Fundamentals of Nuclear Pharmacy (eBook)

1: The Atom 19
Electronic Structure of the Atom 19
Chemical Bonds 20
Electrovalent or Ionic Bond 22
Covalent Bond 23
Coordinate Covalent Bond 23
Complex Formation 24
Structure of the Nucleus 25
Nomenclature 26
Questions 28
Suggested Reading 28
2: Radioactive Decay 29
Decay of Radionuclides 29
Spontaneous Fission 29
Alpha (a) Decay 29
Beta (beta-) Decay 30
Positron or beta+ Decay 32
Electron Capture 32
Isomeric Transition 33
Radioactive Decay Equations 36
General Equation 36
Half-Life and Mean Life 37
Units of Radioactivity 39
Calculations 40
Successive Decay Equations 41
General Equation 41
Transient Equilibrium 41
Secular Equilibrium 43
Statistics of Counting 45
Error, Accuracy, and Precision 45
Standard Deviation 45
Standard Deviation of Count Rates 46
Propagation of Errors 47
Questions 48
Suggested Reading 49
3: Instruments for Radiation Detection and Measurement 50
Gas-Filled Detectors 50
Dose Calibrators 50
Geiger-Müller Counters 52
Scintillation Detecting Instruments 53
Collimator 53
Detector 54
Photomultiplier Tube 54
Preamplifier 55
Linear Amplifier 55
Pulse Height Analyzer 55
Display or Storage 56
Scintillation Camera 56
Collimator 58
Detector 58
X, YPositioning Circuit 59
Pulse Height Analyzer 59
Digital Image 60
Display and Storage 60
Tomographic Imagers 61
Single Photon Emission Computed Tomography 62
Positron Emission Tomography 62
PET/CT and SPECT/CT 64
Questions 65
Suggested Reading 65
4: Production of Radionuclides 66
Cyclotron-Produced Radionuclides 66
Gallium-67 69
Iodine-123 69
Indium-111 70
Thallium-201 70
Short-Lived Radionuclides 71
Carbon-11 71
Nitrogen-13 71
Oxygen-15 72
Fluorine-18 72
Reactor-Produced Radionuclides 72
Fission or (n, f) Reaction 73
Iodine-131 74
Molybdenum-99 74
Neutron Capture or (n, gamma) Reaction 74
Target and Its Processing 75
Equation for Production of Radionuclides 76
Specific Activity 81
Questions 82
References and Suggested Reading 83
Chapter 5: Radionuclide Generators 84
Principles of a Generator 84
Important Radionuclide Generators 87
99Mo-99mTc Generator 87
Construction 87
Liquid Column Generator 87
Solid Column Generator 87
Yield of 99mTc 90
99mTc Content in 99mTc-Eluate 93
Quality Control of 99mTc-Eluate 94
99Mo Breakthrough 94
Other Radionuclide Contamination 95
Aluminum Breakthrough 95
pH 96
Radiochemical Purity 96
68Ge-68Ga Generator 96
90Sr-90Y Generator 96
62Zn-62Cu Generator 97
82Sr-82Rb Generator (Cardiogen-82) 97
Questions 98
References and Suggested Reading 98
Chapter 6: Radiopharmaceuticals and Methods of Radiolabeling 100
Definition of a Radiopharmaceutical 100
Ideal Radiopharmaceutical 101
Easy Availability 101
Short Effective Half-Life 101
Particle Emission 102
Decay by Electron Capture or Isomeric Transition 102
High Target-to-Nontarget Activity Ratio 103
Design of New Radiopharmaceuticals 104
General Considerations 104
Factors Influencing the Design of New Radiopharmaceuticals 105
Compatibility 105
Stoichiometry 105
Charge of the Molecule 106
Size of the Molecule 106
Protein Binding 106
Solubility 106
Stability 107
Biodistribution 107
Methods of Radiolabeling 108
Isotope Exchange Reactions 108
Introduction of a Foreign Label 109
Labeling with Bifunctional Chelating Agents 109
Biosynthesis 109
Recoil Labeling 110
Excitation Labeling 110
Important Factors in Labeling 110
Efficiency of the Labeling Process 110
Chemical Stability of the Product 111
Denaturation or Alteration 111
Isotope Effect 111
Carrier-Free or No-Carrier-Added State 111
Storage Conditions 111
Specific Activity 112
Radiolysis 112
Purification and Analysis 112
Shelf Life 113
Specific Methods of Labeling 113
Radioiodination 113
Principles of Iodination 114
Methods of Iodination 114
Triiodide Method 115
Iodine Monochloride Method 115
Chloramine-T Method 115
Electrolytic Method 115
Enzymatic Method 116
Conjugation Method 116
Demetallation Method 116
Iodogen Method 116
Iodo-Bead Method 117
Radioiodinated Compounds 117
Labeling with 99mTc 118
General Properties of Technetium-99m 118
Chemistry of Technetium 118
Reduction of 99mTc$$ {/hbox{O}}_4^{-} $$ 119
Labeling with reduced Technetium 120
Free Pertechnetate in 99mTc-Radiopharmaceuticals 120
Hydrolysis of Reduced Technetium and Tin 121
Formation of 99mTc-Complexes by Ligand Exchange 122
Structure of 99mTc-Complexes 123
Oxidation States of 99mTc in 99mTc-Radiopharmaceuticals 124
Tc7+ 124
Tc5+ 125
Tc4+ 125
Tc3+ 125
Tc1+ 126
Oxidation States in 99mTc-Labeled Proteins 126
Kits for 99mTc-Labeling 126
Colloids and Labeled Particles 127
Additives and Preservatives 128
Questions 129
References and Suggested Reading 130
Chapter 7: Characteristics of Specific Radiopharmaceuticals 131
99mTc-Labeled Radiopharmaceuticals 131
99mTc-Sodium Pertechnetate 131
99mTc-Macroaggregated Albumin 132
99mTc-Phosphonate and Phosphate Radiopharmaceuticals 132
99mTc-Sulfur Colloid 134
Filtered 99mTc-Sulfur Colloid 135
99mTc-Albumin Colloid (Nanocolloid) 135
99mTc-Pentetate (DTPA) 135
99mTc-Labeled Red Blood Cells 136
In Vitro Method 136
In Vivo Method 137
Modified In Vivo Method 137
99mTc-Iminodiacetic Acid Derivatives 137
99mTc-Hexamethylpropylene Amine Oxime (Ceretec) 138
99mTc-Sestamibi (Cardiolite Miraluma)
99mTc-Tetrofosmin (Myoview) 141
99mTc-Mercaptoacetylglycylglycylglycine (MAG3) 141
99mTc-Ethyl Cysteinate Dimer (Neurolite) 142
99mTc-Dimercaptosuccinic Acid (Succimer) 142
99mTc-Gluceptate 143
99mTc-Technegas 143
Radioiodinated Radiopharmaceuticals 143
131I-Sodium Iodide 143
123I-Sodium Iodide 144
125I-Albumin 145
123I- or 131I-Metaiodobenzylguanidine 145
125I-Sodium Iothalamate 145
131I-Tositumomab (Bexxar) 146
Miscellaneous Radiopharmaceuticals of Clinical Interest 146
111In-DTPA 146
133Xe Gas 146
201Tl-Thallous Chloride 147
67Ga-Citrate 147
32P-Sodium Orthophosphate 147
89Sr-Strontium Chloride (Metastron) 148
153Sm-Ethylenediaminetetramethylene Phosphonic Acid (Quadramet) 148
57Co- or 58Co-Cyanocobalamin 148
51Cr-Labeled Red Blood Cells 148
Radiolabeled Leukocytes and Platelets 149
Leukocyte Separation 149
Platelet Separation 149
111In-Labeling 149
111In-Oxine 149
111In-Labeling of Leukocytes and Platelets 150
99mTc-Labeling 151
Radiolabeled Monoclonal Antibodies 152
Production of Monoclonal Antibody 153
Radiolabeling of Monoclonal Antibody 155
Radioiodination of Antibody 155
111In- or 90Y-Labeling of Antibody 155
111In-Capromab Pendetide (ProstaScint) 156
111In- and 90Y-Ibritumomab Tiuxetan (Zevalin) 156
90Y-TheraSphere 157
90Y-SIR-Spheres (SIRTeX) 157
99mTc-Labeling of Antibody 157
Direct Method 157
Indirect Method Using Preformed 99mTc-Chelate 158
Indirect Labeling Using Bifunctional Chelating Agent 158
99mTc-Sulesomab (LeukoScan) 160
Radiolabeled Peptides 160
111In-Pentetreotide (OctreoScan) 161
Other Radiopharmaceuticals of Clinical Importance 161
PET Radiopharmaceuticals 161
18F-Sodium Fluoride 161
18F-Fluorodeoxyglucose 162
18F-Fluorodopa 162
18F-Fluorothymidine 163
15O-Water 163
n-15O-Butanol 163
13N-Ammonia 164
11C-Sodium Acetate 164
11C-Flumazenil 164
11C-Methylspiperone 164
11C-L-Methionine 165
11C-Raclopride 165
82Rb-Rubidium Chloride 165
Questions 166
References and Suggested Reading 167
8: Quality Control of Radiopharmaceuticals 169
Physicochemical Tests 169
Physical Characteristics 169
pH and Ionic Strength 170
Radionuclidic Purity 170
Radiochemical Purity 171
Precipitation 172
Paper and Instant Thin-Layer Chromatography 172
Gel Chromatography 174
Paper or Polyacrylamide Gel Electrophoresis 177
Ion Exchange 178
Solvent Extraction 178
High-Performance Liquid Chromatography 179
Distillation 180
Chemical Purity 180
Radioassay 181
Dose Calibrator Quality Control 181
Constancy 181
Accuracy 182
Linearity 182
Geometry 183
Measurement of Radioactivity 184
Biological Tests 184
Sterility 184
Methods of Sterilization 184
Autoclaving 184
Membrane Filtration 185
Sterility Testing 185
Apyrogenicity 186
Pyrogenicity Testing 187
USP Rabbit Test 187
Bacterial Endotoxin Test 187
Toxicity 188
Record Keeping 189
Questions 189
References and Suggested Reading 190
9: Nuclear Pharmacy 191
Concept 191
Design of a Nuclear Pharmacy 191
USP Chapter 797: Pharmaceutical Compounding: Sterile Preparations 195
Operation of a Nuclear Pharmacy 196
Receiving and Monitoring of Radioactive Packages 196
Preparation of Radiopharmaceuticals 197
Quality Control of Radiopharmaceuticals 201
Storage 201
Dispensing 201
Pediatric Dosages 202
Radioactive Waste Disposal 204
Infectious Waste Disposal 205
Centralized Nuclear Pharmacy 205
Questions 207
References and Suggested Reading 207
Chapter 10: Internal Radiation Dosimetry 209
Radiation Units 209
Radiation Dosimetry 211
Calculation of Radiation Absorbed Dose 212
Radiation Dose in SI Units 215
Effective Dose 215
Questions 221
References and Suggested Reading 221
Chapter 11: Radiation Regulations, Protection, and Uses 222
Food and Drug Administration 222
Investigational New Drug 223
New Drug Application 223
Exploratory IND 224
Radioactive Drug Research Committee 226
Difference Between RDRC and Exploratory IND 226
PET Radiopharmaceuticals 227
FDA Regulations for Compounding in Nuclear Pharmacies 228
State Boards of Pharmacy 230
Nuclear Regulatory Commission 231
Agreement States 231
Licenses 232
Accreditation of Nuclear Medicine Facilities 233
Radiation Protection 234
Definitions 234
Caution Signs and Labels 235
Occupational Dose Limits 236
ALARA Program 237
Principles of Radiation Protection 237
Time 238
Distance 238
Shielding 239
Activity 240
Receiving and Monitoring of Radioactive Packages 240
Radioactive Waste Disposal 240
Decay-in-Storage 241
Release into a Sewerage System 241
Transfer to an Authorized Recipient 242
Other Disposal Methods 242
Radioactive Spill 242
Personnel Monitoring 243
Dos and Donts in Radiation Protection Practice 245
Medical Uses of Radioactive Materials 245
Applications, Amendments, and Notifications 246
Authority and Responsibilities of the License 246
Supervision 247
Mobile Nuclear Medicine Service 247
Written Directives 247
Measurement of Dosages 247
Calibration, Transmission, and Reference Sources 248
Requirement for Possession of Sealed Sources 248
Labeling of Vials and Syringes 248
Surveys of Ambient Radiation Exposure Rate 249
Training and Experience Requirements for Medical Uses of Byproduct Materials 249
Report and Notification of a Medical Event 250
Report and Notification of a Dose to an Embryo/Fetus or a Nursing Child 251
Bioassay 251
Release of Patients Administered with Radiopharmaceuticals 252
Verification Card for Radioactive Patients 253
Record Keeping 254
Department of Transportation 254
European Regulations Governing Radiopharmaceuticals 257
Drug Registration 258
Good Manufacturing Practice 259
European Pharmacopoeia 259
Radiation Protection 260
Questions 261
References and Suggested Reading 262
Chapter 12: In Vitro and In Vivo Nonimaging Tests 264
Radioimmunoassay 264
Principle 264
Methodology 265
Sensitivity and Specificity 266
Application 266
Schilling Test 267
Blood Volume 268
125I-Serum Albumin Method 268
51Cr-Labeled Red Blood Cell Method 268
Application 269
Red Blood Cell Survival 269
Questions 270
Suggested Reading 270
13: Diagnostic Uses of Radiopharmaceuticals in Nuclear Medicine 272
Central Nervous System 272
Anatomy and Physiology 272
Radiopharmaceuticals and Imaging Techniques 274
Brain Imaging 274
99mTc-Ethyl Cysteinate Dimer (Neurolite) 274
99mTc-Hexamethylpropylene Amine Oxime (Ceretec) 276
Interventional Studies 277
18F-Fluorodeoxyglucose 278
18F-Fluorodopa 280
Other Radiopharmaceuticals 280
Cisternography 281
111In-DTPA 281
Diagnosis 281
Thyroid 282
Anatomy and Physiology 282
Radiopharmaceuticals and Imaging Techniques 283
131I- or 123I-Sodium Iodide 283
99mTc-Sodium Pertechnetate 284
Other Radiopharmaceuticals 286
Diagnosis 286
Lung 287
Anatomy and Physiology 287
Radiopharmaceuticals and Imaging Techniques 288
Perfusion Imaging 289
99mTc-Labeled Macroaggregated Albumin 289
Ventilation Studies 289
133Xe Gas 291
99mTc-Labeled Aerosol 291
99mTc-Technegas 292
Studies of Nonembolic Lung Diseases 292
67Ga-Citrate 292
Diagnosis 294
Liver 294
Anatomy and Physiology 294
Radiopharmaceuticals and Imaging Techniques 295
99mTc-Labeled IDA Derivatives 296
99mTc-Sulfur Colloid and 99mTc-Albumin Colloid 297
Other Radiopharmaceuticals 300
Diagnosis 301
Spleen 301
Anatomy and Physiology 301
Radiopharmaceuticals and Imaging Techniques 301
99mTc-Sulfur Colloid or 99mTc-Albumin Colloid 301
99mTc-Labeled Red Blood Cells 302
Diagnosis 302
Kidney 303
Anatomy and Physiology 303
Radiopharmaceuticals and Imaging Techniques 304
99MTc-Mercaptoacetylglycylglycylglycine 304
Effective Renal Plasma Flow 307
99mTc-DTPA 308
99mTc-Gluceptate 309
99mTc-DMSA 310
Captopril Renography 311
Diagnosis 311
Skeleton 312
Anatomy and Physiology 312
Radiopharmaceuticals and Imaging Techniques 312
99mTc-Phosphonate Compounds 312
18F-Sodium Fluoride 313
Diagnosis 314
Heart 314
Anatomy and Physiology 314
Radiopharmaceuticals and Imaging Techniques 318
Perfusion Imaging 318
201Tl-Thallous Chloride 318
99mTc-Sestamibi (Cardiolite) 321
99mTc-Tetrofosmin (Myoview) 322
82Rb-Rubidium Chloride 325
13N-Ammonia 325
Other Perfusion Radiopharmaceuticals 326
Metabolic Imaging 327
18F-Fluorodeoxyglucose 327
Other Metabolic Radiopharmaceuticals 328
Myocardial Infarct Imaging 329
99mTc-Pyrophosphate 329
Cardiac Innervation Imaging 330
123I-MIBG 330
Radionuclide Angiography 331
First-Pass Method 331
Gated Equilibrium Cardiac Blood Pool Method 331
Radionuclide Stress Ventriculography 332
Diagnosis 333
Miscellaneous Imaging Procedures 334
Tumor Imaging 334
67Ga-Citrate 334
99mTc-Sestamibi (Miraluma) 336
123I- or 131I-MIBG 337
201Tl-Thallous Chloride 337
18F-FDG 338
18F-FDG Whole Body Imaging 338
111In-Pentetreotide 340
Radiolabeled Antibody 341
111In-Capromab Pendetide (ProstaScint) 342
111In-Ibritumomab Tiuxetan (Zevalin) 343
Thrombus Detection 343
Lymphoscintigraphy 344
Gastric Emptying Imaging 345
Meckel´s Diverticulum Imaging 346
Gastrointestinal Bleeding Detection 346
Inflammatory Diseases and Infection Imaging 347
67Ga-Citrate 347
111In- or 99mTc-Leukocytes 348
Parathyroid Imaging 349
Questions 350
References and Suggested Reading 352
Chapter 14: Molecular Imaging 355
Methodology of Molecular Imaging 356
Conventional Molecular Imaging 356
Gene-Based Molecular Imaging 356
Oligodeoxynucleotide Antisense Probes to Image mRNA 360
Reporter Genes for Imaging 361
Gene Therapy 363
Gene Delivery 363
Adenoviral Vectors 363
Retroviral Vectors 363
Nonviral Vectors 364
Specific Diseases 364
Nanoparticle Imaging 365
Questions 368
References and Suggested Reading 368
15: Therapeutic Uses of Radiopharmaceuticals in Nuclear Medicine 370
Treatment of Hyperthyroidism 370
Treatment of Thyroid Cancer 371
Whole-Body Imaging 372
Treatment with 131I 372
Treatment of Bone Pain 374
32P-Sodium Orthophosphate 374
89Sr-Strontium Chloride (Metastron) 374
153Sm-EDTMP (Quadramet) 375
Treatment of Liver Cancer 375
90Y-TheraSpheres 375
90Y-SIR-Spheres (SIR-TeX) 376
Treatment of Non-Hodgkin´s Lymphoma 377
90Y-Ibritumomab Tiuxetan (Zevalin) 377
131I-Tositumomab (Bexxar) 378
Polycythemia Vera and Leukemia 378
Pretargeted Radioimmunotherapy of Cancer 379
Questions 380
References and Suggested Reading 380
16: Adverse Reactions to and Altered Biodistribution of Radiopharmaceuticals 382
Adverse Reactions 382
Iatrogenic Alterations in the Biodistribution of Radiopharmaceuticals 383
Questions 385
References and Suggested Reading 385