origins can be found in 19th century photography, the field
only properly emerged in 1895 following W. C. Ro¨ntgen’s discovery of Xrays. Since then, insights from across physics and chemistry have devised

many more modalities, such as magnetic resonance imaging (MRI), optical
imaging (including fluorescence), X-ray imaging (including X-ray Computed
Tomography, CT), gamma imaging (including Single Photon Emission Computed Tomography, SPECT), positron emission tomography (PET) and
ultrasound techniques.
In this exemplary new book a distinguished group of experts from both
industry and academia present a comprehensive review on how medical imaging is being used in screening, diagnosis, patient management, clinical research
and to assist in the development of new therapeutic drugs.
Biomedical Imaging: The Chemistry of Labels, Probes and Contrast Agents
begins with a comprehensive introduction to endogenous and exogenous
contrast in medical imaging. The book is then broken down into four sections.
Section one presents a review of some of the more important advances in
recent years such as the development of radiotracers and radiopharmaceuticals as biomedical imaging tools, recent developments in imaging
agents for selected brain targets that are of clinical relevance in psychiatry and
neurology and of pharmacological interest in drug discovery and development and the synthesis of radiopharmaceuticals for application in SPECT
imaging. Section two focuses on the design and synthesis of contrast agents,
MRI and X-ray modalities. Topics covered include the synthesis and applications of MRI contrast agents, synthetic methods used for the preparation of
DTPA and DOTA derivative ligands, MRI contrast agents based on metallofullerenes, applications of MRI in radiotherapy treatment and the use of
autoradiography in the pharmaceutical discovery and development of
RSC Drug Discovery Series No. 15
Biomedical Imaging: The Chemistry of Labels, Probes and Contrast Agents
Edited by Martin Braddock
r Royal Society of Chemistry 2012
Published by the Royal Society of Chemistry, www.rsc.org

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Preface

xenobiotics. Section three concentrates on optical imaging techniques and the
value of fluorescence optical imaging in pharmacological research and drug
development. There are also chapters on fluorescence lifetime imaging applied
to microviscosity mapping and fluorescence modification studies in cells and
the design and use of contrast agents for ultrasound imaging. The final section
focuses on physical techniques and application, with a review of recent
advances in brain imaging that provide opportunities to develop biomarkers
for diseases of the central nervous system (CNS) and current progress and
future prospects of using MRI to assist in the drug discovery and development
process. The final chapter brings the book to a close peering into the future of
MRI contrast agents.
This book will be essential reading for medicinal and physical scientists
working in both industry and academia in the fields of chemistry, physics,
radiology, biochemistry and pharmaceutical sciences.


Contents
Chapter 1

Medical Imaging: Overview and the Importance of Contrast
John C Waterton
1.1
1.2

Introduction
Medical Imaging Modalities
1.2.1 Some General Ideas
1.2.2 Imaging and the Electromagnetic Spectrum
1.2.3 Radio Frequencies and Below

1.2.4 Magnetic Resonance
1.2.5 Microwaves
1.2.6 Optical Imaging
1.2.7 Ultraviolet
1.2.8 X-Ray
1.2.9 Gamma Rays and Nuclear Medicine
1.2.10 Single Photon Emission Computed
Tomography
1.2.11 Positron Emission Tomography
1.2.12 Ultrasound
1.2.13 Multimodal Techniques
1.3 How is Medical Imaging Used?
1.3.1 Prognostic or Diagnostic Biomarkers
1.3.2 Predictive Biomarkers or Companion
Diagnostics
1.3.3 Monitoring Biomarkers
1.3.4 Response Biomarkers
1.4 Regulatory and Cost Issues
1.5 Conclusion
References

RSC Drug Discovery Series No. 15
Biomedical Imaging: The Chemistry of Labels, Probes and Contrast Agents
Edited by Martin Braddock
r Royal Society of Chemistry 2012
Published by the Royal Society of Chemistry, www.rsc.org

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Contents

Biomedical Imaging: Advances in Radiotracer and
Radiopharmaceutical Chemistry
Robert N Hanson

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2.1

21

Background
2.1.1 Factors in Radiopharmaceutical Design and
Synthesis
2.2 Recent Examples of Integrated Radiotracer and
Radiopharmaceutical Development
2.2.1 b-Amyloid Targeted Agents for Imaging in
Alzheimer’s Disease
2.2.2 PSMA Targeting for Imaging Prostate Cancer
2.2.3 Integrin Receptor Targeted Agents for
Imaging Cancer
2.3 Conclusions
Acknowledgments
References
Chapter 3

Recent Developments in PET and SPECT Radioligands
for CNS Imaging
David Alagille, Ronald M. Baldwin and Gilles D. Tamagnan

3.1 Introduction
3.2 Amyloid Plaque
3.2.1 2-(4-([11C]Methyl amino)phenyl)benzo[d]
thiazol-6-ol ([11C]PIB)
3.2.2 2-(1-(6-((2-[18F]fluoroethyl)(methyl)amino)-2naphthyl)ethylidene)malononitrile ([18F]FDDNP)
3.2.3 6-[123I]iodo-2-(4’-dimethylamino)phenylimidazo[1,2-a]pyridine ([123I]IMPY)
3.2.4 2-(2-(2-Dimethylaminothiazol-5-yl)ethenyl)6-(2([18F]fluoro)ethoxy)benzoxazole
([18F]BF227) and 2-(2-(2-N-methyl-N[11C]methyl-aminothiazol-5-yl)ethenyl)-6(2(fluoro)ethoxy)benzoxazole ([11C]BF-227)
3.2.5 trans-4-(N-Methylamino)-4’-(2-(2-(2-[18F]
fluoroethoxy)ethoxy)stilbene ([18F]BAY94–
9172 or [18F]florbetaben)
3.3 Metabotropic Glutamate Receptors
3.3.1 mGluR1
3.3.2 Metabotropic Glutamate Type 5 (mGluR5)
Receptor
3.4 Monoamine Transporter Targets
3.4.1 Dopamine Transporter (DAT)
3.4.2 Norepinephrine Transporter (NET)
3.4.3 Serotonin Transporter (SERT or 5-HTT)

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3.5

3.6

3.7

3.8

3.9

3.10

Vesicular Monoamine Transporter Type 2
(VMAT2)
3.5.1 [11C]-Tetrabenazine ([11C]TBZ)
3.5.2 [11C]-Methoxytetrabenazine
([11C]MTBZ)
3.5.3 [125I]-Iodovinyltetrabenazine
([123I]IV-TBZOH)
3.5.4 [11C]Dihydrotetrabenazine ([11C]TBZOH)
3.5.5 Fluoroalkyl dihydrotetrabenazine
([18F]FE-DTBZ and [18F]FP-DTBZ)
Post-Synaptic Dopamine Receptor D3 (D3r)
3.6.1 [11C](þ)-4-Propyl-3,4,4a,5,6,10bhexahydro-2H-naphto-[1,2-b][1,4]oxazin9-ol ([11C](þ)-PHNO) (Figure 3.8)
Post-Synaptic Serotonin Receptor Targets
3.7.1 Serotonin Receptor Subtype 4 (5-HT4)
3.7.2 Serotonin Receptor Subtype 6 (5-HT6)
Peripheral Benzodiazepine Receptor, PBR
(Translocator Protein 18kD, TSPO)
3.8.1 1-(2-Chlorophenyl)-N-[11C]methyl-N(1-methylpropyl)-3-isoquinoline
carboxamide ([11C]PK11195)
3.8.2 N-[18F]Fluoroacetyl-N-(2,5-dimethoxybenzyl)2-phenoxyaniline ([18F]PBR06) and N-acetylN-(2-[11C]methoxybenzyl)-2-phenoxy-5pyridinamine ([11C]PBR28)
3.8.3 N-Acetyl-N-(2-[11C]methoxybenzyl)-2phenoxy-5-pyridinamide ([11C]PBR06)
Phosphodiesterase Inhibitors
3.9.1 PDE4
3.9.2 PDE10
Adenosine Receptor A1 and A2A

3.10.1 8-Dicyclopropylmethyl-1-[11C]methyl-3propylxantine ([11C]MPDX)
3.10.2 8-cyclopentyl-3-[(E)-3-iodoprop-2-en-1-yl]1-propylxanthine ([131I]CPIPX)
3.10.3 8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1propylxanthine ([18F]CPFPX)
3.10.4 [11C]2-(1-Methyl-4-piperidinyl)-6-(2phenylpyrazolo[1,5-a]pyridine-3-yl)3(2H)-pyridazinone ([11C]FR194921)
3.10.5 (E)-8-(3,4-Dimethoxystyryl)-1,3-dipropyl-7[11C]methylxanthine ([11C]KF17837)
3.10.6 [7-Methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)1,3,7-trimethylxanthine ([11C]KF18446
or [11C]TMSX)

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3.10.7

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(E)-1,3-Diethyl-8-(3,4[ C]-dimethoxystyryl)7-methyl-3,7-dihydro-1H-purine-2,6-dione
([11C]KW6002
3.10.8 5-Amino-7-(3-(4-[11C]methoxy)
phenylpropyl)-2-(2-furyl)pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine
([11C]SCH442416)
3.11 Cannabinoid Receptors
3.11.1 CB1
3.11.2 CB2
References

Chapter 4

Design and Synthesis of Radiopharmaceuticals for
SPECT Imaging
David Hubers and Peter J. H. Scott
4.1
4.2

Introduction
Radiopharmaceuticals Labeled with
Technetium-99m
4.2.1 Production of Technetium-99m
4.2.2 Radiolabeling Strategies using
Technetium-99m
4.2.3 Examples of Technetium-99m based
Radiopharmaceuticals
4.3 Radiopharmaceuticals Labeled with
Radioactive Iodine
4.3.1 Production of Iodine-123 and Iodine-131
4.3.2 Radiolabeling Strategies with Iodine-123
and Iodine-131
4.3.3 Examples of Iodine-123 and Iodine-131
Based Radiopharmaceuticals
4.4 Radiopharmaceuticals Labeled with
Radioactive Metal Ions
4.4.1 Production of Commonly used Radioactive
Metal Ions
4.4.2 Radiolabeling Strategies with Radioactive
Metal Ions
4.4.3 Examples of Radiopharmaceuticals
Labeled with Radioactive
Metal Ions

4.5 Summary
References

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Chapter 5.1 MRI Contrast Agents: Synthesis, Applications and
Perspectives
Pier Lucio Anelli, Luciano Lattuada and Massimo Visigalli
5.1.1
5.1.2

Introduction
Currently Available Contrast Agents
5.1.2.1 Complexes of Paramagnetic Metal Ions
5.1.2.2 Superparamagnetic Particles
5.1.3 Future Trends
5.1.3.1 New Ligands
5.1.3.2 Responsive Contrast Agents
5.1.3.3 Nanosized Contrast Agents
5.1.3.4 Agents for innovative MRI approaches
References
Chapter 5.2 The Future of Biomedical Imaging: Synthesis and
Chemical Properties of the DTPA and DOTA
Derivative Ligands and Their Complexes
E. Bru¨cher, Zs. Baranyai and Gy. Tircso´
5.2.1
5.2.2

5.2.3

Introduction
Synthesis of the DTPA and DOTA Derivative
Ligands and their Complexes
5.2.2.1 Synthesis of Substituted DTPA and DOTA
Derivatives
5.2.2.2 Synthesis of the Most Important DTPA
Based Intermediates and CAs
5.2.2.3 N-functionalization of DOTA Derivative
Macrocyclic Ligands
5.2.2.4 Structure and Synthesis of Bifunctional
Ligands Derived from DTPA and DOTA
5.2.2.5 Synthesis of the Complexes
Equilibrium Properties of the DTPA and DOTA
Derivative Complexes
5.2.3.1 Experimental Methods and Computer
Programs used for the Characterization of
Complexation Equilibria
5.2.3.2 Protonation Sequence and Protonation
Constants of the DTPA and DOTA
Derived Ligands
5.2.3.3 Complexation Equilibria of the DTPA
and DOTA Based Ligands
5.2.3.4 Equilibria of the Transmetallation
Reactions of the DTPA and DOTA
Derivative Complexes

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5.2.4

Kinetic Properties of the Complexes
5.2.4.1 Formation Kinetics of Complexes
of DOTA Derivatives
5.2.4.2 Kinetics of Dissociation of Complexes
5.2.4.3 Kinetics of Decomplexation of Complexes
of DTPA Derivatives
5.2.4.4 Kinetics of Decomplexation of DOTA
Derivative Complexes
5.2.5 Summary
Acknowledgements
References
Chapter 5.3 MRI Contrast Agents Based on Metallofullerenes
Chun-Ying Shu and Chun-Ru Wang
5.3.1
5.3.2

Introduction
MRI Contrast Agents Based on Gadofullerenes
5.3.2.1 MRI Contrast Agent Based on
Gadofullerene Gd@C82
5.3.2.2 MRI Contrast Agent Based on
Gadofullerene Gd@C60
5.3.2.3 MRI Contrast Agent Based on
Gadofullerene Gd3N@C80
5.3.3 MRI Contrast Agents Based on Confined
Gadonanotubes and Silicon Nanoparticles

5.3.4 Prospect
Acknowledgements
References

Chapter 5.4 Application of Magnetic Resonance Imaging (MRI)
to Radiotherapy
Jenghwa Chang, Gabor Jozsef, Nicholas Sanfilippo,
Kerry Han, Bachir Taouli, Ashwatha Narayana and
Keith DeWyngaert
5.4.1

Introduction to Radiotherapy
5.4.1.1 Treatment Equipments
5.4.1.2 Radiotherapy Process
5.4.1.3 Radiobiology
5.4.2 Radiotherapy Treatment Planning Process
5.4.2.1 Steps of Radiotherapy Treatment Planning
5.4.2.2 Target Definition
5.4.2.3 Image Fusion
5.4.3 Chemoradiation
5.4.3.1 Chemotherapy

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5.4.3.2

Combining Chemotherapy and
Radiotherapy
5.4.3.3 Administration of Chemoradiation
5.4.4 MRI for Radiotherapy
5.4.4.1 Anatomic MRI
5.4.4.2 Functional MRI
5.4.4.3 Applications of MRI in Radiotherapy
5.4.5 Chemoradiation of Head & Neck Tumors
5.4.5.1 MRI Evaluation of Head and Neck Cancer
5.4.5.2 A Clinical Case
5.4.6 The Use of MRI for Gamma Knife Treatment
Planning
5.4.6.1 Leksell Gamma Knife
5.4.6.2 Imaging for Gamma Knife
5.4.6.3 Treatment Planning for Gamma Knife
5.4.7 MRI for Monitoring Radiation Therapy
in Prostate Cancer
5.4.7.1 Radiotherapy of Prostate Cancer
5.4.7.2 MRSI for Assessing Radiotherapy Response
5.4.7.3 DWI and DCE MRI for Assessing
RT Response
5.4.8 MRI for Monitoring Chemoradiation of
High-Grade Glioma
5.4.8.1 Chemoradiation of Glioma
5.4.8.2 A Clinical Case
5.4.9 Conclusion
References
Chapter 6

Autoradiography in Pharmaceutical Discovery
and Development
Eric G. Solon
6.1
6.2

Introduction
Whole-Body Autoradiography
6.2.1 History of Whole-Body Autoradiography
6.2.2 Strengths of Whole-Body Autoradiography
6.2.3 Limitations of Whole-Body Autoradiography
6.2.4 Whole-Body Autoradiography Applications
6.2.5 Whole-Body Autoradiography Conclusion
6.3 Micro-Autoradiography
6.3.1 History of Micro-Autoradiography
6.3.2 Micro-Autoradiography Limitations
6.3.3 Micro-Autoradiography Applications
6.4 Conclusions
References

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Chapter 7.1 In vivo Fluorescence Optical and Multi-Modal Imaging in
Pharmacological Research: From Chemistry to Therapy
Monitoring
Rainer Kneuer, Hans-Ulrich Gremlich, Nicolau Beckmann,
Thomas Jetzfellner and Vasilis Ntziachristos
7.1.1
7.1.2
7.1.3
7.1.4

Introduction
In Vivo Optical Fluorescence Imaging
Multi-Modal Imaging
Molecular Probes and Tracers for
Optical Imaging
7.1.4.1 Small Organic Dyes
7.1.4.2 Nanoparticles
7.1.4.3 Design of Optical Imaging Probes
7.1.4.4 Labeling of Biologics
7.1.5 Optical Imaging in Drug Discovery: From
Research to the Clinics
7.1.5.1 Cancer
7.1.5.2 Rheumatoid Arthritis
7.1.5.3 Alzheimer’s Disease
7.1.5.4 Inflammation

7.1.5.5 Cardiology
7.1.6 Summary
Abbreviations
References
Chapter 7.2 Fluorescence Lifetime Imaging applied to
Microviscosity Mapping and Fluorescence Modification
Studies in Cells
Klaus Suhling, Nicholas I. Cade, James A. Levitt,
Marina K. Kuimova, Pei-Hua Chung, Gokhan Yahioglu,
Gilbert Fruhwirth, Tony Ng and David Richards
7.2.1
7.2.2

Introduction
Theoretical Background of Fluorescence
Time-Resolved Fluorescence Anisotropy
Fluorescent Molecular Rotors
Metal-Induced Fluorescence Lifetime Modifications
Fluorescence Decay Analysis
FLIM Instrumentation
Biological Motivation—Diffusion Studies
Anisotropy Measurements
Metal-Modified FLIM for Increased Axial Specificity
Conclusion
Acknowledgements
References

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Chapter 7.3 Design and Use of Contrast Agents for Ultrasound Imaging
Fabian Kiessling, Georg Schmitz and Jessica Ga¨tjens
7.3.1
7.3.2

Indications for Ultrasound Contrast Agents
Microbubbles
Soft Shell Microbubbles
Hard Shell Microbubbles
Targeted Microbubbles
Non Microbubble-based Ultrasound Contrast Agents
Microbubbles as Carriers for Drugs and Genes
7.3.3 Contrast Enhanced Ultrasound Imaging Methods
Use-oriented Characterisation of Microbubbles
Non destructive Imaging
Destructive Imaging
7.3.4 Main Applications of Contrast Enhanced
Ultrasound
Oncology
Lymph Node Imaging
Cardiology
Other Applications

7.3.5 Safety of Ultrasound Contrast Agents
7.3.6 Outlook
References
Chapter 8.1 Imaging as a CNS Biomarker
Richard Hargreaves, Lino Becerra and David Borsook
8.1.1
8.1.2

Introduction
Brain Disease and Subjective Measures – In Search
of Better Information
8.1.3 Can CNS Biomarkers come to the Rescue?
8.1.4 Criteria for CNS Biomarkers
8.1.5 CNS Biomarker Technologies
8.1.5.1 Anatomical CNS Biomarkers
8.1.5.2 Functional CNS Biomarkers
8.1.5.3 Chemical CNS Measures for Biomarkers
8.1.6 Brain State and Biomarker Targets:
Hurdles to Navigate
8.1.7 Biomarkers and Neuro-Psychiatric Clinical Practice
8.1.8 CNS Biomarker Selection and Validation
8.1.8.1 CNS Biomarker Validation
8.1.9 CNS Biomarkers for Drug Development
8.1.10 Potential CNS Neuroimaging Biomarkers
8.1.10.1 CNS Biomarkers and the FDA
8.1.11 Conclusions
Acknowledgements
References

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Chapter 8.2 Magnetic Resonance Imaging in Drug Development
Jin Xie and Xiaoyuan Chen
8.2.1
8.2.2
8.2.3
8.2.4
8.2.5

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Introduction
Preclinical and Clinical Trials
Basics of MRI
Advanced MRI Technologies

MRI in Drug Development
8.2.5.1 Degenerative Joint Diseases
8.2.5.2 Stroke
8.2.5.3 Oncology
8.2.5.4 Cardiovascular Disorders
8.2.5.5 Respiratory Diseases
8.2.6 Cell Trafficking
8.2.7 Target Specific Molecular Imaging
8.2.8 Multimodality
8.2.9 Conclusion
References

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Chapter 8.3 MRI in Practical Drug Discovery
K. K. Changani, M. V. Fachiri and S. Hotee

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8.3.1
8.3.2

Introduction
The Drug Development Process
8.3.2.1 Target Identification and Validation
8.3.2.2 Screening and Hits to Leads
8.3.2.3 Preclinical Studies
8.3.2.4 Clinical Trials (Phase I-III)
8.3.2.5 Regulator Review, Market Approval
and Monitoring
8.3.2.6 Attrition Rates in Pharma
8.3.2.7 Technological Advances in Pharma
8.3.3 Imaging Technology
8.3.3.1 Advantages of Imaging Technology
8.3.3.2 Combined Imaging Technology
8.3.4 MRI
8.3.4.1 Theory and Technological Advances
8.3.4.2 Advantages of MRI Technology
8.3.5 MRI Applications
8.3.5.1 Animal Models
8.3.5.2 Dissecting Disease Mechanisms
8.3.5.3 Specific Disease Areas
8.3.5.4 Comparison of MRI Technology with
Conventional Analytical Techniques
8.3.5.5 Target Validation and Candidate
Drug Evaluation

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8.3.5.6 Imaging Endpoints
8.3.5.7 Analysis of Drug-Release Mechanisms

8.3.5.8 Toxicology
8.3.6 Translational Applicability
8.3.7 Limitations of MRI Technology
8.3.8 Conclusion
References
Chapter 8.4 Peering Into the Future of MRI Contrast Agents
Darren K. MacFarland
8.4.1
8.4.2
8.4.3

Introduction
Current Commercial Agents
Design Criteria Moving Forward: What Will
Make a Good Contrast Agent?
8.4.4 Targeting Groups
8.4.5 Directions in MRI Contrast Agent Design
8.4.5.1 Alternative Gadolinium-chelate delivery
systems
8.4.5.2 Gadolinium Encapsulation in
Nanoparticles
8.4.5.3 SPIO
8.4.6 Multi-use MRI Contrast Agents
8.4.6.1 Multimodal Agents
8.4.6.2 Theranostics
8.4.7 Conclusion
References
Subject Index

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483
484
485
486
490

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493
495
497
498
498
503
508
509
509
510
511
511
521



CHAPTER 1

Medical Imaging: Overview and
the Importance of Contrast
JOHN C WATERTON, PhD CChem CSci FRSC(UK)a,b

a

Personalised Healthcare & Biomarkers, AstraZeneca, Alderley Park,
Macclesfield, Cheshire, SK10 4TG UK; b Biomedical Imaging Institute,
University of Manchester, Stopford Building, Oxford Road, Manchester,
M13 9PT UK

1.1 Introduction
The concept of medical imaging—using a device to capture images which have
medical utility from living humans—is one of the cornerstones of modern
medicine. Although its origins can be found in 19th century photography, the
field emerged properly following W. C. Ro¨ntgen’s discovery, in 1895, that Xrays could image the skeleton inside a living human, an achievement for which
he was awarded, in 1901, the first Nobel Prize for Physiology or Medicine.
Since then, insights from across physics and chemistry have been used to devise
many more imaging modalities that can be used in living humans. Some of
these other modalities, such as Magnetic Resonance Imaging (MRI), or X-ray
Computed Tomography (CT), have themselves also been associated with Nobel
prizes, and are reportedly considered by physicians to be among the most
important medical advances of the 20th century.1 While such extraordinarily
complex (and expensive) 3D imaging techniques have become essential tools in
the diagnosis and management of many conditions, including cancer and cardiovascular diseases, traditional inexpensive medical imaging techniques such
as planar X-ray images are still routinely used, for example to diagnose and
RSC Drug Discovery Series No. 15
Biomedical Imaging: The Chemistry of Labels, Probes and Contrast Agents
Edited by Martin Braddock
r Royal Society of Chemistry 2012
Published by the Royal Society of Chemistry, www.rsc.org

1

2

Chapter 1

treat fractures. In developed countries, almost everyone is imaged at least once
by ultrasound when a foetus, and is usually imaged again throughout life for
screening, diagnosis, and treatment monitoring. In addition to its critical role in
patient care, medical imaging has also revolutionised our understanding of
human function and physiology, perhaps most notably in the brain, and in our
understanding of psychiatric illness. Before brain imaging, psychiatrists had
only a vague and ill-defined concept of the ‘‘mind’’, but after two or three
decades of brain imaging research, neuroscientists are now beginning to be able
to describe exactly how the activation and wiring of specific structures in the
brain makes a mind work or malfunction.2
There are several distinct medical imaging modalities, some more familiar
than others. Each relies on a different physical principle. The most important
are listed in Table 1.1, and mapped in Figure 1.1 according to the signal they
detect.
The over-arching requirement for any useful medical imaging technology is
contrast. We need to exploit some physical principle that permits one structure
in the body to report a different signal than another. So, for example, soft
X-rays are stopped more by higher atomic number (Z) nuclei than by low Z
nuclei, so that the skeleton (containing calcium and phosphorus in hydroxylapatite) has a higher signal than the brain (composed largely of water),
which in turn has a higher signal than the air-filled lungs. A hypothetical
medical imaging technique based on the absorption of, say, neutrinos, is most
unlikely to be useful, because all tissues of the body are essentially transparent
to neutrinos. On the other hand, medical imaging in the terahertz range is
almost equally useless, because water absorbs terahertz radiation very strongly:
the radiation cannot penetrate past the outermost layers of the skin, and deep

organs are obscured.
Contrast may be classified as endogenous or exogenous. Familiar examples of
endogenous contrast are the difference between signal from bone and soft tissue
in X-ray imaging, or the difference between signal from grey and white matter
in MRI (due to differences in the nuclear magnetic relaxation of water protons
in the respective brain tissues). Exogenous contrast, on the other hand, is
created by administering a foreign substance, usually called a tracer or a contrast agent. Many are listed in the MICAD database.3 It is exogenous contrast
that is of particular interest to the medicinal chemist, since tracers and contrast
agents only exist because of chemists’ creativity and ingenuity. These substances are discussed in detail in subsequent chapters. Fewer than 100 tracers
and contrast agents have ever been approved by regulatory authorities for use
in human healthcare, but they cover a wide variety of chemistries, including
small inorganics, small organic molecules, chelates, tagged peptides, tagged
proteins e.g. monoclonal antibodies, noble gases, nanoparticles and microbubbles. Many more have been used investigationally in humans or animals.
Section 1.2 in this chapter describes the most important medical imaging
modalities, and how they achieve contrast.
Once we have a new medical imaging modality, based on a physical principle
which creates endogenous contrast, or with some chemistry to provide


Significant Imaging Modalities.
Endogenous Examples of exogenous contrast chemistries approved for human
contrast
usea[additional investigational chemistries in square brackets]

Names and synonyms

Physical principle

 Ultrasound, sonography
 Echocardiography

Transmission and reflection Yes
of sound waves

Sometimes Microbubbles

 Magnetic Resonance Imaging (MRI), Nuclear magnetic resonance Yes
Magnetic Resonance Tomography
and relaxation
(MRT), Nuclear Magnetic Resonance
(NMR) Imaging
 Magnetic Resonance Spectroscopy
(MRS), Magnetic Resonance
Spectroscopic Imaging (MRSI)
 Functional MRI (fMRI)

Sometimes Gadolinium chelates, manganese chelates, iron
nanoparticles, [other paramagnetic substances
such as nitroxyls or O2], [small molecules containing 19F or 17O], [hyperpolarised noble gases],
[hyperpolarised small molecules containing 13C],
[small diamagnetic or paramagnetic compounds
containing exchangeable protons]

 Optical imaging
 Fluorescence imaging
 Endoscopy

Excitation of valence
electron: absorption,
fluorescence

Yes

Sometimes Substances which absorb or fluoresce in the visible
or NIR

 X-Ray imaging, X-radiography
(planar)
 X-Ray computed tomography (CT)
(tomographic)
 Fluoroscopy
 Dual-energy X-ray absorptiometry
(DEXA)

Photoelectron absorption,
Compton scattering

Yes

Sometimes Organoiodines, BaSO4, [other substances containing heavy atoms]

Almost
noneb

Always

Substances containing gamma-emitting isotopes
such as 99mTc, 111In, 201Tl, 133Xe, 67Ga, 123I, 131I,
51
Cr, 169Yb, 81mKr

Always

Substances containing positron-emitting isotopes
e.g. 18F, 82Rb, 13N, [11C, 15O, 64Cu, 76Br,
89
Zr,124I]

 Gamma-camera, scintigraphy (planar) Radioactive decay with
 Single Photon Emission Computed
emission of gamma ray
Tomography (SPECT) (tomographic)
 Positron Emission Tomography
(PET) (tomographic)

Source: regulatory agency websites (FDA, EMA), accessed 2011.
There is a very weak signal from endogenous 40K.

b

3

a

Radioactive decay with
No
emission and annihilation
of positron

Medical Imaging: Overview and the Importance of Contrast

Table 1.1


4

Chapter 1

exogenous contrast, there are two further conditions which must be fulfilled
before it can come into practical use. Firstly, society demands that the benefits
of imaging with the new modality must exceed the costs and risks. Many clever
medical imaging techniques have been devised but never came into widespread
use, because they lacked a commercially viable application. Secondly, it is
essential to have a regulatory and legal framework within which medical
imaging can be performed while ensuring acceptable levels of patient safety.
Section 1.3 discusses the various uses of medical imaging, using the ‘‘biomarker’’ concept, while Section 1.4 outlines some regulatory and economic
considerations.

1.2 Medical Imaging Modalities
1.2.1
1.2.1.1

Some General Ideas
Formats: 2-D planar, 2-D tomographic, 3-D and 4-D

Medical images can be created and displayed in a number of different formats.
The oldest is a simple 2-D planar image typified, say, by a chest X-ray. Here the
signal represents X-ray absorption, a silhouette, summed and projected
through the body. Gamma scintigraphy is also a planar projection technique.
More modern techniques like CT, MRI, ultrasound, SPECT, and PET can

produce full 3-D data sets which can be rendered for display, although usually
2-D tomographic sections (slices) through the body are extracted for viewing.
Time, of course, is also a dimension, and to understand the functioning, say, of
the heart, 4-D data may be acquired from ultrasound, MRI or CT.

1.2.1.2

Molecular or Functional Imaging vs. Anatomic Imaging

This term ‘‘molecular imaging’’ is sometimes used to describe modalities
that rely on signal from a specific molecule, labelled perhaps (in the case of PET
or SPECT) with a radioisotope. These modalities can provide functional or
physiological information such as receptor occupancy or enzyme flux. In
contrast, imaging modalities such as ultrasound or MRI, sometimes seem to
provide predominantly anatomic information such as organ size and shape.
However this is not a rigid distinction, and in reality all modalities offer a
mixture of anatomic and functional information.

1.2.1.3

Dynamic Scans

The term ‘‘dynamic’’ imaging implies repetitive imaging before and during the
(usually) intravenous administration or inhalation of a tracer or contrast agent.
Examples include dynamic contrast-enhanced (DCE) MRI, CT or ultrasound,
and dynamic PET. From these time-dependent data, maps of uptake, distribution and clearance of the agent can be made. The pharmacokinetic


5

Medical Imaging: Overview and the Importance of Contrast

parameters obtained from compartmental modelling of these maps are
frequently useful in quantitative imaging biomarker studies (see Section 1.3).

1.2.2

Imaging and the Electromagnetic Spectrum

Most medical imaging employs electrical and magnetic fields, or electromagnetic radiation. The remainder use pressure waves or sound. Modalities can
be classified according to the frequency at which they operate. Electromagnetic
fields and electromagnetic radiation penetrate well into the body at very low
frequencies (below, say, 200 MHz), or at very high frequencies (wavelengths
below, say, 0.1 nm), so most useful medical imaging techniques use either the
low-energy or high-energy window (Figure 1.1). In addition, electromagnetic

ELECTROMAGNETIC
WAVES, PHOTONS

PET

511keV
hard
soft

SPECT
X-ray, DEXA, CT

pm

nm

blue
red
NIR

Optical, NIR

µm

MeV

keV

eV

mm

GHz

EPR

MRI/S
MHz
MEG

EEG

Figure 1.1

ECG

MPI

EIT

m
ELECTRIC,
MAGNETIC
FIELDS

PRESSURE WAVES
(SOUND)

GHz
NEAR-FIELD

THz

THz

FAR-FIELD

thermography

ultrasound
MHz
infrasound

palpation

auscultation

Imaging modalities mapped onto the electromagnetic spectrum (and its
equivalent for pressure and sound waves). In white text in black boxes are
the six most medically significant modalities. In smaller black font in white
boxes are shown some other investigational or lesser-used imaging modalities, together with related modalities which similarly use a device to
detect a signal (electromagnetic or pressure) from a patient, but do not
necessarily produce an image. Abbreviations: PET: Positron Emission
Tomography; SPECT: Single Photon Emission Computed Tomography;
DEXA: Dual Energy X-ray Absorptiometry; NIR: Near Infra-Red; EPR:
Electron Paramagnetic Resonance; MRI/S: Magnetic Resonance Imaging
and in vivo Magnetic Resonance Spectroscopy; MEG: Magnetoencephalography; EEG: Electroencephalography; ECG: Electrocardiography;
MPI: Magnetic Particle Imaging; EIT: Electrical Impedance Tomography.


6

Chapter 1

radiation can penetrate tissue to some extent at visible and near-infrared
frequencies, and these also can be useful.

1.2.3

Radio Frequencies and Below

In the low-energy window, the electromagnetic wavelength exceeds the size of
the human body, so we are using not waves, or photons, but time-varying
magnetic and electrical fields described by the equations for near-field effects. In

addition to MRI, investigational or specialist techniques in this low-frequency
range include Electrical Impedance Tomography (EIT),4 and Magnetic Particle
Imaging (MPI).5 MPI uses iron nanoparticles to create contrast. These techniques are potentially attractive in that they do not use ionising radiation, but
have not yet come into widespread use. Other important modalities (albeit
not necessarily imaging modalities) in this window include magnetoencephalography (MEG), electrocardiography (ECG), and electroencephalography
(EEG), together with related electrophysiological techniques.

1.2.4
1.2.4.1

Magnetic Resonance
Acquiring MRI

The most commonly used technique in the low-frequency window is Magnetic
Resonance Imaging (MRI). MRI is a form of Nuclear Magnetic Resonance
(NMR). It relies on the insight that, since the NMR Larmor frequency is
proportional to the magnetic field, if the field is caused to vary across the
sample (body), then nuclei at different positions will resonate at different frequencies. Some of the earliest experiments were performed literally by varying
the field, and scanning point by point through the sample, but this technique is
very inefficient: much faster and more efficient pulse sequences are used today.
Many are variations of the two-dimensional MR techniques familiar to chemists. Just as in other forms of 2-D MR, pulse sequences start with excitation
of the NMR signal, followed by an evolution period in which a phase shift
accumulates, and an acquisition period. However, unlike conventional 2-D
NMR, the parameters obtained are not spectral parameters such as chemical
shifts or scalar couplings, but are spatial positions encoded by gradients in
the magnetic field. Hundreds of pulse sequences have been developed for MRI,
each weighting the signal according to different combinations of contrast
mechanisms, and optimised for a specific body location.
An MRI system has a lot in common with the chemist’s NMR spectrometer.
The most obvious difference is that most MRI magnets have horizontal rather

than vertical access to allow patients to be scanned while lying down, and of
course the bore size is much larger, almost a metre, to allow human beings to be
scanned. In addition, the B0 magnetic field strengths are much smaller. Typical
MRI magnets in hospitals operate at 1.5 Tesla (63 MHz for 1H) or 3 T (126
MHz), and experimental systems for human use have been built at fields as high