Imaging in CNS Drug Discovery and Development (eBook)

David Borsook, MD, Ph.D., trained in medicine and neurobiology at the University of the Witwatersrand, Medical School, Johannesburg, South Africa. He graduated in 1980. Following his internship he trained in Neurology at Boston City Hospital and then was the first Pain Fellow at the Massachusetts General Hospital, Department of Neurology. He subsequently was the Director of the Pain Center at the Hospital from 1994 – 2004. He has completed doctoral studies in Neurobiology and later started the Pain Imaging Program in the Department of Radiology at Massachusetts General Hospital. In 2002 he led an effort to cofound a Biotech – Descartes Therapeutics Inc, with his colleague Lino Becerra Ph.D. to use imaging in drug development, where he was Senior Vice President and Chief Scientific Officer. He currently directs an integrated imaging program – Pain & Analgesia Imaging Neuroscience (p.a.i.n.) Group at three Harvard Medical School Affiliated Hospitals, Massachusetts General Hospital, McLean Hospital and Children’s Hospital Boston. A component of this is a consortium of pharmaceutical and academic centers involved in the evaluation of fMRI in drug development known as ICD (Imaging Consortium for Drug Development). He has participated in a number of NIH meetings on future directions of pain research. His research is supported by grants from the National Institutes of Health, Foundations and Pharamaceutical Companies interested in the use of imaging in defining pain phenotype. He has published over 85 papers that include various aspects of pain, imaging in pain and analgesia. He is married with sons living in Concord Massachusetts. Dr. Lino Becerra Ph.D., is Lecturer in Psychiatry at Harvard Medical School, he has co-appointments in the Departments of Psychiatry at McLean Hospital and Massachusetts General Hospital (MGH), and Radiology at MGH. He’s the Director of the Imaging and Analysis Group at the Brain Imaging Center, McLean Hospital; and Co-Director of the Imaging Consortium for Drug Development (ICD) and the Pain Imaging and Analgesics Neuroscience Group (P.A.I.N. Group) at the same institution. Dr. Becerra was a co-founder of Descartes Therapeutics Inc., a biotech company dedicated to the development of drugs for chronic pain patients. Dr. Becerra’s research interests are focused on the optimization of functional imaging for its utilization in drug development, in particular for chronic pain. Dr. Becerra specifically is interested in the translational aspects of drug development through the study of preclinical and clinical early phase trials with the aid of neuroimaging. Dr. Becerra is author of over 50 publications, reviews and book chapters appearing in journals such as Neuron, Neuroscience, Journal of Neuroscience, Journal of Neurophysiology, NeuroImage, and European Journal of Pain. He is a reviewer for these Journals, and also for Biological Psychiatry and Archives of General Psychiatry. Edward Bullmore, MD, Ph.D., trained in medicine at Oxford and St. Bartholomew's Hospital, London, graduating in 1985. Following a period of further medical training as a Lecturer in Medicine at the University of Hong Kong (MRCP 1989), he started specialist training in psychiatry at St. George's Hospital, London, and then at the Bethlem Royal & Maudsley Hospital as a registrar from 1990 (MRCPsych 1992). From 1993, he was supported by the Wellcome Trust as a Research Training Fellow (then as an Advanced Research Training Fellow 1996-99) at the Institute of Psychiatry in London, where he completed doctoral studies on statistical analysis of magnetic resonance imaging data (PhD 1997). In 1999, he moved to the University of Cambridge as a Professor of Psychiatry and since 2005 he has been Clinical Director of the Behavioural & Clinical Neurosciences Institute at Cambridge. Also since 2005, he has combined his academic roles with a 50% secondment to GlaxoSmithKline as Vice-President for Experimental Medicine and head of GSK's Clinical Unit in Cambridge (CUC). His research in Cambridge has been supported by grants from the National Institutes of Health (Human Brain Project), the Wellcome Trust and the MRC; he has published more than 200 papers on various aspects of neuroimaging, neuroscience and psychiatry. In 2008 he was elected a Fellow of the Academy of Medical Sciences. He is married with three sons and enjoys living without a car in central Cambridge. Richard Hargreaves, Ph. D., trained at Chelsea College, London University in the UK where he obtained a First class honors degree in pharmacology. After completing his doctorate through the Physiology Department at King’s College London University UK, he joined Merck’s Neuroscience Research Center in Harlow UK in 1988 where he occupied positions of increasing seniority. Richard led the discovery biology teams that contributed to the development of MAXALT® (rizatriptan) for the treatment of migraine and EMEND® (aprepitant) and IVEMEND® (fosaprepitant), novel agents that advance the protective pharmacotherapy of acute and delayed chemotherapy-induced nausea and vomiting and post-operative nausea and vomiting. In 1999 Richard moved to the USA to establish and lead a worldwide imaging research strategy for Merck Research Laboratories. Since that time, he built a global multimodality Imaging group that supports decision making in drug discovery and development across Merck's key therapeutic areas. A key component of this imaging strategy has been the use of pre-competitive initiatives to combine expertise and share the costs of developing and characterizing new imaging tools and technologies that can be used to improve the evaluation of the safety and efficacy of novel drug candidates. Richard was awarded the 2007 Gary Neill Award for "Innovation in Drug Development" by the American Society of Clinical Pharmacology and Therapeutics (ASCPT) for his work on imaging in drug discovery and development. In February 2008, he was named Worldwide Head of Basic Research, Neuroscience for Merck Research Laboratories.

Preface 5
Reference 7
Contributors 11
About the Editors 15
The Challenges and Opportunities 18
Introduction 18
Failure: A Driving Force for Improved Approaches 19
New Approaches and Indications 19
Integration of Processes in CNS Drug Development 19
Chasing the Ideal: Can Neuroimaging Help? 20
Animal–Human Translation 20
CNS Target Engagement and Dosing 21
Human Surrogate Models 22
Clinical Phenotype 22
Pharmaco-Phenotype 23
Challenges in Adopting Neuroimaging Technologies 23
References 23
Imaging of CNS Systems: Importance for Drug Development 25
Introduction 25
Imaging Biomarkers for Target–Compound Interaction in Alzheimer’s disease 28
Imaging Biomarkers of Disease and Disease Modification in Alzherimer’s Disease 29
Imaging Biomarkers of Patient Selection in Stroke and Cerebrovascular Disease 31
Imaging Biomarkers in Schizophrenia 35
Imaging Biomarkers in Mood Disorders 37
Conclusions 38
References 39
Anatomical Imaging: Volumetric Analysis 44
Introduction 44
Early Impact of MRI on Clinical Diagnosis: Volumetric Approaches 45
Refining Definitions of Disease 45
Implications for CNS Therapy 45
Analytical Approaches to Assess Whole–Brain Volumetric Change 46
Voxel-Based Morphometry and Related Measures of CNS Disease 46
The Role of Whole-Brain Atrophy Measures in CNS Drug Therapy 47
Distinguishing Measures Contributing to Cortical Density 48
From Focal Atrophy to Hodology: Imaging Structural Systems in CNS Disease 49
Methodological Considerations 51
Analytical Assumptions 51
Interpreting Measures of Volumetric Changes 52
Therapeutic Horizons 52
Conclusion 53
References 54
Diffusion Tensor Imaging and Drug Development 59
Introduction 59
Diffusion Magnetic Resonance Imaging 59
Physical Concepts 60
Diffusion Tensor Imaging 61
Physical Concepts 61
Diffusion Tensor Imaging in Human Brain Pathologies 62
Oncology 63
Head Trauma 63
Huntington’s Disease 64
Pain 64
Stroke 65
Multiple Sclerosis 66
Depression 66
Autism 66
Obsessive Compulsive Disorder 67
Schizophrenia 67
Alzheimer’s Disease 68
DTI and Drug Development 68
Oncology 69
Other Applications 71
Limitations 71
Concluding Remarks 72
References 72
Functional Magnetic Resonance Imaging in Drug Development 78
Introduction 78
Measuring the BOLD Response with fMRI 79
Previous and Common Uses of fMRI 81
Pharmacological fMRI: Applications in Drug Development 83
fMRI of Drug Effects: Interactions Between Drug and Processing of Stimulus 86
Standardization and Reproducibility 91
Nonphysiological 91
Physiologic or Cognitive 92
Conclusion 93
References 93
Magnetic Resonance Imaging of Pharmacological Systems 101
What Is Pharmacological MRI 101
What Can Be Measured 102
Hemodynamic Signals 102
Animal phMRI-Specific Contrast Mechanisms 103
Nonhemodynamic-Based Animal phMRI Methods 104
Resting-State fMRI 105
Imaging Direct Effect of Drugs 105
Imaging Indirect Effects of Drugs 106
Biomarkers 106
Interpretation of the phMRI Signal 107
Control Procedures 108
Analysis Issues 109
References 112
Molecular Imaging: Basic Approaches 115
Introduction 115
Imaging Modalities and Imaging Agents 116
Nuclear Imaging (Phelps 2004 Beekman and Vastenhouw 2004)
MR Imaging (Merbach et al. 2001) 118
Ultrasound Imaging (Foster et al. 2000) 119
Optical Imaging 120
Design and Examples of Molecular Imaging Probes 121
Design of Target-Specific Probes 121
Probe Delivery 123
Suitable Amplification Strategies (Chemical or Biological) 123
Applications in Neurological Diseases 124
Drug Development 126
Conclusions 126
References 127
Chemical Imaging. Magnetic Resonance Spectroscopy: The Basics 130
Introduction 130
Proton Magnetic Resonance Spectroscopy 133
In Vivo 1H-MRS Measurement 133
The In Vivo Brain 1H-MR Spectrum 135
Analyzing In Vivo 1H-MRS Data 138
1H-MRS Metabolite Spectral Editing 139
References 141
Animal Imaging 144
Introduction 144
Technical Approaches to Animal fMRI 146
Application of fMRI to CNS Drug Discovery 150
Concluding Remarks 155
References 156
Incorporating Functional MRI into Clinical Pharmacology Trials 159
The Use of fMRI in Decision-Making for CNS Drug Development 159
Operational Issues for Using fMRI Methodology in Drug Studies 160
The Choice of fMRI Paradigms in Drug Studies 163
Additional Logistical Considerations 165
References 167
Imaging Placebo Responses in the Brain 169
Introduction 169
Pain and Analgesia 170
Parkinson’s Disease 175
Depression and Drug Addiction 178
Conclusions 179
References 180
Structural Imaging of Drug Actions in Neurodegenerative Diseases 183
Background 183
Definition of Structural Imaging 183
Role of Structural Imaging in the Treatment of Neurodegenerative Diseases 184
Volumetric MRI 185
Diffusion Weighted Imaging or Diffusion Tensor Imaging 186
Summary 187
Application of Structural MRI to Monitor Drug Action 187
Drug Effects in Alzheimer’s Disease 188
Drug Effects in Cerebrovascular Disease and Vascular Dementia 190
Conclusion 192
References 192
Molecular Imaging of the CNS: Drug Actions 197
Introduction: Neuroreceptor and Functional Imaging 197
Application of Neuroreceptor and Functional Imaging to Psychiatric Disorders 198
Major Depression and Bipolar Affective Disorder 198
Anxiety Disorders 204
Psychotic Disorders 205
Application of Neuroreceptor and Molecular Imagingto Neurodegenerative Disorders 207
Alzheimer’s Disease 207
Diagnosis and Imaging Targets 207
Imaging of Energy Turnover 207
PET Imaging of Cholinergic Neurotransmission: Radioligands for Muscarinic and Nicotinic Acetylcholine Receptors and Acetylcholi 208
Imaging of Abeta 209
Parkinson’s Disease 209
Diagnosis and Imaging Targets 209
Imaging in PD 210
References 211
Translational MRI in CNS Drug Discovery 219
Introduction 219
Translational Imaging in Alzheimer’s Disease 220
Clinical Imaging in AD patients 220
Preclinical MRI in Transgenic Mouse Models of AD 222
Translational MR Imaging in Psychiatric Disorders 224
Clinical Imaging in Schizophrenia 225
Preclinical MRI in Animal Models of Schizophrenia 227
Conclusion 228
References 229
In Vivo Mouse Imaging and Spectroscopy in Drug Discovery 233
Introduction 233
Techniques for in Vivo Brain Imaging and Spectroscopy of Mice 234
Ultrasound and Drug Delivery to the Brain 236
Microcomputerized Tomography 236
Magnetic Resonance Imaging and Spectroscopy 238
Positron Emission Tomography 238
Single Photon Emission Computed Tomography 240
In Vivo Optical Imaging 240
Bioluminescence 240
Fluorescence Imaging 240
Multimodality Imaging 241
Contrast Agents, Molecular Probes and Tracers 241
Imaging of Mouse Models of Alzheimer’s Disease 243
Final Remarks 247
References 248
Neuroimaging in Understanding Chronic Pain Mechanisms and the Development of New Therapies 255
Introduction 255
The Role of Neuroimaging in Understanding Pain Processing 256
Differences in Brain Activation in Response to Experimental and Clinical Pain 256
Differences in Brain Activation in Response to Evoked and Spontaneous Pain in Chronic Pain Patients 258
Towards Mechanism-Based Classification of Chronic Pain 258
Neuroimaging in Primary Headaches 259
Structural Brain Changes as a Result Of Chronic Pain 259
Neuroimaging as a Tool in Studies on Analgesia 260
Conclusions 261
References 262
Neuroimaging Human Drug Addiction 266
Introduction 266
Defining Drug Addiction 267
Characteristic Features of Drug Addiction 267
Neurobiological Models of Drug Addiction 268
Neural Circuitry Underlying Drug Addiction 269
The Impaired Response Inhibition and Salience Attribution (I-RISA) Model of Addiction 270
Core Features of Human Drug Addiction 271
Drug Intoxication 271
The Role of Dopamine 271
Drug Craving 272
Compulsive Drug Administration (Bingeing) 273
Drug Withdrawal and Relapse 274
Dysphoria 276
Neurocognitive Mechanisms 276
Salience Attribution 276
Impaired Response Inhibition 277
Deficits in Decision Making 280
Expectation 281
Clinical Applications and Future Research Directions 282
References 283
Anxiety: Uncover Roles of Stress Related Genes by Imaging Genetics 293
Introduction 293
Anxiety and Stress Responses Accessed by Brain Imaging 293
Genetic Variation of NPY Gene Affects Emotion and Stress Response Demonstrated by Brain Imaging 295
References 301
Imaging CNS Disease States: Alzheimer’s Disease 304
Introduction 304
Imaging Biomarkers of AD-Related Alterations in Brain Anatomy 306
Imaging Biomarkers of AD-Related Alterations in Brain Chemistry 309
Imaging Biomarkers of AD-Related Alterations in Brain Function 309
Brain Metabolism and Perfusion at Rest: FDG PET and SPECT 310
Task-Related Brain Hemodynamics and Metabolism: fMRI and FDG PET 312
Imaging Biomarkers of AD-Related Brain Pathology 312
Conclusions 314
References 315
Brain Development and CNS Plasticity 320
Introduction 320
Structural Brain Development 321
Progressive Maturational Events 321
General Brain Growth 321
Myelination 321
Axonal Growth and Synaptic Exuberance 322
Regressive Anatomical Maturational Events 322
Pruning of Exuberant Axons and Synapses 322
Functional Brain Development 323
Development of Spontaneous Neural Activity 325
Theories of Functional Brain Development 328
Developmental Neuroplasticity 328
Neuroplasticity Is Not Always Beneficial and Often Insufficient 331
Neuroplasticity and Its Relationship to Neuropsychiatric Disorders 331
Chapter Review and Clinical Implications 332
References 333
Imaging in CNS Disease States: PTSD 340
Lasting Effects of Posttraumatic Stress Disorder 340
Neural Circuits of PTSD 340
Changes in Brain Structure in PTSD 342
Functional Neuroimaging Studies in PTSD 344
Effects of Pharmacotherapy on Brain Function and Structure in PTSD 354
Summary and Conclusions 354
References 355
Reasons to Believe: The Potential of Imaging in CNS Drug Development 380
Introduction 380
Imaging in Preclinical Drug Discovery 381
Imaging in Clinical Development 381
Reasons for Optimism 384
Reasons to Believe 384
References 385
Integrative Processes: Neuroscience Clinical Imaging Biomarkers 363
Introduction 363
Imaging Platforms for Drug Discovery and Development 365
Nuclear PET Imaging 365
Magnetic Resonance Imaging 368
Examples of the Use of Clinical PET Imaging Biomarkers 372
Pre-competitive Clinical Imaging Consortia – Shared Risk and Reward 373
Conclusions 376
References 376
Index 386