Biomedical Imaging The Chemistry of Labels, Probes and Contrast Agents

Edited by

Martin Braddock AstraZeneca, Loughborough, UK

Publishing

Contents

Chapter 1 Medical Imaging: Overview and the Importance of Contrast 1 John C Waterton

1.1 Introduction 1 Medical Imaging Modalities 4

1.2.1 Some General Ideas 4 1.2.2 Imaging and the Electromagnetic Spectrum 5 1.2.3 Radio Frequencies and Below 6 1.2.4 Magnetic Resonance 6 1.2.5 Microwaves 10 1.2.6 Optical Imaging 10 1.2.7 Ultraviolet 1.2.8 X-Ray 12 1.2.9 Gamma Rays and Nuclear Medicine 13

1.2.10 Single Photon Emission Computed Tomography

1.2.11 Positron Emission Tomography 14 1.2.12 Ultrasound 15 1.2.13 Multimodal Techniques 16

1.3 How is Medical Imaging Used? 16 1.3.1 Prognostic or Diagnostic Biomarkers 17 1.3.2 Predictive Biomarkers or Companion

Diagnostics 17 1.3.3 Monitoring Biomarkers 17 1.3.4 Response Biomarkers 18

1.4 Regulatory and Cost Issues 18 1.5 Conclusion 19 References 20

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

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Chapter 2 Biomedical Imaging: Advances in Radiotracer and Radiopharmaceutical Chemistry 21 Robert N Hanson

2.1 Background 21 2.1.1 Factors in Radiopharmaceutical Design and

Synthesis 22 2.2 Recent Examples of Integrated Radiotracer and

Radiopharmaceutical Development 25 2.2.1 Targeted Agents for Imaging in

Alzheimer's Disease 27 2.2.2 PSMA Targeting for Imaging Prostate Cancer 30 2.2.3 Integrin Receptor Targeted Agents for

Imaging Cancer 35 2.3 Conclusions 38 Acknowledgments 39 References 39

Chapter 3 Recent Developments in PET and SPECT Radioligands for CNS Imaging 49 David Alagille, Ronald M. Baldwin and Gilles D. Tamagnan

3.1 Introduction 49 3.2 Amyloid Plaque 50

3.2.1 amino)phenyl)benzo[d] thiazol-6-ol 51

3.2.2 l)amino)-2-naphthyl)ethylidene)malononitrile 54

3.2.3 55

3.2.4 2-(2-(2-Dimethylaminothiazol-5-yl)ethenyl)-

and 2-(2-(2-N-methyl-N- C]methyl-aminothiazol-5-yl)ethenyl)-6-

(2(fluoro)ethoxy)benzoxazole 56 3.2.5

9172 or 57 3.3 Metabotropic Glutamate Receptors 58

3.3.1 58 3.3.2 Metabotropic Glutamate Type 5 (mGluR5)

Receptor 60 3.4 Monoamine Transporter Targets 64

3.4.1 Dopamine Transporter (DAT) 64 3.4.2 Norepinephrine Transporter (NET) 71 3.4.3 Serotonin Transporter (SERT or 5-HTT) 75

Contents ix

3.5 Vesicular Monoamine Transporter Type 2 (VMAT2) 80 3.5.1 81 3.5.2

82 3.5.3

83 3.5.4 83 3.5.5 Fluoroalkyl dihydrotetrabenazine

and 85 3.6 Post-Synaptic Dopamine Receptor D3 (D3r) 85

3.6.1

9-ol (Figure 3.8) 86 3.7 Post-Synaptic Serotonin Receptor Targets 88

3.7.1 Serotonin Receptor Subtype 4 (5-HT4) 89 3.7.2 Serotonin Receptor Subtype 6 (5-HT6) 90

3.8 Peripheral Benzodiazepine Receptor, PBR (Translocator Protein TSPO) 91 3.8.1 C]methyl-N-

-methylpropyl)-3-isoquinoline 93

3.8.2 and

94 3.8.3 C]methoxybenzyl)-2-

phenoxy-5-pyridinamide 95 3.9 Phosphodiesterase Inhibitors 95

3.9.1 PDE4 97 3.9.2 PDE10 98

3.10 Adenosine Receptor and A2A 99 3.10.1

100

-propylxanthine I]CPIPX) 3.10.3

propylxanthine -Methyl-4-piperidinyl)-6-(2-

3(2H)-pyridazinone 103

3.10.5 (E)-8-(3,4-Dimethoxystyryl)-l,3-dipropyl-7- 104

18446

104

3.10.7 7-methyl-3,7-dihydro-lH-purine-2,6-dione

105 C]methoxy)

phenylpropyl)-2-(2-furyl)pyrazolo[4,3-e]-

106 Cannabinoid Receptors 107

3.11.1 CB1 107 3.11.2 CB2 113

References

Chapter 4 Design and Synthesis of Radiopharmaceuticals for SPECT Imaging 144 David Hubers and Peter J. H. Scott

4.1 Introduction 144 4.2 Radiopharmaceuticals Labeled with

Technetium-99m 145 4.2.1 Production of Technetium-99m 145 4.2.2 Radiolabeling Strategies using

Technetium-99m 147 4.2.3 Examples of Technetium-99m based

Radiopharmaceuticals 151 4.3 Radiopharmaceuticals Labeled with

Radioactive Iodine 153 4.3.1 Production of and 154 4.3.2 Radiolabeling Strategies with

and 4.3.3 Examples of and

Based Radiopharmaceuticals 160 4.4 Radiopharmaceuticals Labeled with

Radioactive Metal Ions 162 Production of Commonly used Radioactive

Metal Ions 162 4.4.2 Radiolabeling Strategies with Radioactive

Metal Ions 163 4.4.3 Examples of Radiopharmaceuticals

Labeled with Radioactive Metal Ions 164

4.5 Summary 167 References 168

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Chapter 5.1 Contrast Agents: Synthesis, Applications and Perspectives 173 Pier Lucio Anelli, Luciano Lattuada and Massimo Visigalli

5.1.1 Introduction 173 5.1.2 Currently Available Contrast Agents 175

5.1.2.1 Complexes of Paramagnetic Metal Ions 175 5.1.2.2 Superparamagnetic Particles 184

5.1.3 Future Trends 186 5.1.3.1 New Ligands 186 5.1.3.2 Responsive Contrast Agents 190 5.1.3.3 Nanosized Contrast Agents 195 5.1.3.4 Agents for innovative MRI approaches 201

References 202

Chapter 5.2 The Future of Biomedical Imaging: Synthesis and Chemical Properties of the DTPA and DOTA Derivative Ligands and Their Complexes 208 E. Briicher, Zs. Baranyai and Gy. Tircso

5.2.1 Introduction 208 5.2.2 Synthesis of the DTPA and DOTA Derivative

Ligands and their Complexes Synthesis of Substituted DTPA and DOTA

Derivatives 5.2.2.2 Synthesis of the Most Important DTPA

Based Intermediates and CAs 212 5.2.2.3 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 225

5.2.3 Equilibrium Properties of the DTPA and DOTA Derivative Complexes 227 5.2.3.1 Experimental Methods and Computer

Programs used for the Characterization of Complexation Equilibria 228

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 236

5.2.3.4 Equilibria of the Reactions of the DTPA and DOTA Derivative Complexes 239

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5.2.4 Kinetic Properties of the Complexes 240 5.2.4.1 Formation Kinetics of Complexes

of DOTA Derivatives 241 5.2.4.2 Kinetics of Dissociation of Complexes 243 5.2.4.3 Kinetics of Decomplexation of Complexes

of DTPA Derivatives 244 5.2.4.4 Kinetics of Decomplexation of DOTA

Derivative Complexes 247 5.2.5 Summary 249 Acknowledgements 250 References

Chapter 5.3 MRI Contrast Agents Based on Metallofullerenes 261 Chun- Ying Shu and Chun-Ru Wang

5.3.1 Introduction 261 5.3.2 MRI Contrast Agents Based on Gadofullerenes 262

5.3.2.1 MRI Contrast Agent Based on Gadofullerene 263

5.3.2.2 MRI Contrast Agent Based on Gadofullerene 268

5.3.2.3 MRI Contrast Agent Based on Gadofullerene 271

5.3.3 MRI Contrast Agents Based on Confined Gadonanotubes and Silicon Nanoparticles 278

5.3.4 Prospect 280 Acknowledgements References

Chapter 5.4 Application of Magnetic Resonance Imaging (MRI) to Radiotherapy 285 Jenghwa Chang, Gabor Jozsef, Nicholas Sanfilippo, Kerry Han, Bachir Taouli, Ashwatha Narayana and Keith DeWyngaert

5.4.1 Introduction to Radiotherapy 285 5.4.1.1 Treatment Equipments 286 5.4.1.2 Radiotherapy Process 287 5.4.1.3 Radiobiology 288

5.4.2 Radiotherapy Treatment Planning Process 288 5.4.2.1 Steps of Radiotherapy Treatment Planning 289 5.4.2.2 Target Definition 289 5.4.2.3 Image Fusion 290

5.4.3 291 5.4.3.1 Chemotherapy 291

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5.4.3.2 Combining Chemotherapy and Radiotherapy 291

5.4.3.3 Administration of Chemoradiation 292 5.4.4 MRI for Radiotherapy 292

5.4.4.1 Anatomic MRI 293 5.4.4.2 Functional MRI 294 5.4.4.3 Applications of MRI in Radiotherapy 296

5.4.5 Chemoradiation of Head & Neck Tumors 296 MRI Evaluation of Head and Neck Cancer 296

5.4.5.2 A Clinical Case 297 5.4.6 The Use of MRI for Gamma Knife Treatment

Planning 298 5.4.6.1 Leksell Gamma Knife 298 5.4.6.2 Imaging for Gamma Knife 299 5.4.6.3 Treatment Planning for Gamma Knife 299

5.4.7 MRI for Monitoring Radiation Therapy in Prostate Cancer 301 5.4.7.1 Radiotherapy of Prostate Cancer 301 5.4.7.2 for Assessing Radiotherapy Response 302 5.4.7.3 and DCE MRI for Assessing

RT Response 302 5.4.8 MRI for Monitoring Chemoradiation of

High-Grade Glioma 303 5.4.8.1 Chemoradiation of Glioma 303 5.4.8.2 A Clinical Case 304

5.4.9 Conclusion 305 References 305

Chapter 6 Autoradiography in Pharmaceutical Discovery and Development 309 Eric G. Solon

6.1 Introduction 309 6.2 Whole-Body Autoradiography 313

6.2.1 History of Whole-Body Autoradiography 315 6.2.2 Strengths of Whole-Body Autoradiography 317 6.2.3 Limitations of Whole-Body Autoradiography 319 6.2.4 Whole-Body Autoradiography Applications 328 6.2.5 Whole-Body Autoradiography Conclusion 333

6.3 Micro-Autoradiography 333 6.3.1 History of Micro-Autoradiography 334 6.3.2 Micro-Autoradiography Limitations 336 6.3.3 Micro-Autoradiography Applications 337

6.4 Conclusions 339 References 340

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Chapter 7.1 In vivo Fluorescence Optical and Multi-Modal Imaging in Pharmacological Research: From Chemistry to Therapy Monitoring 343 Rainer Kneuer, Gremlich, Nicolau Thomas Jetzfellner and Vasilis Ntziachristos

7.1.1 Introduction 343 In Vivo Optical Fluorescence Imaging 344

7.1.3 Multi-Modal Imaging 346 7.1.4 Molecular Probes and Tracers for

Optical Imaging 347 7.1.4.1 Small Organic Dyes 348 7.1.4.2 Nanoparticles 348 7.1.4.3 Design of Optical Imaging Probes 352 7.1.4.4 Labeling of 354

7.1.5 Optical Imaging in Drug Discovery: From Research to the Clinics 357 7.1.5.1 Cancer 358 7.1.5.2 Rheumatoid Arthritis 359 7.1.5.3 Alzheimer's Disease 360 7.1.5.4 Inflammation 361 7.1.5.5 Cardiology 363

7.1.6 Summary 364 Abbreviations 365 References 365

Chapter 7.2 Fluorescence Lifetime Imaging applied to Microviscosity Mapping and Fluorescence Studies in Cells 371 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 Introduction 371 7.2.2 Theoretical Background of Fluorescence 373

Time-Resolved Fluorescence Anisotropy 374 Fluorescent Molecular Rotors 375 Metal-Induced Fluorescence Lifetime Modifications 376 Fluorescence Decay Analysis 376

Instrumentation 377 Biological Studies 377 Anisotropy Measurements 382 Metal-Modified FLIM for Increased Axial Specificity 383

Conclusion 385 Acknowledgements 386 References 386

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Chapter 7.3 Design and Use of Contrast Agents for Ultrasound Imaging 391 Fabian Georg Schmitz and Jessica

7.3.1 Indications for Ultrasound Contrast Agents 391 7.3.2 Microbubbles 394

Soft Shell Microbubbles 395 Hard Shell Microbubbles 395 Targeted Microbubbles 396 Non Ultrasound Contrast Agents 397 Microbubbles as Carriers for Drugs and Genes 397

7.3.3 Contrast Enhanced Ultrasound Imaging Methods 398 Use-oriented Characterisation of Microbubbles 398 Non destructive Imaging 400 Destructive Imaging 401

7.3.4 Main Applications of Contrast Enhanced Ultrasound 402 Oncology 402 Lymph Node Imaging 405 Cardiology 406 Other Applications 407

7.3.5 Safety of Ultrasound Contrast Agents 407 7.3.6 Outlook 409 References 409

Chapter 8.1 Imaging as a CNS Biomarker 411 Richard Hargreaves, Lino Becerra and David Borsook

8.1.1 Introduction 8.1.2 Brain Disease and Subjective Measures - In Search

of Better Information 413 8.1.3 Can CNS Biomarkers come to the Rescue? 414 8.1.4 Criteria for CNS Biomarkers 419 8.1.5 CNS Biomarker Technologies 419

8.1.5.1 Anatomical CNS Biomarkers 420 8.1.5.2 Functional CNS Biomarkers 422 8.1.5.3 Chemical CNS Measures for Biomarkers 423

8.1.6 Brain State and Biomarker Targets: Hurdles to Navigate 424

8.1.7 Biomarkers and Neuro-Psychiatric Clinical Practice 425 8.1.8 CNS Biomarker Selection and Validation 426

8.1.8.1 CNS Biomarker Validation 426 8.1.9 CNS Biomarkers for Drug Development 427

8.1.10 Potential CNS Neuroimaging Biomarkers 428 8.1.10.1 CNS Biomarkers and the FDA 429

Conclusions 431 Acknowledgements References

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Chapter 8.2 Magnetic Resonance Imaging in Drug Development 441 Jin Xie and Xiaoyuan Chen

8.2.1 Introduction 441 8.2.2 Preclinical and Clinical Trials 442 8.2.3 Basics MRI 443 8.2.4 Advanced MRI Technologies 444 8.2.5 MRI in Drug Development 445

8.2.5.1 Degenerative Joint Diseases 445 8.2.5.2 Stroke 447 8.2.5.3 Oncology 448 8.2.5.4 Cardiovascular Disorders 450 8.2.5.5 Respiratory Diseases 452

8.2.6 Cell Trafficking 453 8.2.7 Target Specific Molecular Imaging 454 8.2.8 456 8.2.9 Conclusion 458 References 459

Chapter 8.3 MRI in Practical Drug Discovery 465 K. K. Changani, M. V. Fachiri and S. Hotee

8.3.1 Introduction 465 8.3.2 The Drug Development Process 466

8.3.2.1 Target Identification and Validation 466 8.3.2.2 Screening and Hits to Leads 466 8.3.2.3 Preclinical Studies 467 8.3.2.4 Clinical Trials (Phase 467 8.3.2.5 Regulator Review, Market Approval

and Monitoring 467 8.3.2.6 Attrition Rates in 468 8.3.2.7 Technological Advances in Pharma 468

8.3.3 Imaging Technology 468 8.3.3.1 Advantages of Imaging Technology 469 8.3.3.2 Combined Imaging Technology 470

8.3.4 MRI 472 8.3.4.1 Theory and Technological Advances 472 8.3.4.2 Advantages of MRI Technology 473

8.3.5 MRI Applications 474 8.3.5.1 Animal Models 475 8.3.5.2 Dissecting Disease Mechanisms 475 8.3.5.3 Specific Disease Areas 475 8.3.5.4 Comparison of MRI Technology with

Conventional Analytical Techniques 476 8.3.5.5 Target Validation and Candidate

Drug Evaluation 477

Contents xvii

8.3.5.6 Imaging Endpoints 479 8.3.5.7 Analysis of Mechanisms 480 8.3.5.8 Toxicology 481

8.3.6 Translational Applicability 483 8.3.7 Limitations of MRI Technology 484 8.3.8 Conclusion 485 References 486

Chapter 8.4 Peering Into the Future of MRI Contrast Agents 490 Darren K. MacFarland

8.4.1 Introduction 490 8.4.2 Current Commercial Agents 493 8.4.3 Design Criteria Moving Forward: What Will

Make a Good Contrast Agent? 495 8.4.4 Targeting Groups 497 8.4.5 Directions in MRI Contrast Agent Design 498

8.4.5.1 Alternative delivery systems 498

8.4.5.2 Gadolinium Encapsulation in Nanoparticles 503

8.4.5.3 508 8.4.6 Multi-use MRI Contrast Agents 509

8.4.6.1 Multimodal Agents 509 8.4.6.2 Theranostics 510

8.4.7 Conclusion 511 References

Subject Index 521