PET AND SPECT OF NEUROBIOLOGICAL SYSTEMS.

Foreword
Preface
Contents
Part I: Basics
	1: Animal Models for Brain Research
		1.1	 Introduction to Animal Modelling for Human Brain Disease
			1.1.1	 Relevance of Animal Models
			1.1.2	 Validity of Animal Models
				1.1.2.1	 Face Validity
				1.1.2.2	 Construct Validity
				1.1.2.3	 Aetiological Validity
				1.1.2.4	 Predictive Validity
			1.1.3	 Homology, Analogy and Isomorphism
			1.1.4	 Generalisation and Extrapolation
		1.2	 Animal Models of Psychiatric Disorders
			1.2.1	 The Endophenotype Concept in Psychiatry
			1.2.2	 Approaches to Modelling Psychiatric Disease
				1.2.2.1	 Behavioural Approach
				1.2.2.2	 Pharmacological Models
				1.2.2.3	 Genetic Models
			1.2.3	 Animal Models of Schizophrenia
				1.2.3.1	 Aetiology and Symptomatology of Schizophrenia
				1.2.3.2	 Validating Animal Models of Schizophrenia
					Electrophysiological Endophenotypes
					Cognitive Endophenotypes
					Locomotor Activity
					Sensory Discrimination
					Negative Symptoms
				1.2.3.3	 Neurodevelopmental Schizophrenia Models
				1.2.3.4	 Drug-Induced Schizophrenia Models
					Psychostimulant Models
					Hallucinogen Models
				1.2.3.5	 Lesion-Induced Schizophrenia Models
				1.2.3.6	 Genetic Schizophrenia Models
					Inbred and Selectively Bred Rodent Strains
					Genetically Modified Models
		1.3	 Animal Models of Neurological Disorders
			1.3.1	 Approaches to Modelling Neurological Disorders
			1.3.2	 Animal Models of Alzheimer’s Disease
				1.3.2.1	 Aetiology and Symptomatology of Alzheimer’s Disease
				1.3.2.2	 Validating Animal Models of Alzheimer’s Disease
					Cognitive Symptoms
					BPSD-Related Symptoms
					Pathological Alterations
					Neurochemical Alterations
				1.3.2.3	 Spontaneous and Selectively Bred Alzheimer’s Disease Models
					Pharmacological, Chemical and Lesion-Induced Rodent Models of Alzheimer’s Disease
				1.3.2.4	 Amyloid-β Infusion Rodent Models of Alzheimer’s Disease
				1.3.2.5	 Genetically Modified Alzheimer’s Disease Mouse Models
		1.4	 Imaging in Rodent Models of Brain Disease
			1.4.1	 Imaging in Schizophrenia
			1.4.2	 Imaging in AD
		1.5	 Conclusion
		References
	2: The Use of Small Animal Molecular Imaging (μPET) Exemplified in a Neurobiological Pathology
		2.1	 Introduction on μPET
			2.1.1	 Physics and Principle of PET
			2.1.2	 Pharmacokinetic Modelling
			2.1.3	 Compartment Models
				2.1.3.1	 Volume of Distribution
				2.1.3.2	 Input Function
				2.1.3.3	 One-Tissue Compartment Model
				2.1.3.4	 Two-Tissue Compartment Model
				2.1.3.5	 Logan Plot
			2.1.4	 Reference Tissue Models
				2.1.4.1	 Binding Potential
				2.1.4.2	 Simplified Reference Tissue Model
			2.1.5	 Receptor Occupancy and Displacement
			2.1.6	 Semiquantitative Approach
			2.1.7	 Radioligands
		2.2	 PET Motion Correction: State of the Art
			2.2.1	 The Need for Awake PET: Anesthesia, Stress, and Its Impact on Small Animal PET
			2.2.2	 Motion Correction in PET Reconstruction
			2.2.3	 Head Motion Tracking for Awake Small Animal PET
				2.2.3.1	 State of the Art
				2.2.3.2	 Optical Tracking Methods
					Stereovision
				2.2.3.3	 PET-Based Motion Tracking
					Point Source Tracking
			2.2.4	 Awake [18F]FDG PET Imaging of Memantine-Induced Brain Activation and Test-Retest in Freely Running Mice
				2.2.4.1	 Mouse Behavior in Awake Scans
				2.2.4.2	 Brain Regional Quantification
		2.3	 Illustration of PET Applications Exemplified for a Neuropsychiatric Disorder
			2.3.1	 Obsessive Compulsive Disorder
			2.3.2	 Animal Models for Obsessive Compulsive Disorder
				2.3.2.1	 A Pharmacological Rat Model
					Imaging of Cerebral Glucose Consumption
					Dopamine D2 Receptor Imaging
				2.3.2.2	 A Genetic Mouse Model
					Metabotropic Glutamate Receptor 5 PET Imaging
		2.4	 Summary/Conclusion
		References
	3: Total-Body PET
		3.1	 Introduction
		3.2	 The Importance of Detection
		3.3	 The Effect of the Scanner Configuration on the Sensitivity
		3.4	 State of the Art in Total-Body PET
			3.4.1	 The Road Toward Total-Body PET
			3.4.2	 The EXPLORER Project
			3.4.3	 Gain Versus System Length
		3.5	 Total-Body PET Applications
			3.5.1	 Applications in Oncology
			3.5.2	 Applications in Neurology
			3.5.3	 Research on New Radiopharmaceuticals
		3.6	 Conclusion
		References
	4: Cerebral Glucose Metabolism
		4.1	 Energy Requirements of Brain Tissue
		4.2	 Brain Energy Metabolism
			4.2.1	 Glycolysis and Oxidative Phosphorylation
			4.2.2	 Determination of the Regional Cerebral Metabolic Rate for Glucose (rCMRGlc)
			4.2.3	 Normal Glucose Consumption of the Brain
			4.2.4	 Coupling of Neuronal Activity to Metabolism and Flow
			4.2.5	 Clinical Applications of FDG-PET
		References
	5: Cerebral Blood Flow Measurement with Oxygen-15 Water Positron Emission Tomography
		5.1	 Introduction
		5.2	 Radiochemistry of [15O]H2O
		5.3	 [15O]H2O Brain PET Data Generation
		5.4	 Kinetic Modeling of CBF
		5.5	 Role of PET for CBF Measurements
			5.5.1	 General Principles for CBF Measurements
			5.5.2	 Advantages and Disadvantages of Perfusion Imaging Methods
				5.5.2.1	 Nuclear Medicine Methods
				5.5.2.2	 Computed Tomography Methods
				5.5.2.3	 Magnetic Resonance Methods
		5.6	 Applications for CBF PET
			5.6.1	 Acute Cerebral Ischemia
				5.6.1.1	 PET Perfusion Imaging in Preclinical Stroke Research
			5.6.2	 Chronic Cerebral Ischemia
			5.6.3	 Brain Activation Studies
			5.6.4	 Other Applications for CBF PET
		5.7	 Simplification/Improvement of CBF Quantification by [15O]H2O PET
		5.8	 Future Alternatives to [15O]H2O PET Imaging in Determining CBF
		5.9	 Summary and Conclusions
		References
	6: The Impact of Genetic Polymorphisms on Neuroreceptor Binding: Results from PET and SPECT Neuroreceptor Imaging Studies
		6.1	 Introduction
		6.2	 Serotonin
			6.2.1	 The Serotonin Transporter
			6.2.2	 Serotonin Transporter Gene-Linked Polymorphic Region (5-HTTLPR)
			6.2.3	 Effects of 5-HTTLPR on Serotonin Transporter Binding
			6.2.4	 Serotonin 2A Receptor Polymorphisms
			6.2.5	 Brain-Derived Neurotrophic Factor (BDNF) Polymorphisms (Val66Met)
			6.2.6	 The Serotonin 1A Receptor
			6.2.7	 The Serotonin 4 Receptor
			6.2.8	 The Serotonin 2C Receptor
		6.3	 Dopamine
			6.3.1	 Dopamine D2/3 Receptors
			6.3.2	 The Dopamine Transporter
			6.3.3	 Measuring Dopamine Transporter Function
		6.4	 Other Polymorphisms
			6.4.1	 The Catechol-O-methyltransferase Val158Met Polymorphism
			6.4.2	 Monoamine Oxidase A
			6.4.3	 18-kD Translocator Protein
			6.4.4	 Translocase of Outer Mitochondrial Membrane 40 (TOMM40)
			6.4.5	 AKT1
		6.5	 Summary and Outlook
		References
Part II: Systems
	7: PET Imaging of Acetylcholinesterase
		7.1	 Introduction
		7.2	 PET Radiotracers for Acetylcholinesterase
			7.2.1	 Cholinesterase Inhibitors
			7.2.2	 Acetylcholine Analogue Substrates
				7.2.2.1	 Carbon-11-Labeled Compounds
				7.2.2.2	 Kinetics Analysis of [11C]MP4A and [11C]PMP
				7.2.2.3	 Fluorine-18-Labeled Compounds
		7.3	 Clinical Applications of Acetylcholinesterase Imaging
			7.3.1	 Healthy Older Adults
			7.3.2	 Alzheimer’s Disease and Related Disorders
			7.3.3	 Parkinson’s Disease and Related Disorders
			7.3.4	 Other Disorders
		7.4	 Conclusions
		References
	8: Imaging of Adenosine Receptors
		8.1	 Introduction
		8.2	 A1 Adenosine Receptor Ligands
		8.3	 A2A Adenosine Receptor Ligands
		8.4	 A2B Adenosine Receptor
		8.5	 A3 Adenosine Receptor
		8.6	 Conclusion
		References
	9: Imaging of Central Benzodiazepine Receptors in Chronic Cerebral Ischemia
		9.1	 Introduction
			9.1.1	 Chronic Hemodynamic Compromise and Risk for Stroke
			9.1.2	 Selective Neuronal Damage/Loss or Incomplete Infarction
		9.2	 Imaging of Central-Type Benzodiazepine Receptors
		9.3	 Pathophysiology of Selective Neuronal Damage Demonstrated as Decreased BZR
			9.3.1	 Selective Neuronal Damage and Chronic Hemodynamic Cerebral Ischemia
			9.3.2	 Selective Neuronal Damage and Low-Flow Infarction
			9.3.3	 Selective Neuronal Damage and Misery Perfusion
				9.3.3.1	 A Cross-Sectional Study
				9.3.3.2	 Follow-Up Study
		9.4	 Silent Cortical Neuronal Damage in Asymptomatic Patients
		9.5	 Clinical Impact of Selective Neuronal Damage: Cognitive Impairment
		9.6	 Selective Neuronal Damage as Outcome Measures
			9.6.1	 Vascular Reconstruction Surgery
			9.6.2	 Blood Pressure Control
		9.7	 Conclusions
		References
	10: PET Imaging of Cyclooxygenases in Neuroinflammation
		10.1	 Introduction
			10.1.1	 Neuroinflammation
			10.1.2	 Cyclooxygenases, Neuroinflammation, and Neurodegenerative Diseases
		10.2	 PET Imaging Agents for COX-1
			10.2.1	 [11C]Ketoprofen Methyl Ester
				10.2.1.1	 [11C](1,5-bis(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H -1,2,4 triazoles ([11C]PS13, [11C]PS1, [2H2,18F]PS2, and [11C]PS13)
		10.3	 PET Imaging Agents for COX-2
			10.3.1	 (6-[11C]Methoxy-2-(4-(methylsulfonyl)phenyl)-N-(thiophen-2-ylmethyl)-pyrimidin-4-amine ([11C]MC1)
				10.3.1.1	 [1-(4-Fluorophenyl)-3-(2-[11C]methoxyethyl)-2-methyl-5-(4-(methylsulfonil)phenyl)-1H-pyrrole] (11C-VA426)
				10.3.1.2	 4-(5-([11C]Methoxymethyl)-3-phenylisoxazol-4-yl)benzenesulfonamide ([11C]MOV)
		10.4	 Summary and Conclusion
		References
	11: PET and SPECT Imaging of the Central Dopamine System in Humans
		11.1	 Introduction
		11.2	 Imaging of the Presynaptic Dopamine System
			11.2.1	 [18F]FDOPA and [18F]FMT
			11.2.2	 Imaging of the VMAT-2
			11.2.3	 Imaging of the Dopamine Transporter
		11.3	 Imaging of the Postsynaptic Dopaminergic System
			11.3.1	 Imaging of Dopamine D1 Receptors
			11.3.2	 Imaging of Dopamine D2-Like Receptors
				11.3.2.1	 Dopamine D2/3 Receptor Imaging
				11.3.2.2	 Dopamine D4 Receptor Imaging
		11.4	 Conclusion
		References
	12: PET Imaging of the Endocannabinoid System
		12.1	 Introduction
			12.1.1	 Endocannabinoid System
			12.1.2 Physiology of the Endocannabinoid System
			12.1.3 Pharmacology of the Endocannabinoid System
			12.1.4 Special Considerations for Radioligand Development and PET Imaging of the Endocannabinoid System
				12.1.4.1	 Radioligand Requirements
				12.1.4.2	 Binding Site Density and the Radioligand Binding Affinity
		12.2	 Imaging of CB1 Receptors
			12.2.1 Initial CB1 Radioligands and Imaging Studies
				12.2.1.1	 (−)-5′-[18F]-Δ8-THC
				12.2.1.2	 Radiolabeled CB1 Antagonists, Derivatives of SR141716 (Rimonabant)
				12.2.1.3	 Radiolabeled Aminoalkylindole Derivatives and Structurally Related Compounds
			12.2.2 Current CB1 Receptor Radioligands for Human PET Imaging
				12.2.2.1	 [11C]OMAR ([11C]JHU75528)
				12.2.2.2	 [18F]MK-9470
				12.2.2.3	 [11C]MePPEP and [18F]FMPEP-d2
				12.2.2.4	 [11C]SD5024
			12.2.3 Considerations in Imaging CB1 Receptors and Its Interpretation
		12.3	 CB1 Receptor Imaging in Neuropsychiatric Disorders
			12.3.1	 Substance-Use Disorders
				12.3.1.1	 Cannabis-Use Disorder
				12.3.1.2	 Alcohol-Use Disorder
				12.3.1.3	 Tobacco Use and Nicotine Exposure
			12.3.2 Eating and Metabolic Disorders
			12.3.3 Schizophrenia
			12.3.4 Mood and Anxiety Disorders
			12.3.5 Neurodegenerative Diseases
				12.3.5.1	 Alzheimer’s Disease
				12.3.5.2	 Huntington’s Disease
				12.3.5.3	 Parkinson’s Disease
				12.3.5.4	 Multiple Sclerosis
				12.3.5.5	 Amyotrophic Lateral Sclerosis
			12.3.6 Pain and Migraine
			12.3.7 Epilepsy
			12.3.8 Stroke
			12.3.9 Non-CNS Applications
			12.3.10 Considerations and Conclusions on the Use of Current CB1 Receptor PET Radioligands
		12.4	 Imaging of CB2
			12.4.1 Development of First-Generation CB2 Radioligands
			12.4.2 Update of CB2 PET Tracer Development
			12.4.3 CB2 Imaging Studies
			12.4.4 Potential Clinical Application of CB2 Imaging
		12.5	 Imaging of FAAH
			12.5.1 Tissue-Trapped FAAH Substrates
			12.5.2 Irreversible FAAH Inhibitors
			12.5.3 Reversible FAAH Inhibitors
		12.6	 Imaging of MAGL
		12.7	 Imaging of TRPV1
		12.8	 Conclusion and Future Directions
		References
	13: Current Radioligands for the PET Imaging of Metabotropic Glutamate Receptors
		13.1	 Introduction
			13.1.1	 Gutamate Receptors
			13.1.2	 PET
			13.1.3	 General Requirements for CNS Radiotracers
				13.1.3.1	 High Affinity and Selectivity
				13.1.3.2	 Concentration of Target Sites (Bmax)
				13.1.3.3	 BBB Permeability
				13.1.3.4	 In Vivo Stability
				13.1.3.5	 Efficient Radiosynthesis
		13.2	 MGluR1 PET Tracers
			13.2.1	 11C-Labeled mGluR1 Tracers
			13.2.2	 18F-Labeled mGluR1 Tracers
				13.2.2.1	 18F-Labeled Triazole Analogues
				13.2.2.2	 18F-Labeled Thiazole Analogues
				13.2.2.3	 [18F]cEFQ
		13.3	 mGluR2/3 PET Tracers
		13.4	 mGluR4 PET Tracers
		13.5	 mGluR5 PET Tracers
			13.5.1	 MPEP-Derived mGluR5 Tracers
			13.5.2	 MTEP-Derived mGluR5 Tracers
			13.5.3	 ABP688-Related mGluR5 Tracers
			13.5.4	 Other Type of mGluR5 Radioligands Without Alkyne Moiety in MPEP
		13.6	 Application of mGluR Tracers
		References
	14: PET and SPECT Imaging of Steroid Hormone Receptors in the Brain
		14.1	 Introduction
		14.2	 Steroid Hormones and Their Receptors in Brain Disorders
			14.2.1	 Estrogens in Brain Disorders
			14.2.2	 Progestins in Brain Disorders
			14.2.3	 Androgens in Brain Disorders
			14.2.4	 Corticosteroids in Brain Disorders
		14.3	 Radiopharmaceuticals for Imaging of Steroid Hormone Receptors
			14.3.1	 Estrogen Receptor Imaging
				14.3.1.1	 PET Tracers for Estrogen Receptors
				14.3.1.2	 SPECT Tracers for Estrogen Receptors
			14.3.2	 Progesterone Receptor Imaging
				14.3.2.1	 PET Tracers for Progesterone Receptors
				14.3.2.2	 SPECT Tracers for Progesterone Receptors
			14.3.3	 Androgen Receptor Imaging
				14.3.3.1	 PET Tracers for Androgen Receptors
				14.3.3.2	 SPECT Tracers for Androgen Receptors
		14.4	 Corticoid Receptor Imaging
			14.4.1	 PET Tracers for Glucocorticoid Receptors
			14.4.2	 PET Tracers for Mineralocorticoid Receptors
		14.5	 Imaging of Steroid Hormone Receptors in the Brain
			14.5.1	 Imaging of Estrogen Receptors in the Brain
			14.5.2	 Imaging of Other Hormone Receptors in the Brain
		14.6	 Conclusion and Perspectives
		References
	15: PET Imaging of Monoamine Oxidase B
		15.1	 Neurobiology and Clinical Relevance of MAO-B
			15.1.1	 Neurobiology of MAO-B
			15.1.2	 Molecular Neuroanatomy of MAO-B
			15.1.3	 MAO-B as Therapeutic Target
		15.2	 Requirements to Develop PET Tracers for Imaging MAO-B
		15.3	 Development and Pharmacokinetic Characterization of MAO-B PET Tracers
			15.3.1	 Tracers with Irreversible Binding Kinetics
				15.3.1.1	 Carbon-11-Labelled Tracers
				15.3.1.2	 Fluorine-18-Labelled Tracers
			15.3.2	 Tracers with Reversible Binding Kinetics
				15.3.2.1	 Carbon-11-Labelled Tracers
				15.3.2.2	 Fluorine-18-Labelled Tracers
		15.4	 In Vitro Molecular Imaging of MAO-B by Autoradiography
		15.5	 Applications of In Vivo PET Imaging of MAO-B in Health and Disease
			15.5.1	 Aging
			15.5.2	 Effects of Smoking
			15.5.3	 Neuroinflammation in Neurodegenerative Diseases
			15.5.4	 Neuroinflammation in Other Neurological Diseases
			15.5.5	 Depression
			15.5.6	 Evaluation of Clinical Trials of MAO-B Inhibitors
		15.6	 Conclusions and Future Prospects
		References
	16: Attempts to Image MRP1 Function in the Blood-Brain Barrier Using the Metabolite Extrusion Method
		16.1	 Introduction
		16.2	 Metabolite Extrusion Method (MEM)
			16.2.1	 Concept of the MEM
			16.2.2	 Design of a Protracer and Tracer for Imaging MRP1 Activity
			16.2.3	 Imaging of MRP1 Activity in the Brain Using 6-Bromo-7-[11C]Methylpurine
			16.2.4	 MRP1 Imaging in Peripheral Tissues Using 6-Bromo-7-[11C]Methylpurine
		16.3	 Other Potential Tracers or Probes for the Imaging of MRP1, MRP2, and MRP4
		16.4	 Feasibility of MRP1 Imaging in the Blood-Brain Barrier
			16.4.1	 Type of Protracer
			16.4.2	 MRP1 at the Blood-Brain Barrier Versus Brain Parenchymal Cells
			16.4.3	 Involvement of MRP4 and OAT3 in the Efflux of S-(7-[11C]Methylpurin-6-Yl)Glutathione
			16.4.4	 The Efflux Process Via Mrp1 Is Not the Rate-Limiting Step in the Mouse Brain
		16.5	 Application of the MEM to Other Efflux Transporters
		16.6	 Conclusions and Perspectives
		References
	17: Neuroinflammation: From Target Selection to Preclinical and Clinical Studies
		17.1	 Introduction
		17.2	 Basic Principles of Neuroinflammation
		17.3	 Potential Imaging Targets
			17.3.1	 DAMPs
			17.3.2	 Chemokines
			17.3.3	 Microglia/Macrophages
			17.3.4	 Lymphocytes
			17.3.5	 Astrocytes
			17.3.6	 Target Considerations
			17.3.7	 Tracer Considerations
		17.4	 Preclinical Imaging and Clinical Imaging in Neurological Diseases
		17.5	 From Ex Vivo Validation to First-in-Man Studies: The Story of [18F]DPA-714
		17.6	 Conclusions
		References
	18: Preclinical and Clinical Aspects of Nicotinic Acetylcholine Receptor Imaging
		18.1	 Introduction
		18.2	 Advances in Animal PET and SPECT Technology
		18.3	 PET and SPECT Radioligands Targeting nAChR
			18.3.1	 Radioligands for α4β2 nAChRs
				18.3.1.1	 Nicotine Derivatives
				18.3.1.2	 Cytisine Derivatives
				18.3.1.3	 Epibatidine Derivatives
				18.3.1.4	 3-Pyridyl Ethers
				18.3.1.5	 Non-Epibatidine-and-Non-A-85380-Related Compounds
			18.3.2	 Imaging of Heteromeric β4-Containing nAChR Subtype
			18.3.3	 Radioligands for α7 nAChRs
				18.3.3.1	 Quinuclidine-Based Ligands
				18.3.3.2	 GTS-21
				18.3.3.3	 Diazabicyclononane Derivatives
				18.3.3.4	 [11C]A-582941 and [11C]A-844606
				18.3.3.5	 [125I]I-TSA
				18.3.3.6	 R-[11C]MeQAA
			18.3.4	 Radioligands for α3β4 nAChRs
		18.4	 nAChR Imaging of Neurodegenerative Diseases
			18.4.1	 Alzheimer’s Disease
			18.4.2	 Movement Disorders
		18.5	 Epilepsy
		18.6	 nAChR Imaging of Stroke and Neuroinflammation
		18.7	 nAChR Imaging of Traumatic Brain Injury
			18.7.1	 Animal Models of TBI
			18.7.2	 Human TBI Studies
		18.8	 nAChR Imaging of Addiction and Psychiatric Disorders
			18.8.1	 Physiological Effects of Nicotine in the Context of Addiction
			18.8.2	 Alcohol Dependence
			18.8.3	 Schizophrenia and Depression
		18.9	 nAChR Imaging for Measurement of Endogenous Acetylcholine
		18.10	 Conclusion
		References
	19: Development of PET and SPECT Radioligands for In Vivo Imaging of NMDA Receptors
		19.1	 Introduction
			19.1.1	 Radioligands for PCP-Binding Site
				19.1.1.1	 Dissociative Anesthetic Derivatives
					PCP and TCP Derivatives
					MK-801 Derivatives
					[11C]Ketamine
					Memantine Derivatives
				19.1.1.2	 Diarylguanidine Derivatives
				19.1.1.3	 Other Open Channel Blocker Derivatives
			19.1.2	 Radioligands for Glutamate-Binding Site
			19.1.3	 Radioligands for Glycine-Binding Site
				19.1.3.1	 Radioligands Based on Cyclic Amino Acids
				19.1.3.2	 5-Aminomethylquinoxaline-2,3-Dione Derivative
				19.1.3.3	 4-Hydroxyquinolone Derivatives
			19.1.4	 Development of Radioligands for Ifenprodil-Binding Site
				19.1.4.1	 Ifenprodil Derivatives
				19.1.4.2	 Non-ifenprodil-Related GluN2B Antagonist Derivatives
			19.1.5	 Conclusion and Perspectives
		References
	20: Progress in PET Imaging of the Norepinephrine Transporter System
		20.1	 Introduction
		20.2	 Challenges in NET Imaging of the Brain
			20.2.1	 NET Has a Relatively Low Density in the Brain
			20.2.2	 NET Has a Widespread Distribution in the Brain
			20.2.3	 NET Has a Lower Contrast Between NET-Poor and NET-Rich Regions
			20.2.4	 The Locus Coeruleus (LC), the Highest NET Density Region, Has a Small Structure That Makes It Difficult to Be Delineated and Quantitated
		20.3	 Translational PET Imaging Studies of NET
			20.3.1	 NET Imaging in Substance Abuse
				20.3.1.1	 NET Abnormalities in Cocaine Dependence
				20.3.1.2	 Duration of Abstinence Effect on NET Binding
			20.3.2	 NET Imaging in ADHD
				20.3.2.1	 ATX Occupancy Study on NET in Humans and Nonhuman Primates
				20.3.2.2	 ATX Occupancy Study on SERT: Implications for Treatment of Depression and ADHD
				20.3.2.3	 Summary of the Comparative Occupancy Studies of ATX for NET (Using [11C]MRB) and SERT (Using [11C]AFM)
				20.3.2.4	 The Mechanisms of Action of ATX in ADHD and Depression
				20.3.2.5	 MPH Occupancy Study on NET in Humans
			20.3.3	 NET Imaging in PTSD
			20.3.4	 NET Imaging in Alcohol Dependence
			20.3.5	 NET Imaging in Brown Adipose Tissue (Brown Fat)
				20.3.5.1	 Novel Strategy to Imaging BAT in the Basal State Using NET-[11C]MRB: Preclinical Evaluation
				20.3.5.2	 Novel Strategy to Imaging BAT in the Basal State Using NET-[11C]MRB in Humans
			20.3.6	 NET Imaging in Obesity
				20.3.6.1	 Linking NET to Emotional Distress and Obesity
				20.3.6.2	 Central In Vivo NET Availability Is Altered in Emotional Eating of Individuals with Obesity
				20.3.6.3	 NET Availability and Success of Weight Loss in Obese Individuals
			20.3.7	 NET in Parkinson’s Disease (PD)
			20.3.8	 NET in Aging and Alzheimer’s Disease (AD)
			20.3.9	 Kinetic Modeling for NET Imaging Studies in the Brain
		20.4	 Summary and Outlook
		References
	21: Positron Emission Tomography (PET) Imaging of Opioid Receptors
		21.1	 Introduction
		21.2	 Opioid Receptor Ligands for PET: A Historical Overview
		21.3	 Characteristics of Widely Used Radioligands
			21.3.1	 Cyclofoxy
			21.3.2	 CFN (Fig. 21.1)
			21.3.3	 DPN (Fig. 21.1)
			21.3.4	 MeNTI
			21.3.5	 GR103545
			21.3.6	 LY2795050
			21.3.7	 LY2459989
		21.4	 PET Studies in Healthy Volunteers
			21.4.1	 Influence of Gender, Hormonal Status, and Age
			21.4.2	 Feeding
			21.4.3	 Personality Traits
			21.4.4	 Affective Responses
			21.4.5	 Physical Exercise
			21.4.6	 Pain
			21.4.7	 Vestibular Processing
			21.4.8	 Myocardial Opioid Receptors
			21.4.9	 Occupancy Studies
		21.5	 PET Studies in Patients and Drug Addicts
			21.5.1	 Major Depressive, Borderline Personality, and Posttraumatic Stress Disorder
			21.5.2	 Pain
			21.5.3	 Pain Treatment
			21.5.4	 Substance Abuse
				21.5.4.1	 Cocaine Dependence
				21.5.4.2	 Opioid Dependence
				21.5.4.3	 Alcohol Dependence
				21.5.4.4	 Nicotine Dependence
			21.5.5	 Eating Disorders
			21.5.6	 Obesity
			21.5.7	 Epilepsy
			21.5.8	 Neurodegenerative Diseases
				21.5.8.1	 Huntington’s Disease
				21.5.8.2	 Alzheimer Disease
				21.5.8.3	 Parkinson Disease and Related Disorders
			21.5.9	 Opioid Receptor Expression in Lung Tumors
		21.6	 Conclusion
		References
	22: PET Imaging of ABC Transporters at the Blood-Brain Barrier
		22.1	 ABC Transporter Expression at the Blood-Brain Barrier in Neurological Diseases
			22.1.1	 Blood-Brain Barrier
			22.1.2	 ABC Transporters
			22.1.3	 P-Glycoprotein
			22.1.4	 BCRP
				22.1.4.1	 MRP Family and MRP1
				22.1.4.2	 Alzheimer’s Disease
				22.1.4.3	 Parkinson’s Disease
				22.1.4.4	 Epilepsy and Antiepileptic Drugs
				22.1.4.5	 Ischemic Stroke
				22.1.4.6	 Aging
				22.1.4.7	 Polymorphism, Genotyping, and Individualized Medicine
				22.1.4.8	 Drug Resistance and ABC Transporters
		22.2	 Mechanism of Action of ABC Transporter-Binding Substances
		22.3	 Use of P-gp Modulators to Treat Drug Resistance, Neurological Disorders, and Other Conditions
			22.3.1	 P-gp Inhibitors and Drug Resistance
			22.3.2	 P-gp Inducers and Activators to Treat Neurodegenerative Disease and Intoxications
		22.4	 PET
		22.5	 PET Tracers for Imaging of ABC Transporter Function and Expression in the BBB: Background
		22.6	 Substrates as Tracers for Measuring P-gp Function
			22.6.1	 Strong Substrates (Fig. 22.2)
				22.6.1.1	 [11C]Verapamil
				22.6.1.2	 [11C]N-Desmethyl-Loperamide
				22.6.1.3	 Fluorine-18 Verapamil Analogs
				22.6.1.4	 [18F]MPPF
			22.6.2	 Weak P-gp Substrates (Fig. 22.3)
				22.6.2.1	 [11C]Phenytoin
				22.6.2.2	 [11C]Emopamil
				22.6.2.3	 [18F]MC225
				22.6.2.4	 [11C]Metoclopramide
		22.7	 P-gp Inhibitors as Tracers for Measuring P-gp Expression
			22.7.1	 [11C]Elacridar, [11C]Tariquidar, and [11C]Laniquidar
			22.7.2	 [18F]Fluoroelacridar, [18F]Fluoroethlyelacridar, and [18F]Fluoroethyltariquidar
			22.7.3	 Novel P-gp Inhibitors as PET Tracers
		22.8	 Kinetic Modeling of the P-gp Function
		22.9	 The Use of P-gp Tracers and PET to Assess Brain Disorders in Humans
		22.10	 The Use of P-gp Tracers to Evaluate the Clinical Implications of Drug-Drug Interaction
		22.11	 Discussion and Concluding Remarks
		References
	23: PET Imaging of Phosphodiesterases in Brain
		23.1	 Introduction Phosphodiesterases
			23.1.1	 Drugs Targeting PDEs
		23.2	 PET Studies Targeting Phosphodiesterases
			23.2.1	 PDE1
			23.2.2	 PDE2A
			23.2.3	 PDE4
			23.2.4	 PDE5
			23.2.5	 PDE7
			23.2.6	 PDE9
			23.2.7	 PDE10A
		23.3	 Conclusions
		References
	24: PET Imaging of Purinergic Receptors
		24.1	 Introduction
		24.2	 The P2X4 Receptor
		24.3	 The P2X7 Receptor
		24.4	 The P2Y1 Receptor
		24.5	 The P2Y12 Receptor
		24.6	 Concluding Remarks
		References
	25: Imaging of the Serotonin System: Radiotracers and Applications in Memory Disorders
		25.1	 Introduction
			25.1.1 5-HT Targets for PET and SPECT
		25.2	 Current Radioligands for In Vivo Brain Imaging of the 5-HT System
			25.2.1 5-HT1A Receptor
			25.2.2 5-HT1B Receptor
			25.2.3 5-HT2A Receptor
			25.2.4 5-HT2B and 5-HT2C Receptors
			25.2.5 5-HT3 Receptors
			25.2.6 5-HT4 Receptors
			25.2.7 5-HT5 Receptors
			25.2.8 5-HT6 Receptors
			25.2.9 5-HT7 Receptors
			25.2.10 SERT
		25.3	 PET Imaging of the Serotonergic System in Alzheimer’s Disease
			25.3.1 5-HT1A Receptor Binding in AD
			25.3.2 5-HT2A Receptor Binding in AD
			25.3.3 5-HT4 Receptor Binding in AD
			25.3.4 5-HT6 Receptor Binding in AD
			25.3.5 SERT Binding in AD
		25.4	 Can Serotonergic Dysfunction Explain AD Symptomatology?
		References
	26: Monoamine Oxidase A and Serotonin Transporter Imaging with Positron Emission Tomography
		26.1	 Why Image Indices of Monoamine Oxidase A Density?
		26.2	 Radioligands Available for Neuroimaging Monoamine Oxidase A
		26.3	 Major Depressive Disorder
		26.4	 Early Postpartum and Perimenopause
		26.5	 Cigarette Smoking
		26.6	 Alcohol Dependence (AD)
			26.6.1	 Aggression
		26.7	 Monoamine Oxidase A Occupancy
		26.8	 Why Image Indices of Serotonin Transporter Density?
		26.9	 Radioligands Available for Imaging Serotonin Transporters
		26.10	 Developing New Antidepressants with Serotonin Transporter Neuroimaging
		26.11	 Major Depressive Disorder
		26.12	 Ecstasy Abuse and Serotonin Transporter Imaging
		26.13	 Obsessive Compulsive Disorder
		26.14	 Season and Serotonin Transporter Imaging
		26.15	 Conclusions
		References
	27: PET Imaging of Sigma1 Receptors
		27.1	 Introduction
		27.2	 Brain Imaging of Sigma Receptors
			27.2.1	 Post-mortem Studies
			27.2.2	 Radioligands for Imaging of Sigma Receptors
			27.2.3	 PET Imaging of the Sigma1 Receptors in the Human Brain
				27.2.3.1	 Healthy Subjects
				27.2.3.2	 Kinetic Analysis
				27.2.3.3	 CNS Disease
				27.2.3.4	 Measurement of Sigma1 Receptor Occupancy in the Human Brain
		27.3	 Sigma Receptors in CNS Diseases
			27.3.1	 Schizophrenia
			27.3.2	 Mood Disorders
			27.3.3	 Ischemia
			27.3.4	 Neurodegenerative Diseases
			27.3.5	 Drug Addiction and Alcoholism
		27.4	 Conclusion
		References
	28: Sigma-2 Receptors: An Emerging Target for CNS PET Imaging Studies
		28.1	 Introduction
		28.2	 Pharmacological and Molecular Characterization of the σ2 Receptor
			28.2.1	 In Vitro Binding Studies
			28.2.2	 Microscopy Studies
		28.3	 Identification of the σ2 Receptor and Its Putative Biological Function
			28.3.1	 Progesterone Receptor Membrane Component 1 (PGRMC1)
			28.3.2	 Identification of the Gene Encoding the σ2 Receptor
			28.3.3	 The Role of the σ2 Receptor in Cholesterol Trafficking
		28.4	 Role of the σ2 Receptor in the CNS
			28.4.1	 Pharmacological Studies
			28.4.2	 Autoradiography Studies
			28.4.3	 PET Radiotracers for Imaging the σ2 Receptor
		28.5	 Conclusions and Perspectives
		References
	29: PET Imaging of Synaptic Vesicle Protein 2A
		29.1	 Synaptic Vesicle Protein 2
		29.2	 Development of SV2A PET Radioligands
		29.3	 SV2A as a Biomarker of Synaptic Density
		29.4	 Quantification of SV2A PET Radioligands
		29.5	 PET Studies in Disease Populations
			29.5.1	 Epilepsy
			29.5.2	 Alzheimer’s Disease and Other Dementias
			29.5.3	 Parkinson’s Disease
			29.5.4	 Major Depressive Disorder
			29.5.5	 Schizophrenia
		29.6	 Future Considerations
		References
	30: PET Imaging of Translocator Protein Expression in Neurological Disorders
		30.1	 Introduction
		30.2	 Imaging TSPO with PET
		30.3	 TSPO Imaging in Alzheimer’s Disease
		30.4	 Imaging Inflammation in Frontotemporal Dementia and ALS
		30.5	 Parkinson’s Disease and TSPO Imaging
		30.6	 Atypical Parkinsonian Syndromes and TSPO Imaging
		30.7	 Detecting Preclinical Huntington’s Disease Activity with TSPO PET
		30.8	 Measuring Inflammation in Multiple Sclerosis
		30.9	 Traumatic Brain Injury
		30.10	 Stroke and Microglial Activation
		30.11	 Psychosis
		30.12	 Conclusions
		References
	31: Toward Imaging Tropomyosin Receptor Kinase (Trk) with Positron Emission Tomography
		31.1	 The Role of Trk in Neurology and Oncology
		31.2	 The History of Trk Radioligand Development
			31.2.1	 Positron Emission Tomography
			31.2.2	 The Tropomyosin Receptor and Its Targets: Extra- Vs. Intracellular Target Engagement
				31.2.2.1	 Radioligands for Brain Imaging: General Considerations
				31.2.2.2	 Radioligands Based on the 4-Aza-2-Oxindole Scaffold
				31.2.2.3	 Type-II Trk Inhibitors: 2,4-Diamionopyrimidine and Quinazoline-Derived Radiotracers
				31.2.2.4	 Toward Clinical Application: Synthesis of Imidazo[1,2-b]Pyridazine-Related Radioligands
		31.3	 Conclusion
		References
	32: Radioligand Development for PET Imaging of the Vesicular Acetylcholine Transporter (VAChT) in the Brain
		32.1	 Introduction
			32.1.1	 The Vesicular Acetylcholine Transporter
			32.1.2	 Vesamicol as Basis for the Development of Ligands Targeting the VAChT
			32.1.3	 Considerations on Binding Affinity Data for VAChT Obtained In Vitro
		32.2	 Fluorine-18- and Carbon-11-Labeled PET Radioligands for Imaging the VAChT
			32.2.1	 Vesamicol-Based PET Radioligands
			32.2.2	 Trozamicol-Based PET Radioligands
			32.2.3	 Benzovesamicol-Based PET Radioligands
			32.2.4	 Morpholinovesamicols
			32.2.5	 Other Vesamicol Analogs
		32.3	 The Use of (−)-[123/125]Iodobenzovesamicol as SPECT Imaging Agent for VAChT
		32.4	 Summary and Conclusion
		References
	33: PET Imaging of Vesicular Monoamine Transporters
		33.1	 Introduction
		33.2	 Biology and Pharmacology of the Vesicular Monoamine Transporter Type 2
			33.2.1	 Molecular Biology of the VMAT2
			33.2.2	 Localization of the VMAT2 in Mammalian Brain
			33.2.3	 VMAT2 Substrates and Inhibitors
		33.3	 VMAT2 Radioligands for Autoradiography
			33.3.1	 [3H]Tetrabenazine ([3H]TBZ)
			33.3.2	 α-[3H]Dihydrotetrabenazine ([3H]DTBZ)
			33.3.3	 (±)-[3H]Methoxytetrabenazine ([3H]MTBZ)
			33.3.4	 [3H]/[125I]Reserpine
			33.3.5	 Radioiodinated Tetrabenazines
			33.3.6	 Ketanserin Derivatives
		33.4	 VMAT2 Radioligands for PET Imaging Studies
			33.4.1	 [11C]Tetrabenazine ([11C]TBZ)
			33.4.2	 (±)-α-(9-O-[11C]Methyl)Dihydrotetrabenazine ([11C]DTBZ)
			33.4.3	 2-(O-[11C]Methyl)Dihydrotetrabenazine ([11C]MTBZ)
			33.4.4	 (+)-α-(9-O-[11C]Methyl)Dihydrotetrabenazine ((+)-α-[11C]DTBZ)
			33.4.5	 (+)-α-(10-O-[11C]Methyl)Dihydrotetrabenazine
			33.4.6	 Copper-64 Labeled Dihydrotetrabenazine
			33.4.7	 Fluorine-18 Labeled Dihydrotetrabenazines
		33.5	 Evaluation of VMAT2 Imaging Radioligands in Animals
			33.5.1	 Mouse Brain VMAT2 Studies
			33.5.2	 Rat Brain VMAT2 Studies
			33.5.3	 VMAT2 Radioligand Studies in Non-human Primates
		33.6	 Applications of VMAT2 Radioligands in Human Imaging Studies
			33.6.1	 Pharmacokinetic Studies of VMAT2 Radioligands in Normal Brain
			33.6.2	 Aging
			33.6.3	 Parkinson’s Disease
			33.6.4	 Non-Parkinson Movement Disorders
			33.6.5	 Huntington’s Disease
			33.6.6	 Dementia
			33.6.7	 Genetic Diseases
			33.6.8	 Environmental Toxins
			33.6.9	 Psychiatric Disease
			33.6.10 Drug Abuse
		33.7	 Conclusions
		References