Molecular Imaging and Targeted Therapy: Radiopharmaceuticals and Clinical Applications

Foreword to the First Edition
Foreword to the Second Edition
Preface to the First Edition
Preface to the Second Edition
Contents
About the Author
1: Molecular Imaging and Targeted Radionuclide Therapy: Introduction
1.1 Nuclear Medicine
1.2 Molecular Medicine
1.3 Molecular Imaging
1.3.1 Definitions
1.3.2 Molecular Imaging Technologies
1.3.2.1 Magnetic Resonance Imaging
1.3.2.2 Optical Imaging
1.3.2.3 Ultrasound Imaging
1.3.2.4 PET and SPECT
1.3.2.5 Multimodality Molecular Imaging
1.4 Radiation Therapy
1.4.1 Targeted Radionuclide Therapy (TRT)
1.4.2 Personalized Medicine and Theranostics
1.5 Summary
References
2: Science of Atomism: A Brief History
2.1 Atomism
2.2 Chemical Elements
2.2.1 Chemical Laws
2.2.2 Atomic Theory
2.3 Electricity and Magnetism
2.3.1 Electrolysis
2.3.2 Electromagnetism
2.4 Thermodynamics
2.4.1 Heat, Energy, and Temperature
2.4.2 Emission of Light
2.5 Major Discoveries
2.5.1 Cathode Rays
2.5.2 X-Rays
2.5.3 Electron
2.5.4 Radioactivity
2.5.5 Light Quantum
2.6 Reality of Atoms
2.6.1 Avogadro’s Number
2.6.2 Brownian Motion
2.7 Atomic Structure
2.7.1 Nuclear Atom
2.7.2 Bohr’s Model of Atom
2.7.3 Isotopes
2.7.4 Quantum Atom
2.7.5 Discovery of Antimatter
2.8 The Elementary Particles
Further Reading
3: Atoms and Radiation
3.1 Matter and Energy
3.1.1 Mass–Energy Relationship
3.2 Radiation
3.2.1 Electromagnetic Radiation
3.3 Classification of Matter
3.3.1 Chemical Element
3.4 Atoms
3.4.1 Atomic Structure
3.4.2 The Bohr Model of an Atom
3.4.2.1 Electron Binding Energy
3.5 Nuclear Structure
3.5.1 Composition and Nuclear Families
3.5.2 Nuclear Binding Energy
3.5.3 Nuclear Stability
3.6 Atomic and Nuclear Emissions
3.6.1 Emissions from Electron Shells
3.6.1.1 X-rays
3.6.1.2 Characteristic X-rays
3.6.1.3 Auger Electrons
3.6.2 Nuclear Emissions
3.6.2.1 Gamma Rays and Subatomic Particles
3.6.2.2 Internal Conversion
Further Reading
4: Radioactivity
4.1 The Discovery
4.2 Nuclear Disintegration
4.2.1 Types of Radioactive Decay
4.2.1.1 Alpha (α) Decay
4.2.1.2 Beta (β−) Decay
4.2.1.3 Positron (β+) Decay
4.2.1.4 Electron Capture (EC)
4.2.1.5 Isomeric Transition (IT)
4.2.1.6 Multiple Decay Mode
4.2.2 Radioactive Decay Series
4.2.3 Nuclear Fission
4.3 Radioactive Decay Equations
4.3.1 Exponential Decay
4.3.2 Units of Activity
4.3.3 Half-Life and Average Lifetime
4.3.4 Specific Activity
4.3.5 Serial Radioactive Decay
4.3.5.1 Secular Equilibrium
4.3.5.2 Transient Equilibrium
Further Reading
5: Radioactivity Detection: PET and SPECT Scanners
5.1 Interaction of Radiation with Matter
5.1.1 Interactions of Charged Articles
5.1.1.1 Ionization
5.1.1.2 Bremsstrahlung Radiation
5.1.1.3 Annihilation Radiation
5.1.1.4 Cerenkov Radiation
5.1.2 Interaction of High-Energy Photons
5.1.2.1 Photoelectric Effect
5.1.2.2 Compton Scattering
5.1.2.3 Pair Production
5.1.3 Attenuation
5.2 Radiation Detectors
5.2.1 Ionization Detectors
5.2.1.1 Gas-Filled Detectors
5.2.1.2 Semiconductor Detectors
5.2.2 Scintillation Detectors
5.2.2.1 Photodetectors
5.2.2.2 Radiation Detector Performance
5.3 Radionuclide Imaging Systems
5.3.1 SPECT/CT Scanner
5.3.1.1 SPECT Based on NaI(Tl) Crystal
5.3.1.2 SPECT Based on CZT Detector
5.3.1.3 Absolute Quantitation of SPECT Data
5.3.2 PET Scanners
5.3.2.1 Positron Annihilation and Coincidence Detection
Positron Range and Noncolinearity
Coincidence Event Types
5.3.2.2 Pet Scanner Design
PET Detector Crystals
Block Detector
Digital PET
5.3.2.3 PET Data Acquisition
Attenuation Correction Based on CT
2D vs. 3D PET
PET Imaging Modes
PET Scan Reconstruction Techniques
5.3.3 Small-Animal Imaging Systems
5.3.3.1 State-of-the-Art Preclinical PET Scanners
References
6: Chemistry: Basic Principles
6.1 Chemical Elements
6.1.1 Chemistry and Radioactivity
6.1.2 Periodic Table
6.1.2.1 Electronic Structure of Atom
6.1.2.2 Quantum Model of Atom
6.1.2.3 Arrangement of Electrons in Orbitals
Valence Electrons and Stable Octet
6.1.3 Chemical Bonding
6.1.3.1 Ionic or Electrovalent Bonds
6.1.3.2 Covalent Bond
Coordinate Covalent Bond
6.1.3.3 Hydrogen Bond
6.1.3.4 Electronegativity
6.1.3.5 Lewis Structures
6.1.3.6 Formulas of Compounds
6.1.3.7 Stoichiometry
The Mole
Molar Mass (Molecular Weight)
6.1.3.8 Solutions
Molarity and Normality
Volume Percent
Radioactive Concentration
6.2 Chemical Reactions
6.2.1 Types of Chemical Reactions
6.2.2 Chemical Equilibrium
6.2.2.1 Ionic Equilibria
6.2.2.2 Dissociation of Water
The pH Scale
Buffer Systems
6.3 Organic Chemistry
6.3.1 Hydrocarbons
6.3.1.1 Reactions of Hydrocarbons
Combustion Reaction
Substitution Reaction
Addition Reactions
6.3.1.2 Hydrocarbon Derivatives
6.4 Biochemistry
6.4.1 Proteins
6.4.1.1 Amino Acids
Stereochemistry of Amino Acids
Peptide Linkage
6.4.1.2 Protein Structure and Function
6.4.2 Carbohydrates
6.4.2.1 Stereochemistry of Sugars
Polysaccharides
Sugar Derivatives
6.4.3 Lipids
6.4.3.1 Fats
6.4.3.2 Phospholipids
6.4.3.3 Steroids
6.4.4 Nucleic Acids
6.4.4.1 DNA Structure
6.4.4.2 Protein Synthesis
Further Reading
7: Cell and Molecular Biology
7.1 Introduction
7.2 Cell Structure and Function
7.2.1 The Plasma Membrane
7.2.2 Cytoplasm and Its Organelles
7.2.2.1 The Endoplasmic Reticulum
7.2.2.2 The Golgi Complex
7.2.2.3 Lysosomes
7.2.2.4 Peroxisomes
7.2.2.5 Mitochondria
7.2.2.6 Ribosomes
7.2.3 Cytoskeleton
7.2.4 Nucleus
7.3 Cell Reproduction
7.3.1 The Cell Cycle
7.3.1.1 Mitosis and Cytokinesis
7.3.2 Rates of Cell Division
7.4 Cell Transformation and Differentiation
7.5 Normal Growth
7.5.1 Cell Types
7.5.2 Tissue Types
7.6 Cell-to-Cell Communication
7.6.1 Cell–Cell Interaction
7.6.2 Cell Signaling and Cellular Receptors
7.7 Transport Through the Cell Membrane
7.7.1 Diffusion
7.7.1.1 Simple Diffusion
7.7.1.2 Facilitated Diffusion
7.7.2 Active Transport
7.7.3 Transport by Vesicle Formation
7.7.4 Transmission of Electrical Impulses
7.8 Cellular Metabolism
7.8.1 Role of ATP
7.8.1.1 Production of ATP
7.8.1.2 Glycolysis
7.8.1.3 Oxidative Phosphorylation
7.9 DNA and Gene Expression
7.9.1 DNA: The Genetic Material
7.9.1.1 DNA Structure
7.9.1.2 DNA Replication
7.9.1.3 Gene Mutation
7.9.1.4 DNA Recombination
7.9.2 Gene Expression and Protein Synthesis
7.9.2.1 DNA Transcription
7.9.2.2 RNA Structure
7.9.2.3 Genetic Code
7.9.2.4 DNA Translation: Protein Synthesis
7.10 Disease and Pathophysiology
7.10.1 Homeostasis
7.10.2 Disease Definition
7.10.3 Pathophysiology
7.10.3.1 Altered Cellular and Tissue Biology
Cellular Adaptations
7.10.3.2 Cellular Injury
Biochemical Mechanisms
Intracellular Accumulations
7.10.3.3 Necrosis
7.10.3.4 Apoptosis
Further Reading
8: Production of Radionuclides
8.1 Natural Radioactivity
8.1.1 Decay Chain
8.2 Nuclear Transformation
8.2.1 Artificial Production of Radioactivity
8.2.2 Nuclear Fission
8.2.3 Nuclear Reactions
8.2.3.1 Excitation Energy and Q Value
8.2.3.2 Activation Cross Section
8.2.3.3 Activity
Saturation Yield
Specific Activity (SA)
Carrier-Free
8.3 Production of Radionuclides by Accelerators
8.3.1 Linear Particle Accelerator (LINAC)
8.3.1.1 Proton Accelerator
8.3.1.2 Electron Accelerator
8.3.2 Cyclotron
8.3.2.1 Negative Ion Cyclotron
Particle Energy
Beam Extraction
Types of Cyclotrons
8.3.3 PET Radionuclides
8.3.3.1 Oxygen-15
8.3.3.2 Nitrogen-13 and [13N]Ammonia
8.3.3.3 Carbon-11
8.3.3.4 Fluorine-18
8.3.3.5 Bromine-75 and Br-76
8.3.3.6 Iodine-124
8.3.3.7 Gallium-66 and Gallium-68
8.3.3.8 Copper-64
8.3.3.9 Yttrium-86
8.3.3.10 Zirconium-89
8.3.3.11 Scandium-44
8.3.4 SPECT Radionuclides
8.3.4.1 Gallium-67
8.3.4.2 Indium-111
8.3.4.3 Thallium-201
8.3.4.4 Iodine-123
8.3.5 Therapy Radionuclides
8.3.5.1 Astatine-211
8.3.5.2 Actinium-225
8.4 Production of Radionuclides in a Nuclear Reactor
8.4.1 Nuclear Fission
8.4.2 Radionuclides Produced by Fission
8.4.3 Radionuclides Produced by Neutron Activation
8.4.4 Beta Emitting Radionuclides for Therapy
8.4.4.1 Phosphorous-32
8.4.4.2 Iodine-131
8.4.4.3 Yttrium-90
8.4.4.4 Lutetium-177
8.4.4.5 Copper-67
8.4.4.6 Scandium-47
8.4.4.7 Strontium-89
8.4.4.8 Strontium-90
8.4.4.9 Samarium-153
8.4.4.10 Holmium-166
8.4.4.11 Rhenium-186, Re-188
8.4.4.12 Tin-117 m
8.4.4.13 Molybdenum-99
8.4.4.14 Tungsten-188
8.4.5 Alpha Emitting Radionuclides for Therapy
8.4.5.1 Radium-223
8.4.5.2 Actinium-225
8.5 Radionuclide Generators
8.5.1 Generators for SPECT/PET Imaging
8.5.1.1 99Mo→ 99mTc Generator
8.5.1.2 82Sr→ 82Rb Generator (Cardiogen®)
8.5.1.3 68Ge→ 68Ga Generator
8.5.1.4 62Zn→ 62Cu Generator
8.5.2 Generators for Radionuclide Therapy
8.5.2.1 90Sr→90Y0 Generator
8.5.2.2 188W→188Re Generator
8.5.2.3 227Ac→ 227Th→ 223Ra Generator
8.5.2.4 229Th→225Ac Generator (Thorium Cow)
8.5.2.5 225Ac→ 213Bi Generator
8.5.2.6 228Th→224Ra→ 212Pb→ 212Bi Generator
8.5.2.7 227Ac→ 227Th→ 223Ra Generator
References
9: Radiopharmaceuticals for Molecular Imaging
9.1 Radiotracer Vs. Radiopharmaceutical
9.1.1 Radiopharmaceutical Vs. Radiochemical
9.2 Radiopharmaceuticals for Molecular Imaging (RP-MI)
9.2.1 Molecular Medicine and Theranostics
9.2.2 RPMI: Categories and Types
9.2.3 Choice of Radionuclide for SPECT and PET
9.2.4 General Criteria for the Design of RP-MI
9.2.4.1 The Size of MIP
9.2.4.2 The Position of Radiolabel in the Radiotracer
Design of FDG Molecule
Design of FLT Molecule
Design of MIBG
9.2.4.3 Stereospecificity
Development of [18F]-rhPSMA-7.3
9.2.4.4 Lipophilicity
9.2.4.5 Plasma Protein Binding
9.2.4.6 Metabolism
[18F]FDOPA Metabolism
Thymidine Metabolism
Metabolism of WAY-100,635
9.2.4.7 Specific Activity
9.2.4.8 Radiopharmaceutical: Mechanism of Localization
9.2.5 General Methods of Radiolabeling
9.2.5.1 Important Factors of Radiolabeling
9.2.6 Automated Synthesis Modules
References
10: Radiohalogens for Molecular Imaging (Fluorine and Iodine)
10.1 Fluorine-18 Radiopharmaceuticals for Molecular Imaging
10.1.1 Halogens
10.2 Chemistry of 18F-Labeled Radiopharmaceuticals
10.2.1 Production of Fluorine-18
10.2.1.1 [18F]Fluoride Production Using [18O]H2O Target
10.2.1.2 18F-Labeled Precursors
10.2.2 F-18 Radiochemistry
10.2.3 Fluorination Reactions
10.2.3.1 Nucleophilic Fluorination Reactions
Nucleophilic Aliphatic Substitution
Nucleophilic Aromatic Substitution
10.2.3.2 Electrophilic Fluorination Reactions
10.2.3.3 Organic Precursors for 18F Labeling
10.2.4 Radiotracers Based on Nucleophilic Reactions
10.2.4.1 [18F]FDG
10.2.4.2 [18F]Flt
10.2.4.3 [18F]FMISO Synthesis
10.2.4.4 [18F]Fluoroestradiol (FES)
10.2.4.5 FCH Synthesis
10.2.4.6 [18F]FACBC (Fluciclovine F18, Axumin)
10.2.4.7 Florbetapir and Flutemetamol
10.2.4.8 AV-1451 (Flortaucipir, TauvidTM)
10.2.4.9 DCFPyL (Pylarify)
10.2.5 Radiotracers Based on Electrophilic Reaction
10.2.5.1 Synthesis of 6-[18F]Fluoro-l-DOPA (FDOPA)
10.2.6 F-18 Labeling of Peptides and Biomolecules
10.2.6.1 Click Chemistry for 18F Labeling
10.2.6.2 18F Labeling Based on [18F]AlF2+ Cation
10.3 Radioiodinated Radiopharmaceuticals
10.3.1 Production of 123I and 124I
10.3.2 Chemistry of Iodine and Radioiodination
10.3.2.1 Electrophilic Substitution Reaction
10.3.2.2 Nucleophilic Substitution Reaction
10.3.3 123/131I-Labeled Radiopharmaceuticals
10.3.3.1 Synthesis of [131I]MIBG (Iobenguane)
10.3.3.2 Synthesis of [123I]Ioflupane
10.3.3.3 Synthesis of Radioiodinated Peptides
References
11: Organic Radionuclides for Molecular Imaging (C, N, and O)
11.1 Advantages of Organic Radionuclides
11.2 11C-Labeled Radiopharmaceuticals
11.2.1 Production of 11C
11.2.1.1 Specific Activity (SA) of 11C
11.2.2 11C Precursors
11.2.2.1 [11C]Methylation Reaction
11.2.3 Synthesis of 11C Labeled MIPs
11.2.3.1 l-[S-Methyl-11C]Methionine
11.2.3.2 Synthesis of [O-Methyl-11C]Raclopride
11.2.3.3 Synthesis of R-[N-Methyl-11C]PK11195
11.2.3.4 [11C]PIB
11.2.3.5 Synthesis of [11C]5-Hydroxy-l-Tryptophan (HTP)
11.2.3.6 Synthesis of [11C]Choline (CHO)
11.3 13N-Labeled Radiopharmaceuticals
11.3.1 [13N]Ammonia (NH3)
11.3.2 Synthesis of [13N]Gemcitabine
11.4 15O-Labeled Radiotracers
11.4.1 15O-Labeled Gases
11.4.2 Synthesis of [15O]Water
References
12: Metal Radionuclides for Molecular Imaging
12.1 Introduction
12.2 Radiometals for PET and SPECT
12.2.1 Specific Activity of Radiometals
12.2.2 Decay Characteristics of Radiometals
12.3 Chemistry of Radiometals
12.3.1 Chelators for Metal Complexation
12.3.1.1 Chelating Agents
Acyclic Chelating Agents
Macrocyclic Chelating Agents
12.3.1.2 Stability of Metal-Chelate Complex
12.3.1.3 Bifunctional Chelating Agents
Coupling of BFC to Biomolecule
12.3.2 Chemistry of Post-transition Metals
12.3.2.1 68Ga-Labeled Radiopharmaceuticals
68Ga Generator
68Ga-DOTA-TOC
68Ga-DOTATATATE
68Ga-PSMA-HBED-CC (or 68Ga-PSMA-11)
12.3.3 Chemistry of Transition Metals
12.3.3.1 Scandium-44
12.3.3.2 Yttrium-86
12.3.3.3 Copper-64
64Cu-DOTATATE (DetectNet)
12.3.3.4 Zirconium-89
12.4 Immuno-PET and SPECT
12.4.1 ImmunoPET: Applications
12.5 Tecnetium-99m Chemistry
12.5.1 Tc-Tricarbonyl Core, [Tc(CO)3]+
References
13: Pharmacokinetics and Modeling
13.1 Quantitation
13.1.1 Standardized Uptake Value
13.2 Physiological Modeling
13.2.1 Radiotracer Binding
13.2.1.1 Binding Potential
13.2.1.2 Affinity
13.2.2 Tracer Kinetics
13.2.2.1 Two-Compartment Model
13.2.2.2 Three-Compartment Model
FDG Metabolism: Measurement of MRglc
Receptor Binding
13.2.2.3 Graphical Analysis Methods
Patlak Plot
Logan Plot
References
14: Molecular Imaging in Oncology
14.1 Cancer and Molecular Imaging
14.1.1 Radiopharmaceuticals for Molecular Imaging
14.2 Tumor Pathology and Biology
14.2.1 Histopathology
14.2.1.1 Grading and Staging
14.3 Molecular Basis of Cancer
14.3.1 Hallmarks of Cancer
14.3.2 Genetic Changes
14.3.2.1 Oncogenes
14.3.2.2 Antioncogenes
14.3.2.3 Tumor Antigens
14.3.3 Tumor Angiogenesis
14.3.4 Tumor Microenvironment
14.3.4.1 Apoptosis
14.4 PET and SPECT Radiopharmaceuticals in Oncology
14.4.1 Objectives
14.4.2 Radiopharmaceuticals: Biochemical Basis of Localization
14.4.2.1 Glycolysis
14.4.2.2 Bone Metabolism
14.4.2.3 DNA Synthesis
14.4.2.4 Membrane Lipid Synthesis
14.4.2.5 Amino Acid Transport and Protein Synthesis
14.4.2.6 Tumor Hypoxia
14.4.2.7 Angiogenesis
14.4.2.8 Apoptosis
14.4.2.9 Norepinephrine Transporters (NET)
14.4.2.10 Estrogen Receptors
14.4.2.11 Somatostatin Receptors
14.4.2.12 Glucagon-Like Peptide 1 Receptor (GLP-IR)
14.4.2.13 Chemokine Receptor-4 (CXCR-4)
14.4.2.14 Prostate-Specific Membrane Antigen (PSMA)
14.4.2.15 Fibroblast Activating Protein (FAP)
14.4.3 Antigen-Antibody Binding
14.4.3.1 Antibody Structure and Function
14.4.3.2 Immuno-PET and SPECT
14.4.3.3 Molecular Imaging for Cancer Immunotherapy
References
15: Molecular Imaging in Neurology
15.1 Neuroscience
15.1.1 The Nervous System
15.1.2 Nerve Cells
15.1.3 The Human Brain
15.1.3.1 The Blood-Brain Barrier
15.1.4 Neural Signaling
15.1.5 Synaptic Transmission
15.1.5.1 Chemical Synapses
15.1.6 Neurotransmitters and Receptors
15.2 Neurodegenerative Diseases
15.2.1 Dementia
15.2.1.1 Alzheimer’s Disease (AD)
β-Amyloid
PHF-tau Protein Fibril Deposits
15.2.2 Parkinson’s Disease
15.3 Radiopharmaceuticals for Brain Imaging in Neurology
15.3.1 Cerebral Blood Flow and Perfusion
15.3.2 Cerebral Oxygen Metabolism
15.3.3 Cerebral Glucose Metabolism
15.3.4 β-Amyloid Neuritic Plaque Density
15.3.4.1 [11C]PiB and [18F]-3′-F-PiB (Flutemetamol, Vizamyl)
15.3.4.2 18F-AV-1 (Florbetaben, Neuraceq) and 18F-AV-45 (Florbetapir, Amyvid)
15.3.4.3 [18F]Flutafuranol (AZD4694, NAV4694)
15.3.4.4 [18F]FIBT
15.3.4.5 Brain Amyloid-PET: Clinical Studies
15.3.5 Tau Imaging in Dementia
15.3.5.1 Flortaucipir F18 Injection (AV-1451, T-807, TauvidTM)
15.3.5.2 [18F]THK-5351
15.3.5.3 [18F]MK-6240
The Investigators at Merk Developed [18F]MK-6240, a Novel Ligand
15.3.6 Dopaminergic System
15.3.6.1 Dopamine transporter (DAT)
15.3.6.2 Vesicular Monoamine Transporter (VMAT)
15.3.6.3 Dopamine Receptors
15.3.6.4 Parkinson Disease (PD and Differential Diagnosis)
[18F]FDOPA and 123I-Ioflupane (FP-CIT, DaTscan)
15.3.7 Neuroinflammation
15.3.7.1 Microglia and TSPO Binding Radiotracers
15.4 Epilepsy
15.4.1 Blood Flow and Metabolism
15.5 Neurooncology
15.5.1 Imaging in Neuro-oncology
15.5.2 PET Radiotracers in Neuro-oncology
References
16: Molecular Imaging in Cardiology
16.1 Nuclear Cardiology
16.2 The Clinical Problem
16.2.1 Coronary Artery Disease
16.2.1.1 Vulnerable Plaque
16.2.1.2 Myocardial Infarction
16.2.2 Congestive Heart Failure
16.2.3 Cardiomyopathy
16.2.3.1 Cardiac Sarcoidosis (CS)
16.2.3.2 Cardiac Amyloidosis (CA)
16.2.4 Fibrosis
16.3 Radiopharmaceuticals in Nuclear Cardiology
16.3.1 Myocardial Blood Flow/Perfusion
16.3.1.1 SPECT Radiotracers for Perfusion
16.3.1.2 PET Radiotracers for Perfusion
16.3.2 Myocardial Metabolism
16.3.2.1 Glucose Metabolism
16.3.2.2 Fatty Acid Metabolism
Radiolabeled Fatty Acids for PET
Radiolabeled Fatty Acids for SPECT
16.3.2.3 Oxidative Metabolism
[11C]Acetate
16.3.3 Myocardial Presynaptic Adrenergic Neuronal Imaging
16.3.3.1 Radiotracers for Presynaptic Sympathetic Innervation
[11C]Hydroxyephedrine (HED)
123I-MIBG
16.3.3.2 Radiotracers for Cardiac Neuroreceptors
16.3.3.3 Clinical Applications
16.3.4 Cardiac Sarcoidosis (CS)
16.3.5 Cardiac Amyloidosis (CA)
16.3.6 Cardiac Fibrosis
16.3.7 Inflammation and Atherosclerosis
16.3.7.1 Radiotracers for Vulnerable Plaque
References
17: Radiopharmaceuticals for Therapy
17.1 Introduction
17.2 Radiopharmaceuticals
17.2.1 Therapy Radiopharmaceuticals
17.3 Radionuclides for Therapy
17.3.1 Radionuclides-Emitting Beta Particles
17.3.1.1 Phosphorous-32
17.3.1.2 Iodine-131
17.3.1.3 Yttrium-90
17.3.1.4 Lutetium-177
17.3.1.5 Copper-67
17.3.1.6 Scandium-47
17.3.1.7 Terbium-161
17.3.1.8 Strontium-90
17.3.1.9 Samarium-153
17.3.1.10 Tin-117m
17.3.1.11 Re-186 and Re-188
17.3.1.12 Holmium-166
17.3.1.13 Lead-212
17.3.2 Radionuclides-Emitting Alpha Particles
17.3.2.1 Astatine-211
17.3.2.2 Actinium-225
17.3.2.3 Bismuth-213
17.3.2.4 Thorium-227
17.3.2.5 Radium-223
17.3.2.6 Radium-224
17.3.2.7 Bismuth-212
17.3.2.8 Terbium-149
17.3.3 Radionuclides Emitting Low-Energy Electrons
17.3.4 In Vivo Radionuclide Generators
17.3.5 Mechanism and Biological Effects
17.3.5.1 Linear Energy Transfer (LET)
17.3.5.2 Absorbed Dose vs. Equivalent Dose
17.3.5.3 Relative Biological Effectiveness (RBE)
17.3.6 Biological Effectiveness of Radionuclide Therapy
17.3.6.1 Mechanisms of Cell Death
17.4 Design of Radiopharmaceuticals for TRT
17.4.1 Ideal Characteristics
17.4.2 Selection of Therapeutic Radionuclide
17.4.3 Theranostic Pair of Radionuclides
17.4.4 Biological Target and Targeting Vehicle
17.4.5 Radiolabeling Methods
17.5 Therapy Radiopharmaceuticals Approved for Clinical Use
17.5.1 Inorganic Ions
17.5.1.1 Sodium Iodide I 131 Solution
17.5.1.2 MetastronTM (Strontium-89 Chloride Injection)
17.5.1.3 223Ra Dichloride (Xofigo)
17.5.2 Inorganic Chelate Complex
17.5.2.1 153Sm-Lexidronam (Quadramet®)
17.5.3 Particulate Carriers
17.5.3.1 Theraspheres® Yttrium-90 Glass Microspheres
17.5.3.2 SirSpheres® Microspheres (Yttrium-90 Microspheres)
17.5.4 Small Organic Molecules
17.5.4.1 AZEDRA® (Iobenguane I 131) Injection
17.5.5 Regulatory Peptides Hormone Analogs
17.5.5.1 Somatostatin Receptors
17.5.5.2 Lutathera® (177Lu-Dotatate) Injection
17.5.5.3 Other Peptide Receptors
17.5.6 Monoclonal Antibodies
17.5.6.1 Radioimmunotherapy (RIT)
17.5.6.2 ZEVALIN® (Ibritumomab Tiuxetan) Injection
17.5.6.3 BEXXAR® (Tositumomab and Iodine I 131 Tositumomab) Injection
17.6 Prostate Specific Membrane Antigen (PSMA)
17.6.1 PSMA Inhibitors
17.6.1.1 177Lu-PSMA-617
References
18: Chemistry of Therapeutic Radionuclides
18.1 Targeted Radionuclide Therapy
18.1.1 Radionuclides for Therapy
18.1.2 Production of Radionuclides
18.1.2.1 Radionuclidic Purity (RP) and Specific Activity (SA)
18.1.2.2 Chemical Purity (CP)
18.2 Chemical Groups Radionuclides
18.3 Chemistry of Halogens
18.3.1 Iodine and Radioiodination
18.3.1.1 Electrophilic Substitution Reaction
18.3.1.2 Nucleophilic Substitution Reaction
18.3.1.3 131I-Labeled Therapeutic Radiopharmaceuticals
131I-Tositumomab (BEXXAR®)
Iobenguane I-131 Injection (AZEDRA®)
18.3.2 Chemistry of Astatine
18.4 Chemistry of Radiometals
18.4.1 Chelators for Metal Complexation
18.4.1.1 Chelating Agents
Acyclic Chelating Agents
Macrocyclic Chelating Agents
18.4.1.2 Stability of Metal–Chelate Complex
18.4.2 Bifunctional Chelating Agents
18.4.2.1 Coupling of BFC to Biomolecule
18.4.3 Alkaline Earth Metals
18.4.4 Transition Metals
18.4.5 Post-Transition Metals
18.4.6 Lanthanides
18.4.7 Actinides
References
19: Radiolabeled Antibodies for Imaging and Targeted Therapy
19.1 Introduction
19.2 Antibody Structure and Function
19.2.1 Pharmacokinetics of Antibodies and Fragments
19.3 Hallmarks of Cancer
19.4 Cancer and Immunotherapy
19.4.1 Mechanisms of Action of mAbs
19.5 Radiolabeled Antibodies
19.5.1 FDA-Approved Radiolabeled Antibodies for Imaging and Therapy
19.5.2 Tumor Antigen Targets and Targeting Vehicles
19.5.2.1 Targeting Vectors: Antibody or Antibody Fragments
19.5.2.2 Bispecific and Poly-specific Antibodies (Bs-Ab and PsAb)
19.5.3 Radionuclides for Antibody Therapy and Imaging
19.5.3.1 Therapeutic Radionuclides
19.5.3.2 Radionuclides for Immuno-PET/SPECT
19.5.4 Radiolabeling and Bioconjugation Strategies of Antibodies
19.5.4.1 Direct Labeling of Proteins
19.5.4.2 Indirect Labeling Using BFCs
Choice of BFC
Non-specific Conjugation
Site-Specific Conjugation
19.6 Radioimmunotherapy (RIT)
19.6.1 Direct and Indirect RIT Strategies
19.7 RIT: Clinical Applications
19.7.1 Hematological Malignancies
19.7.1.1 Non-Hodgkin Lymphoma (NHL)
111In- and 90Y-Labeled Zevalin
131I-Bexxar
Clinical Studies
177Lu-Lilotomab Satetraxetan (Betalutin)
227Th-Epratuzumab mAb
19.7.1.2 Leukemias
131I-Apamistamab (Iomab-B™)
211At-BC8-B10 mAb
225Ac-Lintuzumab (Actimab-A)
211At-OKT10-B10 mAb
19.7.2 Solid Tumors
19.7.2.1 Prostate Cancer
RIT with 177Lu-DOTA-huJ591 mAb
RIT with 225Ac-DOTA-huJ591 mAb
19.8 Strategies to Increase the Therapeutic Efficacy of RIT
19.8.1 Dose Fractionation
19.8.2 Pretargeted RIT (PRIT)
19.8.3 Combination RIT
19.9 Immuno-PET and SPECT of Cancer
19.9.1 89Zr for ImmunoPET
19.9.2 124I for ImmunoPET
19.9.3 ImmunoPET: Applications
19.9.4 Molecular Imaging for Cancer Immunotherapy
19.9.4.1 89Zr-Atezolizumab
19.9.4.2 18F-BMS-986192 and 89Zr-Nivolumab
References
20: Design of Radiolabeled Peptide Radiopharmaceuticals
20.1 Introduction
20.1.1 Proteinogenic and Non-proteinogenic AAs
20.1.2 Peptide Therapeutics
20.1.3 Advantages and Disadvantages of Peptides
20.2 Design of Peptide Radiopharmaceuticals (PRP)
20.2.1 Peptide Modification and Insertion of Non-natural AAs
20.2.1.1 Somatostatin (SST) Analogs
20.2.1.2 Cholecystokinin and Minigastrin (MG) Peptide
20.2.2 Peptide Cyclization
20.2.3 Insertion of β-Amino Acids
20.2.4 Substitution of Amides with Sulfonamides
20.2.5 N-Methylation (N-Alkylation)
20.2.6 PEGylation
20.2.7 Glycosylation
20.2.8 Albumin Binding
20.2.9 Spacers/Linkers
20.2.10 Dimerization and Multimerization
20.3 Radiolabeling of Peptides
20.3.1 Radionuclides
20.3.2 Radiolabeling Methods
20.3.3 Peptide Labeling with Radioiodine
20.3.4 Peptide Labeling with Fluorine-18
20.3.5 Peptide Labeling with Trivalent Radiometals
20.3.5.1 Bifunctional Chelators (BFCs)
20.3.5.2 Covalent Attachment of BFC to Peptide
20.3.5.3 Matching BFC to Radiometal
20.3.6 Peptide Labeling with 99mTc
20.3.6.1 Tc-Tricarbonyl Core [Tc(CO)3]+
References
21: Theranostics in Neuroendocrine Tumors
21.1 Introduction
21.1.1 Carcinoid Syndrome
21.1.2 Therapeutic Modalities
21.2 Theranostics in NETs
21.2.1 Biological Targets
21.2.2 Radionuclides for Imaging and Therapy
21.2.3 Radiolabeling Methods
21.3 Somatostatin Receptors and SST Analogs
21.3.1 Imaging SSTR-Positive NETs Radiolabeled SST Agonist Analogs for Imaging
21.3.1.1 SSTR Agonists
111In-DTPA-Octreotide (OctreoScan™)
68Ga-DOTA-TOC
68Ga-DOTATATE
68Ga-DOTA-NOC
64Cu-DOTATATE (DetectNet)
21.3.1.2 SSTR Antagonists
21.3.2 Therapy of SSTR-2-Positive NETs
21.3.2.1 90Y-DOTA-TOC
21.3.2.2 177Lu-DOTATOC
21.3.2.3 177Lu-DOTATATE (LUTATHERA®)
21.3.2.4 177Lu-DOTA-EB-TATE
21.3.2.5 Therapy with SSTR Antagonists
21.3.3 Therapy with Alpha Particles
21.4 Norepinephrine Transporter (NET): Imaging and Therapy Agents
21.4.1 MIBG Analogs for Imaging
21.4.1.1 [18F]MFBG and [18F]FIBG
21.4.1.2 Norepinephrine Analogs
6-[18F]Fluorodopamine (FDA)
[11C]Hydroxyephedrine (HED)
21.4.2 Therapy with MIBG (Azedra®)
21.5 Glucose Transporters (GLUT)
21.6 Amino Acid Transporters (AATs)
21.6.1 [11C]-5-HTP
21.6.2 [18F]FDOPA
21.7 Glucagon-Like Peptide 1 Receptor (GLP-IR)
21.8 Cholecystokinin-2 Receptor (CCK2R)
21.9 Neurotensin Receptor 1 (NTR1)
21.10 Chemokine Receptor-4 (CXCR-4)
21.11 Tumor Antigens and RIT
21.12 Embolization Therapy with 90Y-Microspheres
References
22: Theranostics in Prostate Cancer
22.1 Prostate Cancer
22.1.1 Screening and Diagnosis
22.1.2 Treatment for Localized Prostate Cancer
22.1.3 Role of Imaging in Prostate Cancer
22.2 Biological Targets in mCRPC
22.2.1 Bone Matrix
22.2.2 Androgen Receptor (AR)
22.2.3 Prostate-Specific Membrane Antigen (PSMA)
22.2.3.1 Anti-PSMA mAbs
22.2.3.2 Small-Molecule PSMA Inhibitors
22.2.4 Gastrin Releasing Peptide Receptor (GRPR)
22.3 Radionuclides for Imaging and Therapy
22.3.1 Beta vs. Alpha Dosimetry
22.3.2 Radiolabeling Methods
22.4 Radiopharmaceuticals for SPECT and PET
22.4.1 Bone Matrix
22.4.1.1 99mTc-MDP and 99mTc-HDP
68Ga-DOTAZOL
22.4.1.2 Sodium [18F]Fluoride (NaF)
22.4.2 Glucose Metabolism
22.4.2.1 [18F]Fluoro-2-Deoxyglucose (FDG)
22.4.3 Lipid Metabolism
22.4.3.1 [11C]Choline (CH) and [18F]Fluorocholine (FCH)
22.4.4 Amino Acid (AA) Transport
22.4.4.1 [18F]Fluciclovine (Axumin)
22.4.5 Androgen Receptor
22.4.5.1 [18F]FDHT
22.4.5.2 [18F]Enzalutamide (FEZT)
22.4.6 Radiolabeled Antibodies
22.4.6.1 111In-Capromab Pendetide (ProstaScint™)
22.4.6.2 177In-huJ591 and 177Lu-huJ591 mAb
22.4.6.3 89Zr-huJ591 mAb
22.4.6.4 89Zr-Df-IAB2M Minibody
22.4.6.5 89Zr-DFO-MSTP2109A, Anti-STEP-1 Antibody
22.4.7 Small-Molecule PSMA Inhibitors
22.4.7.1 DCFBC and DCFPyl
[18F]DCFPyl (Pylarify™)
22.4.7.2 MIP-1095 and MIP-1404
99mTc-MIP-1404 (Trofolastat™)
22.4.7.3 PSMA-11, PSMA-617, PSMA-1007, and PSMA-I&T
68Ga-PSMA-HBED-CC (or 68Ga-PSMA-11)
PSMA-11, PSMA-617, PSMA-1007, and PSMA-I&T
22.4.7.4 rhPSMA-7.3
22.4.7.5 Albumin-Binding PSMA Inhibitors
22.4.8 Bombesin and GRPR Analogs
22.5 Radiopharmaceuticals for Bone Pain Palliation
22.5.1 89Sr Dichloride (Metastron®)
22.5.2 Bisphosphonates: 153Sm-EDTMP (Quadramet®)
22.5.2.1 Investigational Agents
177Lu-EDTMP and 177Lu-DOTAZOL
22.6 Radiopharmaceuticals for Targeted Therapy
22.6.1 223Ra Dichloride (Xofigo)
22.6.2 RIT with 177Lu- or 225Ac-Labeled J591 mAb
22.6.2.1 RIT with 177Lu-DOTA-huJ591 mAb
22.6.2.2 RIT with 225Ac-DOTA-huJ591 mAb
22.6.3 Small-Molecule PSMA Inhibitors
22.6.3.1 Lu 177 Vipivotide Tetraxetan (Pluvicto, 177Lu-PSMA-617)
22.6.3.2 177Lu-PSMA-I&T
22.6.3.3 Dosimetry of 177Lu-PSMA Ligands
22.6.3.4 225Ac-PSMA-617 and 225Ac-PSMA-I&T
22.7 Combination Therapy
References
Index