Borsook / Bullmore Imaging in CNS Drug Discovery and Development

Implications for Disease and Therapy
1. Auflage 2010
ISBN: 978-1-4419-0134-7
Verlag: Springer-Verlag
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 396 Seiten

Drug development today needs to balance agility, speed, and risk in defining probability of success for molecules, mechanisms, and therapeutic concepts. New techniques such as fMRI promise to be part of a sequence that could transform drug development. Although numerous review articles exist that discuss the use of imaging in drug development, no one source is available that combines the various techniques and includes a discussion of disease mapping. Imaging in CNS Drug Discovery and Development, Implications for Disease and Therapy will serve to distill the most salient developments in the use of imaging in drug development and disease mapping. It will launch evolving concepts that integrate new imaging technologies and paradigms with molecular medicine and molecular profiling ('monics') as well as consider the ethical issues that arise as a result of disease or state diagnosis and the use of imaging in the public eye.

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.

Autoren/Hrsg.

Borsook, David

Bullmore, Edward

Inhaltsverzeichnis

1;Preface;5
1.1;Reference;7
2;Contributors;11
3;About the Editors;15
4;The Challenges and Opportunities;18
4.1;Introduction;18
4.2;Failure: A Driving Force for Improved Approaches;19
4.2.1;New Approaches and Indications;19
4.3;Integration of Processes in CNS Drug Development;19
4.4;Chasing the Ideal: Can Neuroimaging Help?;20
4.4.1;Animal–Human Translation;20
4.4.2;CNS Target Engagement and Dosing;21
4.4.3;Human Surrogate Models;22
4.4.4;Clinical Phenotype;22
4.4.5;Pharmaco-Phenotype;23
4.5;Challenges in Adopting Neuroimaging Technologies;23
4.6;References;23
5;Imaging of CNS Systems: Importance for Drug Development;25
5.1;Introduction;25
5.2;Imaging Biomarkers for Target–Compound Interaction in Alzheimer’s disease;28
5.3;Imaging Biomarkers of Disease and Disease Modification in Alzherimer’s Disease;29
5.4;Imaging Biomarkers of Patient Selection in Stroke and Cerebrovascular Disease;31
5.5;Imaging Biomarkers in Schizophrenia;35
5.6;Imaging Biomarkers in Mood Disorders;37
5.7;Conclusions;38
5.8;References;39
6;Anatomical Imaging: Volumetric Analysis;44
6.1;Introduction;44
6.2;Early Impact of MRI on Clinical Diagnosis: Volumetric Approaches;45
6.2.1;Refining Definitions of Disease;45
6.2.2;Implications for CNS Therapy;45
6.3;Analytical Approaches to Assess Whole–Brain Volumetric Change;46
6.3.1;Voxel-Based Morphometry and Related Measures of CNS Disease;46
6.3.2;The Role of Whole-Brain Atrophy Measures in CNS Drug Therapy;47
6.4;Distinguishing Measures Contributing to Cortical Density;48
6.5;From Focal Atrophy to Hodology: Imaging Structural Systems in CNS Disease;49
6.6;Methodological Considerations;51
6.6.1;Analytical Assumptions;51
6.6.2;Interpreting Measures of Volumetric Changes;52
6.7;Therapeutic Horizons;52
6.8;Conclusion;53
6.9;References;54
7;Diffusion Tensor Imaging and Drug Development;59
7.1;Introduction;59
7.2;Diffusion Magnetic Resonance Imaging;59
7.2.1;Physical Concepts;60
7.3;Diffusion Tensor Imaging;61
7.4;Physical Concepts;61
7.5;Diffusion Tensor Imaging in Human Brain Pathologies;62
7.5.1;Oncology;63
7.5.2;Head Trauma;63
7.5.3;Huntington’s Disease;64
7.5.4;Pain;64
7.5.5;Stroke;65
7.5.6;Multiple Sclerosis;66
7.5.7;Depression;66
7.5.8;Autism;66
7.5.9;Obsessive Compulsive Disorder;67
7.5.10;Schizophrenia;67
7.5.11;Alzheimer’s Disease;68
7.6;DTI and Drug Development;68
7.6.1;Oncology;69
7.6.2;Other Applications;71
7.7;Limitations;71
7.8;Concluding Remarks;72
7.9;References;72
8;Functional Magnetic Resonance Imaging in Drug Development;78
8.1;Introduction;78
8.2;Measuring the BOLD Response with fMRI;79
8.3;Previous and Common Uses of fMRI;81
8.4;Pharmacological fMRI: Applications in Drug Development;83
8.5;fMRI of Drug Effects: Interactions Between Drug and Processing of Stimulus;86
8.6;Standardization and Reproducibility;91
8.6.1;Nonphysiological;91
8.6.2;Physiologic or Cognitive;92
8.7;Conclusion;93
8.8;References;93
9;Magnetic Resonance Imaging of Pharmacological Systems;101
9.1;What Is Pharmacological MRI;101
9.2;What Can Be Measured;102
9.2.1;Hemodynamic Signals;102
9.2.2;Animal phMRI-Specific Contrast Mechanisms;103
9.2.3;Nonhemodynamic-Based Animal phMRI Methods;104
9.2.4;Resting-State fMRI;105
9.2.5;Imaging Direct Effect of Drugs;105
9.2.6;Imaging Indirect Effects of Drugs;106
9.2.7;Biomarkers;106
9.3;Interpretation of the phMRI Signal;107
9.4;Control Procedures;108
9.5;Analysis Issues;109
9.6;References;112
10;Molecular Imaging: Basic Approaches;115
10.1;Introduction;115
10.2;Imaging Modalities and Imaging Agents;116
10.2.1;Nuclear Imaging (Phelps 2004; Beekman and Vastenhouw 2004);116
10.2.2;MR Imaging (Merbach et al. 2001);118
10.2.3;Ultrasound Imaging (Foster et al. 2000);119
10.2.4;Optical Imaging;120
10.3;Design and Examples of Molecular Imaging Probes;121
10.3.1;Design of Target-Specific Probes;121
10.3.2;Probe Delivery;123
10.3.3;Suitable Amplification Strategies (Chemical or Biological);123
10.4;Applications in Neurological Diseases;124
10.5;Drug Development;126
10.6;Conclusions;126
10.7;References;127
11;Chemical Imaging. Magnetic Resonance Spectroscopy: The Basics;130
11.1;Introduction;130
11.2;Proton Magnetic Resonance Spectroscopy;133
11.2.1;In Vivo 1H-MRS Measurement;133
11.2.2;The In Vivo Brain 1H-MR Spectrum;135
11.2.3;Analyzing In Vivo 1H-MRS Data;138
11.2.4;1H-MRS Metabolite Spectral Editing;139
11.3;References;141
12;Animal Imaging;144
12.1;Introduction;144
12.1.1;Technical Approaches to Animal fMRI;146
12.1.2;Application of fMRI to CNS Drug Discovery;150
12.2;Concluding Remarks;155
12.3;References;156
13;Incorporating Functional MRI into Clinical Pharmacology Trials;159
13.1;The Use of fMRI in Decision-Making for CNS Drug Development;159
13.2;Operational Issues for Using fMRI Methodology in Drug Studies;160
13.3;The Choice of fMRI Paradigms in Drug Studies;163
13.4;Additional Logistical Considerations;165
13.5;References;167
14;Imaging Placebo Responses in the Brain;169
14.1;Introduction;169
14.2;Pain and Analgesia;170
14.3;Parkinson’s Disease;175
14.4;Depression and Drug Addiction;178
14.5;Conclusions;179
14.6;References;180
15;Structural Imaging of Drug Actions in Neurodegenerative Diseases;183
15.1;Background;183
15.1.1;Definition of Structural Imaging;183
15.1.2;Role of Structural Imaging in the Treatment of Neurodegenerative Diseases;184
15.1.2.1;Volumetric MRI;185
15.1.2.2;Diffusion Weighted Imaging or Diffusion Tensor Imaging;186
15.1.3;Summary;187
15.2;Application of Structural MRI to Monitor Drug Action;187
15.2.1;Drug Effects in Alzheimer’s Disease;188
15.2.2;Drug Effects in Cerebrovascular Disease and Vascular Dementia;190
15.3;Conclusion;192
15.4;References;192
16;Molecular Imaging of the CNS: Drug Actions;197
16.1;Introduction: Neuroreceptor and Functional Imaging;197
16.2;Application of Neuroreceptor and Functional Imaging to Psychiatric Disorders;198
16.2.1;Major Depression and Bipolar Affective Disorder;198
16.2.2;Anxiety Disorders;204
16.2.3;Psychotic Disorders;205
16.3;Application of Neuroreceptor and Molecular Imagingto Neurodegenerative Disorders;207
16.3.1;Alzheimer’s Disease;207
16.3.1.1;Diagnosis and Imaging Targets;207
16.3.1.2;Imaging of Energy Turnover;207
16.3.1.3;PET Imaging of Cholinergic Neurotransmission: Radioligands for Muscarinic and Nicotinic Acetylcholine Receptors and Acetylcholi;208
16.3.1.4;Imaging of Abeta;209
16.3.2;Parkinson’s Disease;209
16.3.2.1;Diagnosis and Imaging Targets;209
16.3.2.2;Imaging in PD;210
16.4;References;211
17;Translational MRI in CNS Drug Discovery;219
17.1;Introduction;219
17.2;Translational Imaging in Alzheimer’s Disease;220
17.2.1;Clinical Imaging in AD patients;220
17.2.2;Preclinical MRI in Transgenic Mouse Models of AD;222
17.3;Translational MR Imaging in Psychiatric Disorders;224
17.3.1;Clinical Imaging in Schizophrenia;225
17.3.2;Preclinical MRI in Animal Models of Schizophrenia;227
17.4;Conclusion;228
17.5;References;229
18;In Vivo Mouse Imaging and Spectroscopy in Drug Discovery;233
18.1;Introduction;233
18.2;Techniques for in Vivo Brain Imaging and Spectroscopy of Mice;234
18.2.1;Ultrasound and Drug Delivery to the Brain;236
18.2.2;Microcomputerized Tomography;236
18.2.3;Magnetic Resonance Imaging and Spectroscopy;238
18.2.4;Positron Emission Tomography;238
18.2.5;Single Photon Emission Computed Tomography;240
18.2.6;In Vivo Optical Imaging;240
18.2.6.1;Bioluminescence;240
18.2.6.2;Fluorescence Imaging;240
18.2.7;Multimodality Imaging;241
18.3;Contrast Agents, Molecular Probes and Tracers;241
18.4;Imaging of Mouse Models of Alzheimer’s Disease;243
18.5;Final Remarks;247
18.6;References;248
19;Neuroimaging in Understanding Chronic Pain Mechanisms and the Development of New Therapies;255
19.1;Introduction;255
19.2;The Role of Neuroimaging in Understanding Pain Processing;256
19.3;Differences in Brain Activation in Response to Experimental and Clinical Pain;256
19.4;Differences in Brain Activation in Response to Evoked and Spontaneous Pain in Chronic Pain Patients;258
19.5;Towards Mechanism-Based Classification of Chronic Pain;258
19.6;Neuroimaging in Primary Headaches;259
19.7;Structural Brain Changes as a Result Of Chronic Pain;259
19.8;Neuroimaging as a Tool in Studies on Analgesia;260
19.9;Conclusions;261
19.10;References;262
20;Neuroimaging Human Drug Addiction;266
20.1;Introduction;266
20.2;Defining Drug Addiction;267
20.2.1;Characteristic Features of Drug Addiction;267
20.2.2;Neurobiological Models of Drug Addiction;268
20.2.3;Neural Circuitry Underlying Drug Addiction;269
20.2.4;The Impaired Response Inhibition and Salience Attribution (I-RISA) Model of Addiction;270
20.3;Core Features of Human Drug Addiction;271
20.3.1;Drug Intoxication;271
20.3.1.1;The Role of Dopamine;271
20.3.2;Drug Craving;272
20.3.3;Compulsive Drug Administration (Bingeing);273
20.3.4;Drug Withdrawal and Relapse;274
20.3.4.1;Dysphoria;276
20.4;Neurocognitive Mechanisms;276
20.4.1;Salience Attribution;276
20.4.2;Impaired Response Inhibition;277
20.4.3;Deficits in Decision Making;280
20.4.4;Expectation;281
20.5;Clinical Applications and Future Research Directions;282
20.6;References;283
21;Anxiety: Uncover Roles of Stress Related Genes by Imaging Genetics;293
21.1;Introduction;293
21.2;Anxiety and Stress Responses Accessed by Brain Imaging;293
21.3;Genetic Variation of NPY Gene Affects Emotion and Stress Response Demonstrated by Brain Imaging;295
21.4;References;301
22;Imaging CNS Disease States: Alzheimer’s Disease;304
22.1;Introduction;304
22.2;Imaging Biomarkers of AD-Related Alterations in Brain Anatomy;306
22.3;Imaging Biomarkers of AD-Related Alterations in Brain Chemistry;309
22.4;Imaging Biomarkers of AD-Related Alterations in Brain Function;309
22.4.1;Brain Metabolism and Perfusion at Rest: FDG PET and SPECT;310
22.4.2;Task-Related Brain Hemodynamics and Metabolism: fMRI and FDG PET;312
22.4.3;Imaging Biomarkers of AD-Related Brain Pathology;312
22.5;Conclusions;314
22.6;References;315
23;Brain Development and CNS Plasticity;320
23.1;Introduction;320
23.2;Structural Brain Development;321
23.2.1;Progressive Maturational Events;321
23.2.1.1;General Brain Growth;321
23.2.1.2;Myelination;321
23.2.1.3;Axonal Growth and Synaptic Exuberance;322
23.2.2;Regressive Anatomical Maturational Events;322
23.2.2.1;Pruning of Exuberant Axons and Synapses;322
23.3;Functional Brain Development;323
23.4;Development of Spontaneous Neural Activity;325
23.5;Theories of Functional Brain Development;328
23.6;Developmental Neuroplasticity;328
23.6.1;Neuroplasticity Is Not Always Beneficial and Often Insufficient;331
23.6.2;Neuroplasticity and Its Relationship to Neuropsychiatric Disorders;331
23.7;Chapter Review and Clinical Implications;332
23.8;References;333
24;Imaging in CNS Disease States: PTSD;340
24.1;Lasting Effects of Posttraumatic Stress Disorder;340
24.2;Neural Circuits of PTSD;340
24.3;Changes in Brain Structure in PTSD;342
24.4;Functional Neuroimaging Studies in PTSD;344
24.5;Effects of Pharmacotherapy on Brain Function and Structure in PTSD;354
24.6;Summary and Conclusions;354
24.7;References;355
25;Reasons to Believe: The Potential of Imaging in CNS Drug Development;380
25.1;Introduction;380
25.1.1;Imaging in Preclinical Drug Discovery;381
25.1.2;Imaging in Clinical Development;381
25.2;Reasons for Optimism;384
25.3;Reasons to Believe;384
25.4;References;385
26;Integrative Processes: Neuroscience Clinical Imaging Biomarkers;363
26.1;Introduction;363
26.2;Imaging Platforms for Drug Discovery and Development;365
26.3;Nuclear PET Imaging;365
26.4;Magnetic Resonance Imaging;368
26.5;Examples of the Use of Clinical PET Imaging Biomarkers;372
26.6;Pre-competitive Clinical Imaging Consortia – Shared Risk and Reward;373
26.7;Conclusions;376
26.8;References;376
27;Index;386