Radiopharmaceuticals
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Solve questions (24) →Contents
- 12.1 Principles of Radiopharmaceutical Design
- 12.1.1 Definition and General Concepts
- 12.1.2 Properties of the Ideal Radiopharmaceutical
- 12.1.3 Mechanisms of Radiopharmaceutical Localisation
- 12.1.4 Physiological and Pharmacological Basis of Biodistribution
- 12.2 Tc-99m Labelling Chemistry (Reduction, Ligands)
- 12.2.1 Basics of Tc-99m Chemistry
- 12.2.2 Pertechnetate (TcO₄⁻) and Reduction
- 12.2.3 Tc-99m Oxidation States and Complex Types
- 12.2.4 The Tc-99m Kit Preparation Process
- 12.2.5 Tc-99m Labelling Problems
- 12.3 SPECT Radiopharmaceuticals (by Organ System)
- 12.3.1 Cardiovascular System
- 12.3.2 Skeletal System
- 12.3.3 Urinary System
- 12.3.4 Pulmonary System
- 12.3.5 Neurological System
- 12.3.6 Hepatobiliary System
- 12.3.7 Infection/Inflammation
- 12.3.8 Endocrine System
- 12.4 PET Radiopharmaceuticals
- 12.4.1 F-18 FDG (Fluorodeoxyglucose)
- 12.4.2 F-18 NaF (Sodium Fluoride)
- 12.4.3 F-18/C-11 Choline
- 12.4.4 Ga-68 DOTATATE/DOTATOC/DOTANOC
- 12.4.5 Ga-68/F-18 PSMA
- 12.4.6 Amyloid PET Agents
- 12.4.7 Tau PET
- 12.4.8 DaTscan (I-123 Ioflupane)
- 12.4.9 Other PET Radiopharmaceuticals
- 12.5 Therapeutic Radiopharmaceuticals (I-131, Lu-177, Ra-223, Y-90, etc.)
- 12.5.1 I-131 Sodium Iodide
- 12.5.2 Lu-177 DOTATATE (Lutathera®)
- 12.5.3 Lu-177 PSMA-617 (Pluvicto®)
- 12.5.4 Ra-223 Dichloride (Xofigo®)
- 12.5.5 Y-90 Microspheres (Radioembolisation)
- 12.5.6 Sr-89 Chloride (Metastron®) and Sm-153 EDTMP (Quadramet®)
- 12.5.7 I-131 MIBG Therapy
- 12.5.8 Ho-166 Microspheres (QuiremSpheres®)
- 12.5.9 Y-90 Ibritumomab Tiuxetan (Zevalin®)
- 12.5.10 Radiosynovectomy Agents
- 12.6 Biodistribution and Pharmacokinetics
- 12.6.1 Factors Affecting Biodistribution
- 12.6.2 Routes of Excretion
- 12.6.3 Effective Half-Life
- 12.7 Adverse Effects and Interactions of Radiopharmaceuticals
- 12.7.1 General Safety Profile
- 12.7.2 Specific Adverse Effects
- 12.7.3 Drug Interactions
- 12.8 Radiopharmaceutical Quality Control
- 12.8.1 Quality Control Parameters
- 12.8.2 Mo-99/Tc-99m Generator Quality Control
- 12.8.3 Summary Table of Radiopharmaceutical Quality Control
- Key Points for the Board
- Current guidelines on this chapter's topics
Learning objectives and modules4 modules · about 2 h 35 min
Learning objectives
After this chapter you will be able to:
- Match the localisation mechanisms of radiopharmaceuticals with example agents.
- Explain Tc-99m labelling chemistry (reduction, stannous ion, ligand) and the factors that impair labelling.
- Classify SPECT and PET radiopharmaceuticals by organ system, mechanism and route of excretion.
- Compare therapeutic radiopharmaceuticals by emission type, range and target.
- Recognise drug interactions that alter biodistribution and adverse effects.
- Apply radionuclidic, radiochemical and chemical purity tests with their acceptance limits.
Modules
The chapter is divided into study modules without changing the order of the text: read, watch the animations, then answer the questions linked to those headings.
- Module 112.1–12.2 Principles of Radiopharmaceutical Design · Tc-99m Labelling Chemistry (Reduction, Ligands)30 min · 10 questionsAnswer the questions →
- Module 212.3–12.4 SPECT Radiopharmaceuticals (by Organ System) · PET Radiopharmaceuticals55 min · 19 questionsAnswer the questions →
- Module 312.5–12.7 Therapeutic Radiopharmaceuticals (I-131, Lu-177, Ra-223, Y-90, etc.) · Biodistribution and Pharmacokinetics · Adverse Effects and Interactions of Radiopharmaceuticals35 min · 13 questionsAnswer the questions →
- Module 412.8 Radiopharmaceutical Quality Control · Key Points for the Board35 min · 1 animation · 10 questionsAnswer the questions →
Times are estimates: 130 words per minute, 3 min per animation, 1.5 min per question.
MOST FREQUENTLY ASKED IN THIS CHAPTER
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<40 kDa → capillary extravasation; ≤60 kDa → glomerular filtration; IgG → long blood half-life via FcRn
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EPR → non-specific accumulation of large molecules in tumour
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DRL → typical diagnostic activity recommended in a standard patient
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GLP (non-clinical) vs GMP (production); if terminal sterilisation is not possible, aseptic production + 0.22 µm filtration
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The sterility test is mostly retrospective; the Production and QC managers are independent; the batch is released by the Qualified Person
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The reducing agent in Tc-99m kits = stannous chloride (SnCl₂) → reduces pertechnetate from +7 to a lower oxidation state → forms complexes with ligands
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Excess SnCl₂ → formation of colloidal Tc; insufficient SnCl₂ → free pertechnetate remains
12.1 Principles of Radiopharmaceutical Design
12.1.1 Definition and General Concepts2 questions
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Route of administration: Mostly intravenous; I-131 can be given orally, and Tc-99m-labelled carbon microparticles (Technegas), O-15 and Xe-133 by inhalation
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Diagnostic activity is determined mainly by camera sensitivity (ALARA). The Diagnostic Reference Level (DRL) is a reference value reflecting the typical activity administered for a standard procedure in a standard-sized patient; it is not a dose limit or an ideal value, and it helps to detect unusually high administrations
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The therapeutic activity is ideally determined by individual dosimetry (organ uptake, biological half-life, excretion routes); however, in commercial therapies a fixed activity per cycle is mostly given
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Labelling of blood cells: Granulocytes are labelled in vivo with a labelled antibody, leucocytes and platelets in vitro; red cells can be labelled by either method
A radiopharmaceutical is a pharmaceutical preparation containing a radioactive atom (radionuclide) that is administered to a patient for diagnosis or therapy.
It consists of two basic components:
1. Radionuclide: Source of the radioactive signal (imaging) or of therapeutic radiation (therapy)
2. Carrier molecule (ligand/vector): The chemical structure that carries the radionuclide to the target tissue
Some radiopharmaceuticals do not require a carrier molecule → the radionuclide itself is biologically active:
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I-131 sodium iodide: Iodine is taken up directly by the thyroid (NIS transporter)
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Ga-67 citrate: Gallium binds to the transferrin receptor
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Tl-201 chloride: Thallium enters the cell via Na⁺/K⁺-ATPase
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Rb-82 chloride: Rubidium enters the cell via Na⁺/K⁺-ATPase (potassium analogue)
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Ra-223 dichloride: Radium is a calcium analogue → accumulates on the bone surface
12.1.2 Properties of the Ideal Radiopharmaceutical
Properties related to the radionuclide:
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Suitable half-life: Long enough for the study, short enough not to give unnecessary dose
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Diagnosis: Hours (Tc-99m: 6 hours, F-18: 110 min)
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Therapy: Days (I-131: 8 days, Lu-177: 6.65 days)
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For a diagnostic agent, an effective half-life of about 1.5 times the duration of the study is recommended; this gives enough counts without unnecessary dose
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Suitable radiation type and energy:
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SPECT: Gamma → 100-200 keV ideal (Tc-99m: 140 keV optimal)
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PET: Positron → annihilation photons (511 keV)
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Therapy: Beta-minus, alpha or Auger electrons
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High target/background ratio: Intense uptake in target tissue, minimal uptake in other tissues
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High specific activity: Critical especially for receptor-based agents
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Easy and economical production: Generator or access to a nearby cyclotron
Properties related to the pharmaceutical:
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High target affinity and specificity: Selective binding to the target tissue
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Suitable biodistribution: Rapid target uptake, rapid background clearance
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Metabolic stability: No in vivo defluorination, dehalogenation or transchelation
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Low toxicity: The pharmacological dose is very low (microgram–nanogram level) → "tracer principle"
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Easy preparation: Kit-based preparation is preferred (Tc-99m kits)
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Sterility and apyrogenicity: Mandatory for IV administration
BOARD TIP
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"Tracer principle" → the radiopharmaceutical is given in an amount too small to have a pharmacological effect → it traces the physiological process without disturbing it. The only exception: I-131 therapeutic doses → high activity → destroys thyroid cells (therapeutic effect).
12.1.3 Mechanisms of Radiopharmaceutical Localisation1 questions
Radiopharmaceuticals accumulate in target tissue by different mechanisms:
1. Active transport:
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Via cellular transporter proteins
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I-131/I-123 → into the thyroid cell via NIS (sodium–iodide symporter)
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Tl-201 → into the myocardial cell via Na⁺/K⁺-ATPase
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Note: FDG enters the cell by facilitated diffusion via GLUT-1/GLUT-3, not by active transport; the mechanism that keeps it in the cell is metabolic trapping
2. Receptor binding:
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High-affinity binding to specific receptors
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Ga-68/Lu-177 DOTATATE → somatostatin receptors (SSTR2)
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Ga-68/Lu-177 PSMA → prostate-specific membrane antigen
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In-111 OctreoScan → somatostatin receptors
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I-123 MIBG → norepinephrine transporter (NET) → adrenal medulla
3. Metabolic trapping:
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Metabolised and trapped within the cell
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FDG → phosphorylation by hexokinase → FDG-6-phosphate (cannot be metabolised further → stays in the cell)
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Tc-99m MIBI → retained by the mitochondrial membrane potential
4. Capillary blockade:
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Particles are mechanically trapped in the capillary bed
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Tc-99m MAA → in pulmonary capillaries (10-100 µm particles)
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Y-90 microspheres → at hepatic arteriole level
5. Phagocytosis:
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Engulfment by cells of the reticuloendothelial system (RES)
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Tc-99m sulphur colloid → Kupffer cells (liver), spleen, bone marrow
6. Adsorption onto the bone surface (chemisorption):
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Binding to hydroxyapatite crystals
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Tc-99m MDP/HDP → in areas of osteoblastic activity
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F-18 NaF → the fluoride ion is incorporated into hydroxyapatite
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Ra-223 → accumulates on the bone surface as a calcium analogue
7. Compartmental localisation:
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Remaining within a particular physiological space
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Tc-99m DTPA aerosol → on the alveolar surface
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Tc-99m sulphur colloid → in the peritoneal cavity (shunt assessment)
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In-111 DTPA → in the CSF (cisternography)
8. Cell labelling:
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In vitro labelling of cells with a radionuclide
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Tc-99m/In-111-labelled leucocytes → infection/inflammation
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Tc-99m/Cr-51-labelled red cells → bleeding, haemangioma, MUGA
9. Antibody binding:
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Radiolabelled antibodies bind to specific antigens
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Y-90 ibritumomab tiuxetan (Zevalin) → CD20 antigen (lymphoma)
10. Passive diffusion:
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Movement along a concentration gradient
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Tc-99m DTPA → GFR measurement (glomerular filtration)
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Xe-133 → ventilation (passage across the alveolar membrane)
BOARD TIP
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"Why does FDG accumulate in tumours?"
→ Tumour cells show increased glucose metabolism (Warburg effect) → GLUT-1 upregulation → FDG enters the cell → phosphorylation by hexokinase → FDG-6-phosphate is trapped in the cell (metabolic trapping).
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"Why is FDG taken up intensely by the brain?"
→ The brain uses glucose as its primary energy source → high baseline FDG uptake.
Figure 12.1: The ten basic localisation mechanisms of radiopharmaceuticals and example agents (schematic).
Did this figure help you understand the topic?
12.1.4 Physiological and Pharmacological Basis of Biodistribution3 questions
Molecular size and passage across the vessel wall:
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Under physiological conditions, molecules smaller than ~40 kDa can leave blood capillaries into the extravascular space; molecules up to ~60 kDa can be excreted by glomerular filtration through the fenestrated capillaries of the kidney
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Larger molecules (e.g. intact antibodies of ~150 kDa) can leave the vessels only in tissues with sinusoidal capillaries such as liver and bone marrow
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Lipophilicity and the degree of plasma protein binding determine how quickly small molecules cross the vessel wall
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Albumin and antibodies bind to the neonatal Fc receptor (FcRn), escape degradation inside endothelial cells and are returned to the circulation; this is why their blood half-lives are long
Barriers and degradation:
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The blood–brain barrier prevents most molecules from entering the brain; hypoxia, inflammation and brain tumours can disrupt the barrier and cause non-specific accumulation
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Cellular uptake may occur via transporters (ion, glucose, amino acid transporters); peptides not designed to resist degradation are rapidly broken down by peptidases
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Enhanced permeability and retention (EPR) effect: Non-specific accumulation of large molecules (antibodies, proteins, nanoparticles) in tumour because tumour vessels are leaky and lymphatic drainage is impaired
Targeting and validation:
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The degree of vascularisation and the vessel structure of the target tissue determine how much tracer reaches the target; if vascular supply is poor, FDG uptake may be low
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The extracellularly accessible part of the target may differ from the total expression measured by gene or proteomic analysis
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Confirmation of receptor expression by immunohistochemistry is a fundamental step in the validation of imaging studies
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In imaging the aim is to reach a high target/non-target ratio quickly; in therapy the ratio of decays in the target to those in normal tissues is decisive
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Reducing non-specific background uptake reduces adverse effects in therapy (e.g. salivary gland toxicity)
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In receptor quantification and occupancy studies, the parent compound must be separated from its radioactive metabolites
BOARD TIP
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Below ~40 kDa → exit from capillaries into the extravascular space; up to ~60 kDa → glomerular filtration; intact antibody (~150 kDa) → long blood half-life (FcRn) and extravasation in liver/bone marrow. EPR effect → non-specific accumulation of large molecules in tumour.
Figure 12.2: Passage through capillary types by molecular size and the EPR effect in tumour vessels (schematic).
Did this figure help you understand the topic?
12.2 Tc-99m Labelling Chemistry (Reduction, Ligands)
12.2.1 Basics of Tc-99m Chemistry
Tc-99m is the most widely used radionuclide in nuclear medicine (~80% of all nuclear medicine procedures). The reasons are:
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Ideal gamma energy: 140 keV → optimal for the gamma camera
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Suitable half-life: 6.01 hours → sufficient for imaging, low patient dose
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Pure gamma emitter: Isomeric transition (IT) → no particulate radiation → low dose
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Generator availability: Mo-99/Tc-99m generator → on-site production, no cyclotron needed
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Versatile chemistry: Different oxidation states → can form complexes with various ligands
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Kit-based preparation: Easy, quick, reliable
12.2.2 Pertechnetate (TcO₄⁻) and Reduction3 questions
Tc-99m eluted from the generator is in the form of pertechnetate (TcO₄⁻):
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Oxidation state: +7 (the highest)
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Negatively charged, tetrahedral structure
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Water-soluble, chemically stable
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Cannot bind to ligands in this form → reduction is required
Reduction:
For Tc-99m to form complexes with ligands, its oxidation state must be lowered (+7 → lower oxidation states: +5, +4, +3, +1).
Reducing agent: Tin(II) chloride (SnCl₂)
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The most widely used reducing agent
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Sn²⁺ → Sn⁴⁺ (tin is oxidised)
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TcO₄⁻ (+7) → Tc (+5, +4, +3, +1) (technetium is reduced)
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Most commercial kits contain a tin(II) salt (usually SnCl₂) as the reducing agent
Reduction reaction (general):
Sn²⁺ + TcO₄⁻ → Sn⁴⁺ + Tcⁿ⁺ (n < 7)
The reduced Tc-99m forms a complex with the ligand in the kit → the radiopharmaceutical is ready.
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Ligand exchange (transchelation): Tc first forms a complex with a weakly bound intermediate ligand (gluconate, tartrate, citrate) and is then transferred to the actual ligand. Examples: the tetrofosmin (gluconate), MAG3 (tartrate) and MIBI (citrate) kits
BOARD TIP
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"What is the reducing agent in Tc-99m kits?"
→ Stannous chloride (SnCl₂).
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"Why can pertechnetate not bind directly to ligands?"
→ Oxidation state +7 → very stable → cannot form complexes with ligands → reduction is needed.
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"What does excess tin do?"
→ Excess Sn²⁺ → over-reduces Tc-99m → colloidal Tc-99m forms → taken up by the liver and spleen.
12.2.3 Tc-99m Oxidation States and Complex Types
Tc-99m forms complexes with different ligands in different oxidation states:
+7 oxidation state:
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Pertechnetate (TcO₄⁻) → unreduced form
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Imaging of thyroid, salivary glands, Meckel's diverticulum, gastric mucosa
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Can be blocked by perchlorate (competitive inhibition)
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Tc-99m sulphur colloid: Technetium is not reduced; when heated with thiosulfate in an acidic medium it precipitates as a Tc₂S₇ colloid. It is the only kit radiopharmaceutical in which Tc remains in the +7 state
+5 oxidation state:
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The most common state for complex formation
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Tc-99m MAG3 → tubular secretion → renal imaging
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Tc-99m ECD → cerebral perfusion
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Tc-99m HMPAO → cerebral perfusion, leucocyte labelling (Tc +5, oxo-Tc core)
+4 oxidation state:
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Tc-99m MDP/HDP → bone imaging (phosphonate ligands)
+3 oxidation state:
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Tc-99m DMSA (acidic pH) → renal cortical binding
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Tc-99m IDA derivatives (mebrofenin) → hepatobiliary
+1 oxidation state:
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Tc-99m MIBI (sestamibi) → myocardial perfusion, parathyroid
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Isonitrile (MIBI) is a lipophilic, cationic Tc(I) complex. Tetrofosmin, with its diphosphine structure, is also lipophilic and cationic, but it is a trans-dioxo complex in which Tc is in the +5 state
12.2.4 The Tc-99m Kit Preparation Process
Standard kit preparation steps:
1. The kit vial is brought to room temperature 2. Freshly eluted Tc-99m pertechnetate from the generator is added 3. The vial is shaken gently (without foaming)
4. Incubation for a set time (depending on the kit: 15-30 min; some require boiling) 5. Quality control is performed (radiochemical purity) 6. Patient doses are prepared
Kit components:
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Reducing agent: SnCl₂ (stannous chloride)
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Ligand: A chemical compound specific to the target tissue
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Stabilisers: Ascorbic acid, gentisic acid (prevent radiolysis)
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Radiolysis increases with activity concentration and standing time; therefore no more than the maximum activity recommended by the manufacturer should be added to the kit
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Buffer: pH control
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Lyophilised form: Long shelf life, easy storage
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Nitrogen atmosphere: Prevents oxidation (prevents oxidation of Sn²⁺ to Sn⁴⁺)
BOARD TIP
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"Why is there a nitrogen atmosphere in the kit vial?"
→ To prevent oxidation of Sn²⁺. In the presence of oxygen, Sn²⁺ → Sn⁴⁺ oxidation → insufficient reduction → free pertechnetate increases → radiochemical purity falls.
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"The most common error in kit preparation?"
→ Entry of air (oxygen contamination) → oxidation of Sn²⁺ → insufficient reduction.
12.2.5 Tc-99m Labelling Problems1 questions
Free pertechnetate (free TcO₄⁻):
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Unreduced Tc-99m → not bound to the ligand
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Causes: Insufficient SnCl₂, entry of air (oxidation of Sn²⁺), old kit, excess activity
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Biodistribution: Thyroid, salivary glands, gastric mucosa, choroid plexus
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On the image: Visualisation of thyroid and stomach → artefact
Colloidal Tc-99m (hydrolysed-reduced Tc):
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Forms with excessive reduction or in the absence of a suitable ligand
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Tc-99m is hydrolysed → forms colloidal particles
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Biodistribution: Liver, spleen, bone marrow (RES uptake)
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Causes: Excess SnCl₂, low pH, insufficient ligand
Radiochemical purity:
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Acceptable limit: ≥90% for most Tc-99m kits (pertechnetate ≥95%; varies by kit)
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Measurement: Thin-layer chromatography (TLC) or paper chromatography
Figure 12.3: Tc-99m oxidation states and the labelling outcome by degree of reduction: free pertechnetate, Tc–ligand complex or colloidal Tc (schematic).
Did this figure help you understand the topic?
12.3 SPECT Radiopharmaceuticals (by Organ System)
12.3.1 Cardiovascular System4 questions
Tc-99m MIBI (Sestamibi, Cardiolite®):
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Chemical structure: 6 methoxy-isobutyl-isonitrile ligands → lipophilic cationic complex
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Oxidation state: Tc +1
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Localisation mechanism: Retained by the mitochondrial membrane potential
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Target: Myocardium (perfusion), parathyroid, breast
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Redistribution: Minimal → separate stress and rest injections are needed
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P-glycoprotein (Pgp) substrate → low uptake in MDR (multidrug-resistant) tumours
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Preparation: Kit + Tc-99m pertechnetate → requires boiling at 100°C for 10 min
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Because the free MIBI ligand is volatile, malodorous and unstable, the kit contains it as the copper(I) tetrakis(MIBI) tetrafluoroborate salt; during boiling Tc(I)-MIBI forms via a Tc-citrate intermediate complex
Tc-99m Tetrofosmin (Myoview®):
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Chemical structure: Diphosphines → lipophilic cationic complex
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Oxidation state: Tc +5 (dioxo complex; different from MIBI)
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Localisation: Mitochondrial membrane potential
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Advantages over MIBI: No boiling required (prepared at room temperature), faster hepatic clearance
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Redistribution: Minimal (like MIBI)
Tl-201 Chloride:
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Radionuclide: Tl-201 (cyclotron-produced, EC decay, T½ = 73 hours)
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Energy: 69-83 keV (Hg X-rays) → low energy → poor image quality
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Localisation: Cell entry via Na⁺/K⁺-ATPase (potassium analogue)
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Shows redistribution → viability assessment is possible
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Disadvantages: Long T½ → high patient dose, low energy → poor resolution
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Today largely replaced by Tc-99m agents and PET
BOARD TIP
▸
"Difference between MIBI and tetrofosmin?"
→ Both are lipophilic cationic complexes, retained by the mitochondrial membrane potential, with minimal redistribution. Difference: MIBI requires boiling, tetrofosmin is prepared at room temperature. MIBI has slower hepatic clearance → inferior wall artefact on early imaging.
▸
"Advantage of Tl-201?"
→ Redistribution → viability assessment (rest–redistribution, reinjection protocol).
12.3.2 Skeletal System
Tc-99m MDP (Methylene Diphosphonate) / Tc-99m HDP (Hydroxymethylene Diphosphonate):
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Chemical structure: Phosphonate ligands
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Oxidation state: Tc +4
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Localisation: Chemisorption onto hydroxyapatite crystals on the bone surface
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Determinants of uptake: Osteoblastic activity, blood flow
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After injection: 50-60% bone uptake, the rest renal excretion
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Imaging: 2-4 hours later (for background clearance)
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Three-phase bone scintigraphy: Blood flow (phase 1) → blood pool (phase 2) → delayed static (phase 3)
12.3.3 Urinary System2 questions
Tc-99m MAG3 (Mercaptoacetyltriglycine):
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Localisation: Tubular secretion (98%) → ERPF measurement
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Oxidation state: Tc +5
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Plasma protein binding: 90% → not glomerularly filtered
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The MAG3 kit (S-benzoyl-protected ligand, betiatide) is an exception: 2 mL of filtered air is injected into the vial to oxidise excess Sn²⁺, and the vial is heated in a boiling water bath for 10 min to remove the benzoyl group; the prepared product is used within 6 hours
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Renal clearance: Much faster than GFR agents → good images even in poorly functioning kidneys
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Indications: Renal function, obstruction (diuretic renography), transplant assessment
Tc-99m DTPA (Diethylenetriamine Pentaacetic Acid):
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Localisation: Glomerular filtration → GFR measurement
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Plasma protein binding: Minimal → freely filtered
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Renal clearance: Slower than MAG3
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Indications: GFR measurement, renal function, ventilation imaging as an aerosol
Tc-99m DMSA (Dimercaptosuccinic Acid):
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Localisation: Binding to renal cortical tubular cells (proximal tubule)
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40-50% of the injected dose is retained in the renal cortex
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Indications: Renal cortical imaging, scar detection, ectopic kidney, differential function
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The gold standard for assessing renal scarring after VUR, particularly in paediatric patients
BOARD TIP
▸
"MAG3 vs DTPA?"
→ MAG3 = tubular secretion (ERPF), DTPA = glomerular filtration (GFR). MAG3 clearance is faster → better images in poorly functioning kidneys → the preferred renal agent.
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"What is DMSA used for?"
→ Renal cortical imaging → scar detection, differential function. DMSA is NOT a dynamic study → static imaging (2-4 hours after injection).
12.3.4 Pulmonary System1 questions
Tc-99m MAA (Macroaggregated Albumin):
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Particle size: 10-100 µm (mean ~20-40 µm)
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Localisation: Capillary blockade → mechanical trapping in pulmonary arterioles
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Number of particles: 200,000-700,000 (standard dose)
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Number of precapillary arterioles: ~300 million → fraction blocked: ~0.1%
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Biological half-life: 2-9 hours → particles break down → cleared by the RES
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Contraindications: Severe pulmonary hypertension (number of particles reduced: 100,000-150,000), right-to-left shunt (risk of systemic embolisation)
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In pregnancy: The number of particles is reduced (100,000-200,000)
Ventilation agents:
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Tc-99m DTPA aerosol: Inhaled via a nebuliser → deposited on the alveolar surface
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Xe-133: Gas → inhaled → ventilation imaging → low energy (81 keV)
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Kr-81m: Gas → from a generator (Rb-81/Kr-81m) → T½ = 13 s → very short → ventilation only
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Technegas: Tc-99m pertechnetate is heated in a graphite crucible at 2500°C → ultrafine carbon particles (0.1 µm) → behave like a gas → homogeneous ventilation image
BOARD TIP
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"MAA particle size?"
→ 10-100 µm.
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"What is done in pulmonary hypertension?"
→ The number of particles is reduced (100,000-150,000).
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"Risk of MAA in a right-to-left shunt?"
→ Particles pass into the systemic circulation → risk of cerebral and renal embolisation.
▸
"What is Technegas?"
→ Ultrafine carbon particles (0.1 µm) → behave like a gas → the most homogeneous ventilation image.
12.3.5 Neurological System2 questions
Tc-99m HMPAO (Hexamethylpropyleneamine Oxime, Ceretec®):
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Lipophilic complex → crosses the blood–brain barrier (BBB)
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Converted to a hydrophilic form inside the cell → trapped in the cell (metabolic trapping)
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Oxidation state: Tc +5 (oxo-Tc core)
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Cerebral perfusion imaging
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Also used for leucocyte labelling
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Stability: Low → must be used within 30 minutes of preparation (unstabilised form)
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Stabilised form (with added methylene blue or cobalt chloride): can be used for up to 4 hours
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For HMPAO labelling the pertechnetate must be fresh (≤2 hours after elution) and the generator must have been eluted within the last 24 hours; otherwise accumulated Tc-99 lowers the labelling yield
Tc-99m ECD (Ethyl Cysteinate Dimer, Neurolite®):
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Lipophilic complex → crosses the BBB
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Hydrolysed inside the cell by esterase → hydrophilic form → trapped in the cell
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Oxidation state: Tc +5
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Advantages over HMPAO: More stable (up to 6 hours), less background activity
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Disadvantage: Cannot be used for leucocyte labelling
12.3.6 Hepatobiliary System2 questions
Tc-99m HIDA/DISIDA/Mebrofenin (IDA derivatives):
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Iminodiacetic acid (IDA) derivatives
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Localisation: Taken up by the hepatocyte via the organic anion transport system → excreted in bile
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Uses the same transport mechanism as bilirubin → competition at high bilirubin levels
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Mebrofenin (BrIDA): Highest hepatic extraction → good images even at high bilirubin (up to 20 mg/dL)
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DISIDA: Lower hepatic extraction than mebrofenin
•
Indications: Acute cholecystitis, bile leak, neonatal hepatitis vs biliary atresia, choledochal cyst
Tc-99m Sulphur Colloid:
•
Colloidal particles (100-1000 nm)
•
Localisation: Phagocytosis → Kupffer cells (liver 85-90%), spleen (5-10%), bone marrow (3-5%)
•
Indications: Liver–spleen scintigraphy, bone marrow imaging, lymphoscintigraphy (filtered form), GI bleeding (short blood half-life → disadvantage compared with the red cell method), gastric emptying (as a solid-phase marker)
•
Filtered sulphur colloid: passed through a 0.22 µm filter → particle size <220 nm (mostly ~100 nm) → sentinel lymph node mapping
Tc-99m-Labelled Red Blood Cells (RBC):
•
Labelling methods:
•
In vivo: First cold tin (Sn²⁺) IV → 20 min later Tc-99m pertechnetate IV → Sn²⁺ reduces pertechnetate inside the red cell → Tc-99m binds to haemoglobin. Labelling efficiency: 75-80%
•
Modified in vivo (in vivtro): Cold tin IV → 20 min later blood is drawn → Tc-99m is added in vitro → reinjected. Labelling efficiency: 85-90%
•
In vitro (UltraTag® kit): The whole process in a tube → highest labelling efficiency: >95% → gold standard
•
Indications: GI bleeding, hepatic haemangioma, MUGA (radionuclide ventriculography), splenic scintigraphy (heat-damaged red cells)
BOARD TIP
▸
"Highest efficiency in red cell labelling?"
→ The in vitro method (UltraTag®) → >95%.
▸
"Why does free pertechnetate increase with the in vivo method?"
→ Labelling efficiency is low (75-80%) → unbound pertechnetate is seen in the thyroid, stomach and kidneys → risk of a false positive in a GI bleeding study.
▸
"Which method for MUGA?"
→ In vitro (highest efficiency, least free pertechnetate).
Figure 12.4: Tc-99m red cell labelling methods and their labelling efficiencies (schematic).
Did this figure help you understand the topic?
12.3.7 Infection/Inflammation
Ga-67 Citrate:
•
Radionuclide: Ga-67 (cyclotron-produced, EC decay, T½ = 78 hours)
•
Energies: 93, 185, 300, 394 keV (multiple photopeaks)
•
Localisation: Binding to the transferrin receptor, lactoferrin binding (neutrophils), siderophore binding (bacteria), direct bacterial uptake
•
Ga³⁺ is an analogue of iron (Fe³⁺) (same charge, similar ionic radius); it therefore binds to transferrin in plasma. Lactoferrin and siderophore binding also result from this similarity
•
Indications: Chronic infection, tuberculosis, sarcoidosis, lymphoma (in the pre-FDG PET era), fever of unknown origin (FUO)
•
Disadvantages: Long T½ → high dose, poor resolution, waiting period of 24-72 hours, bowel excretion → abdominal assessment difficult
•
Today largely replaced by FDG PET/CT
In-111 Oxine-Labelled Leucocytes:
•
Radionuclide: In-111 (cyclotron-produced, EC decay, T½ = 67 hours)
•
Energies: 171 keV and 245 keV
•
Labelling: In vitro → blood is drawn from the patient → leucocytes are separated → labelled with In-111 oxine → reinjected
•
Localisation: Labelled leucocytes migrate to the site of infection/inflammation (chemotaxis)
•
Imaging: 18-24 hours later
•
Indications: Acute infection, osteomyelitis, prosthetic infection, inflammatory bowel disease
•
Normal biodistribution: Liver, spleen, bone marrow (RES)
Tc-99m HMPAO-Labelled Leucocytes:
•
An alternative to In-111 oxine
•
Advantages: Better image quality (140 keV), lower dose, same-day imaging (1-4 hours)
•
Disadvantages: Bowel and urinary excretion → care needed in abdominal assessment; short T½ → limited delayed imaging
BOARD TIP
▸
"Normal biodistribution in a labelled leucocyte study?"
→ Liver, spleen, bone marrow. Lung uptake is normal (first 1-4 hours → margination).
▸
"When is lung uptake pathological in leucocyte labelling?"
→ If it persists after 4 hours → consider pneumonia or ARDS.
▸
"In-111 vs Tc-99m HMPAO leucocytes?"
→ In-111 → delayed imaging possible (24 hours), no bowel excretion → preferred for abdominal infection. Tc-99m HMPAO → early imaging, better resolution.
12.3.8 Endocrine System2 questions
I-123 Sodium Iodide:
•
Cyclotron-produced, EC decay, T½ = 13.2 hours
•
Energy: 159 keV → ideal for the gamma camera
•
Localisation: Active transport into the thyroid cell via NIS (sodium–iodide symporter)
•
Indications: Thyroid scintigraphy, uptake test, ectopic thyroid tissue
•
Advantages over I-131: Lower dose, better image quality, no stunning effect
I-131 Sodium Iodide:
•
Reactor-produced (fission), β⁻ + gamma decay, T½ = 8.02 days
•
Gamma energy: 364 keV (imaging), beta energy: Emax 606 keV (therapy)
•
Indications: Treatment of thyroid cancer, treatment of hyperthyroidism, whole-body scan
•
Disadvantages: High dose (beta emission), stunning effect, poor image quality (high energy)
Tc-99m Pertechnetate (Thyroid):
•
Pertechnetate (TcO₄⁻) → enters the thyroid cell via NIS but is not organified
•
Shows trapping but not organification
•
I-123/I-131 → show both trapping and organification
•
Indications: Thyroid scintigraphy (nodule assessment), ectopic thyroid
•
Advantages: Easy availability, low cost, low dose
•
Disadvantage: Organification cannot be assessed → a discordant nodule (hot with Tc-99m, cold with iodine) may occur
I-123/I-131 MIBG (Metaiodobenzylguanidine):
•
Norepinephrine analogue → taken up by the adrenal medulla and sympathetic nerve endings via the norepinephrine transporter (NET/uptake-1)
•
I-123 MIBG: Diagnostic (T½ = 13.2 hours, 159 keV)
•
I-131 MIBG: Diagnostic + therapeutic (T½ = 8 days, beta + gamma)
•
Indications: Phaeochromocytoma, paraganglioma, neuroblastoma, carcinoid, medullary thyroid cancer, cardiac innervation
•
Drug interactions: Tricyclic antidepressants, cocaine, reserpine, labetalol → reduce MIBG uptake → should be stopped before the study
In-111 Pentetreotide (OctreoScan®):
•
Somatostatin analogue (octreotide) + In-111 DTPA
•
Localisation: Somatostatin receptors (especially SSTR2)
•
Indications: Neuroendocrine tumours (carcinoid, gastrinoma, VIPoma, glucagonoma), small cell lung cancer, meningioma
•
Today largely replaced by Ga-68 DOTATATE PET/CT (higher sensitivity and resolution)
•
Octreotide: An 8-amino-acid synthetic analogue of natural 14-amino-acid somatostatin; it is resistant to enzymatic degradation and has a long plasma half-life. Pentetreotide is octreotide conjugated to DTPA
BOARD TIP
▸
"Tc-99m pertechnetate vs I-123 thyroid scintigraphy?"
→ Pertechnetate shows trapping only; iodine shows trapping + organification.
▸
"Discordant nodule"
→ Hot with Tc-99m (trapping present) but cold with iodine (no organification) → carries a risk of malignancy → biopsy needed.
▸
"Drugs to stop before MIBG?"
→ Antipsychotics (~3-4 weeks; depot ~1 month), labetalol (10 days), tricyclic antidepressants (1-3 days).
12.4 PET Radiopharmaceuticals
12.4.1 F-18 FDG (Fluorodeoxyglucose)3 questions
The most widely used PET radiopharmaceutical (~90% of all PET studies).
Chemical structure and mechanism:
•
2-deoxy-2-[¹⁸F]fluoro-D-glucose → glucose analogue
•
Enters the cell via GLUT transporters (especially GLUT-1, GLUT-3)
•
Phosphorylation by hexokinase → FDG-6-phosphate
•
Trapped in cells with low glucose-6-phosphatase activity (metabolic trapping)
•
Tumour cells: Increased GLUT-1 expression + increased hexokinase activity + low glucose-6-phosphatase → intense FDG uptake
Patient preparation:
•
4-6 hours fasting (to lower insulin levels and reduce muscle uptake)
•
Blood glucose control: <150-200 mg/dL (ideally <150 mg/dL)
•
High blood glucose → competition with FDG → tumour uptake decreases, image quality falls
•
In diabetic patients: FDG should be given at least 4 hours after an insulin injection (insulin increases muscle uptake)
•
Wait 60 minutes after injection (uptake time)
•
During the uptake period the patient should stay quiet, still and in a warm environment (to reduce muscle and brown fat uptake)
Physiological FDG uptake:
•
Brain: The most intense uptake (grey matter > white matter)
•
Myocardium: Variable (low in the fasting state, high in the fed state)
•
Myocardium and skeletal muscle contain insulin-sensitive GLUT-4; the fed state and insulin increase myocardial and muscle FDG uptake, leaving less FDG for the tumour
•
Liver: Moderate, homogeneous uptake (reference organ)
•
Kidneys and bladder: Renal excretion → intense uptake
•
Bowel: Variable (peristalsis, lymphoid tissue)
•
Tonsils and adenoids: Lymphoid tissue → physiological uptake
•
Bone marrow: Low-to-moderate diffuse uptake
•
Brown adipose tissue: Especially in the neck and supraclavicular region → increases in cold weather
Causes of false positives:
•
Infection/inflammation (activated macrophages and neutrophils)
•
Granulomatous diseases (sarcoidosis, tuberculosis)
•
Postoperative/post-traumatic changes
•
Post-radiotherapy inflammation (radiation pneumonitis)
•
Brown adipose tissue activation
•
Muscle activity (speaking → laryngeal muscles, chewing → masseter)
Causes of false negatives:
•
Hyperglycaemia (competitive inhibition)
•
Small lesion size (<7-8 mm → partial volume effect)
•
Tumours with low metabolic activity (bronchioloalveolar carcinoma/lepidic adenocarcinoma, mucinous tumours, renal cell carcinoma, hepatocellular carcinoma, low-grade lymphoma, well-differentiated neuroendocrine tumours)
•
Tumours with high glucose-6-phosphatase activity (hepatocellular carcinoma)
•
Early period after chemotherapy/radiotherapy (stunning effect)
BOARD TIP
▸
"False-negative tumours on FDG PET?"
→ Bronchioloalveolar carcinoma (lepidic adenocarcinoma), renal cell carcinoma, hepatocellular carcinoma, prostate cancer, low-grade lymphoma, well-differentiated NET, mucinous tumours.
▸
"How does hyperglycaemia affect FDG PET?"
→ High blood glucose → glucose competes with FDG → tumour uptake decreases + muscle and fat uptake increase → sensitivity falls.
▸
"To reduce brown fat uptake?"
→ Warm environment, anxiolytic (diazepam), beta-blocker (propranolol 20 mg orally, 1 hour before imaging).
12.4.2 F-18 NaF (Sodium Fluoride)
•
A PET agent for bone imaging
•
Fluoride ion → replaces OH⁻ in the hydroxyapatite crystal → forms fluorapatite
•
Advantages over Tc-99m MDP: 2 times higher bone uptake, faster blood clearance, higher target/background ratio, PET resolution
•
Indications: Screening for bone metastases, benign bone lesions, metabolic bone diseases
•
Disadvantage: Requires a cyclotron, not as widely available as FDG
12.4.3 F-18/C-11 Choline
•
A marker of cell membrane synthesis → phosphorylation by choline kinase in phospholipid synthesis
•
Prostate cancer, hepatocellular carcinoma, brain tumours
•
F-18 fluorocholine: T½ = 110 min → more practical
•
C-11 choline: T½ = 20 min → requires an on-site cyclotron
•
In prostate cancer: More sensitive than FDG (prostate cancer shows low glucose metabolism)
•
Today largely replaced by PSMA PET in prostate cancer
12.4.4 Ga-68 DOTATATE/DOTATOC/DOTANOC3 questions
•
Somatostatin receptor imaging → neuroendocrine tumours (NET)
•
Ga-68: Generator-produced (Ge-68/Ga-68), T½ = 68 min, positron emitter
•
DOTATATE → SSTR2-selective (highest affinity)
•
DOTATOC → SSTR2 and SSTR5
•
DOTANOC → SSTR2, SSTR3, SSTR5 (broadest spectrum)
•
Advantages over In-111 OctreoScan: Higher sensitivity, better resolution, lower dose, shorter study time
•
Theranostic partner: Ga-68 DOTATATE (diagnosis) → Lu-177 DOTATATE (therapy/PRRT)
•
Normal uptake: Spleen (most intense), kidneys, liver, adrenal glands, pituitary, thyroid
BOARD TIP
▸
"The most intense physiological uptake with Ga-68 DOTATATE?"
→ Spleen (intense SSTR2 expression).
▸
"DOTATATE vs DOTATOC vs DOTANOC?"
→ DOTATATE = SSTR2-selective (highest affinity), DOTANOC = broadest receptor spectrum.
▸
"The theranostic concept?"
→ A diagnostic (Ga-68) and therapeutic (Lu-177) pair using the same target (SSTR2).
Figure 12.5: Somatostatin receptor subtype binding profiles of DOTATATE, DOTATOC and DOTANOC.
Did this figure help you understand the topic?
12.4.5 Ga-68/F-18 PSMA
•
Prostate-specific membrane antigen (PSMA) → type II transmembrane glycoprotein
•
Overexpressed in prostate cancer cells (100-1000 times normal prostate tissue)
•
Ga-68 PSMA-11: The most widely used PSMA PET agent
•
F-18 PSMA-1007 and F-18 DCFPyL: F-18-based → longer T½, better resolution, less urinary excretion (PSMA-1007)
•
Indications: Staging of prostate cancer, detection of biochemical recurrence, assessment of treatment response
•
Theranostic partner: Ga-68/F-18 PSMA (diagnosis) → Lu-177 PSMA (therapy)
•
Normal/physiological uptake: Salivary glands, kidneys (proximal tubule), small bowel, liver, lacrimal glands, sympathetic ganglia
•
False positives: Ganglia, bone fractures (healing), Paget's disease, other malignancies (renal cell carcinoma, hepatocellular carcinoma, thyroid cancer)
BOARD TIP
▸
"The most intense physiological uptake on PSMA PET?"
→ Salivary glands and kidneys.
▸
"Dose-limiting organ in Lu-177 PSMA therapy?"
→ Salivary glands (risk of xerostomia) and kidneys.
▸
"PSMA-negative prostate cancer?"
→ Prostate cancer with neuroendocrine differentiation → low PSMA → FDG PET is preferred.
12.4.6 Amyloid PET Agents
•
Imaging of brain amyloid plaques → diagnosis of Alzheimer's disease
•
F-18 florbetapir (Amyvid®): The first FDA-approved amyloid PET agent
•
F-18 florbetaben (Neuraceq®)
•
F-18 flutemetamol (Vizamyl®)
•
Target: Beta-amyloid (Aβ) plaques → neuritic plaques
•
Positive scan: Increased uptake in cortical grey matter → loss of grey–white matter contrast
•
Negative scan: Largely excludes Alzheimer's disease (high negative predictive value)
•
Caution: A positive scan is NOT a definitive diagnosis of Alzheimer's disease → amyloid deposition may be present in the elderly (asymptomatic)
12.4.7 Tau PET
•
F-18 flortaucipir (Tauvid®): FDA-approved tau PET agent
•
Target: Neurofibrillary tangles (NFT) → hyperphosphorylated tau protein
•
In Alzheimer's disease: Tau deposition correlates better with clinical symptoms (unlike amyloid)
•
Distribution pattern consistent with Braak staging
12.4.8 DaTscan (I-123 Ioflupane)
•
Technically a SPECT agent but considered together with neurological PET agents
•
Dopamine transporter (DAT) imaging
•
Localisation: Presynaptic dopaminergic neuron terminals → striatum (caudate + putamen)
•
Indications: Distinguishing Parkinson's disease from essential tremor, dementia with Lewy bodies from Alzheimer's disease
•
Normal image: Symmetric, comma-shaped striatal uptake ("comma sign")
•
Abnormal image: Loss of putaminal uptake → "dot sign" (period sign) → nigrostriatal degeneration
Figure 12.6: Normal comma-shaped striatal uptake on DaTscan and the dot sign with putaminal loss in nigrostriatal degeneration (schematic).
Did this figure help you understand the topic?
12.4.9 Other PET Radiopharmaceuticals
Rb-82 Chloride:
•
Generator-produced (Sr-82/Rb-82), T½ = 75 seconds
•
Potassium analogue → into the myocardial cell via Na⁺/K⁺-ATPase
•
Cardiac PET perfusion → measurement of absolute myocardial blood flow (MBF) and coronary flow reserve (CFR)
•
Very short T½ → fast protocol, low dose, stress–rest in the same session
N-13 Ammonia:
•
Cyclotron-produced, T½ = 9.97 min
•
Myocardial perfusion PET → MBF and CFR measurement
•
Advantage over Rb-82: Higher extraction fraction → more accurate MBF measurement
•
Disadvantage: Requires an on-site cyclotron
O-15 Water:
•
Cyclotron-produced, T½ = 2.04 min
•
Gold standard for MBF measurement → diffuses freely → extraction fraction independent of flow
•
Not used in clinical practice: Very short T½, on-site cyclotron, does not produce a perfusion image
F-18 FAZA / F-18 FMISO:
•
Hypoxia imaging → assessment of tumour hypoxia
•
Nitroimidazole derivatives → reduced and trapped in hypoxic cells
•
Potential use in radiotherapy planning
F-18 FLT (Fluorothymidine):
•
Proliferation marker → phosphorylation by thymidine kinase-1 (TK-1)
•
Assessment of tumour proliferation, early assessment of treatment response
F-18 DOPA:
•
Dopamine precursor → metabolised by aromatic amino acid decarboxylase (AADC)
•
Neuroendocrine tumours (especially medullary thyroid cancer, phaeochromocytoma)
•
Assessment of brain dopamine synthesis
C-11 Methionine:
•
Amino acid PET → marker of protein synthesis
•
Brain tumours (glioma) → advantageous over FDG (low brain background uptake)
•
Disadvantage: C-11 → T½ = 20 min → requires an on-site cyclotron
BOARD TIP
▸
"Gold standard for MBF measurement?"
→ O-15 water (diffuses freely, flow-independent extraction).
▸
"MBF measurement in clinical practice?"
→ Rb-82 or N-13 ammonia PET.
▸
"Disadvantage of FDG in brain tumour PET?"
→ High baseline brain FDG uptake → low tumour/background ratio → C-11 methionine or F-18 FET is preferred.
12.5 Therapeutic Radiopharmaceuticals (I-131, Lu-177, Ra-223, Y-90, etc.)
12.5.1 I-131 Sodium Iodide
•
Treatment of thyroid cancer (ablation and treatment of metastases) and of hyperthyroidism
•
Beta emission: Emax = 606 keV → therapeutic effect (tissue penetration: 0.6-2 mm)
•
Gamma emission: 364 keV → scintigraphy/scanning
•
In thyroid cancer: Postoperative remnant ablation ( 1.1 GBq (30 mCi) in low risk, 1.1-5.5 GBq (30-150 mCi) in intermediate risk) and treatment of metastases (5.5-11.1 GBq (150-300 mCi))
•
In hyperthyroidism: Graves (370-555 MBq (10-15 mCi)), toxic adenoma (370-740 MBq (10-20 mCi)), TMNG (555-1110 MBq (15-30 mCi))
•
Adverse effects: Sialadenitis, nausea, bone marrow suppression (at high doses), pulmonary fibrosis (in treatment of diffuse lung metastases), risk of secondary malignancy (leukaemia)
•
Details: → See Chapter 13 (Thyroid) and Chapter 26 (Radionuclide Therapy)
12.5.2 Lu-177 DOTATATE (Lutathera®)1 questions
•
Peptide receptor radionuclide therapy (PRRT) → advanced somatostatin receptor-positive neuroendocrine tumours
•
Lu-177: β⁻ emitter (Emax = 497 keV) + gamma (113, 208 keV → SPECT imaging)
•
T½ = 6.65 days; for the long-lived Lu-177m impurity from direct production see 26.4
•
Dose: 7.4 GBq (200 mCi) × 4 cycles (8 weeks apart)
•
NETTER-1 trial: Lu-177 DOTATATE + octreotide LAR vs high-dose octreotide LAR → clear superiority in PFS
•
Renal protection: Amino acid infusion (lysine + arginine) → reduces proximal tubular reabsorption
•
Dose-limiting organs: Kidneys and bone marrow
12.5.3 Lu-177 PSMA-617 (Pluvicto®)
•
Treatment of metastatic castration-resistant prostate cancer (mCRPC)
•
Targets PSMA-positive lesions
•
Dose: 7.4 GBq (200 mCi) × 6 cycles (6 weeks apart)
•
VISION trial: Lu-177 PSMA-617 + standard care vs standard care alone → significant improvement in both OS and PFS
•
Patient selection: ≥1 PSMA-positive lesion on PSMA PET and no PSMA-negative lesion meeting size criteria (VISION)
•
Dose-limiting organs: Salivary glands (xerostomia), kidneys, bone marrow
•
Adverse effects: Xerostomia, bone marrow suppression (thrombocytopenia, anaemia), fatigue, nausea
•
Theranostic pair: Ga-68/F-18 PSMA (diagnosis) → Lu-177 PSMA (therapy)
Figure 12.7: Pairs of diagnostic and therapeutic radiopharmaceuticals using the same target (the theranostic concept).
Did this figure help you understand the topic?
12.5.4 Ra-223 Dichloride (Xofigo®)2 questions
•
Alpha emitter → castration-resistant prostate cancer with bone metastases
•
Ra-223: Alpha decay, T½ = 11.4 days
•
Calcium analogue → accumulates in osteoblastic bone metastases
•
Alpha particles: High LET, short range (100 µm = 10 cell diameters) → minimal damage to surrounding tissue
•
Dose: 55 kBq/kg IV × 6 cycles (4 weeks apart)
•
ALSYMPCA trial: Ra-223 vs placebo → significant improvement in OS + reduction in symptomatic skeletal events
•
Indication: mCRPC with bone metastases only (contraindicated in the presence of visceral metastases)
•
Adverse effects: Bone marrow suppression (thrombocytopenia), diarrhoea, nausea
BOARD TIP
▸
"Why is Ra-223 used only for bone metastases?"
→ Calcium analogue → accumulates only on the bone surface → ineffective against visceral metastases.
▸
"Ra-223 vs other bone palliation agents (Sr-89, Sm-153)?"
→ Ra-223 is an alpha emitter (high LET, short range) → the only bone palliation agent shown to give a survival benefit. Sr-89 and Sm-153 are beta emitters → palliative only, no survival benefit.
12.5.5 Y-90 Microspheres (Radioembolisation)1 questions
•
Selective internal radiation therapy (SIRT) of liver tumours
•
Y-90: Pure β⁻ emitter (no gamma), Emax = 2.28 MeV, T½ = 64.1 hours
•
Tissue penetration: Mean 2.5 mm, maximum 11 mm
•
Two commercial products:
•
TheraSphere® (glass microspheres): 20-30 µm, high specific activity, fewer particles
•
SIR-Spheres® (resin microspheres): 20-60 µm, low specific activity, more particles → more pronounced embolic effect
•
Indications: Hepatocellular carcinoma (HCC), colorectal liver metastases, liver metastases of neuroendocrine tumours
•
Pre-treatment assessment:
•
Tc-99m MAA shunt study: Injection of Tc-99m MAA into the hepatic artery → the lung shunt is calculated
–
Lung shunt >20% → treatment contraindicated (risk of radiation pneumonitis)
–
Lung shunt 10-20% → dose reduction needed
–
GI shunt → prophylactic coil embolisation (gastroduodenal artery, right gastric artery)
•
Complications: Radiation pneumonitis (lung shunt), GI ulceration (GI shunt), radioembolisation-induced liver disease (REILD), cholecystitis, lymphopenia
Figure 12.8: Decision pathway based on the Tc-99m MAA shunt study before Y-90 radioembolisation.
Did this figure help you understand the topic?
12.5.6 Sr-89 Chloride (Metastron®) and Sm-153 EDTMP (Quadramet®)
Sr-89 Chloride:
•
Calcium analogue → accumulates in osteoblastic bone metastases
•
Almost pure β⁻ emitter (909 keV gamma 0.01%), T½ = 50.5 days
•
Dose: 148 MBq (4 mCi) IV, single dose
•
Indication: Pain palliation in widespread osteoblastic bone metastases
•
Long T½ → prolonged bone marrow suppression (especially thrombocytopenia) → a disadvantage
Sm-153 EDTMP (Quadramet®):
•
Phosphonate ligand (EDTMP) → binds to the bone surface
•
β⁻ emitter + gamma (103 keV → imaging possible)
•
T½ = 46.3 hours (much shorter than Sr-89 → faster bone marrow recovery)
•
Dose: 37 MBq/kg (1 mCi/kg) IV
•
Shipped frozen (−10/−20 °C); thawed at room temperature before administration and must be used within 8 hours of thawing
•
Indication: Pain palliation in osteoblastic bone metastases
•
Advantage over Sr-89: Shorter T½ → less bone marrow toxicity; gamma emission → imaging
BOARD TIP
▸
"Which agents are used for palliation of bone pain?"
→ Sr-89 (calcium analogue, pure beta), Sm-153 (phosphonate, beta + gamma), Ra-223 (calcium analogue, alpha).
▸
"Which one shows a survival benefit?"
→ Only Ra-223 (ALSYMPCA trial).
▸
"Sr-89 vs Sm-153?"
→ Sr-89 T½ = 50.5 days (long → more bone marrow toxicity), Sm-153 T½ = 46.3 hours (short → less toxicity, easier retreatment).
Figure 12.9: Physical decay curves of bone palliation agents: Sm-153 (46.3 hours), Ra-223 (11.4 days) and Sr-89 (50.5 days).
Did this figure help you understand the topic?
12.5.7 I-131 MIBG Therapy1 questions
•
High-dose I-131 MIBG → neuroblastoma, inoperable/metastatic phaeochromocytoma/paraganglioma
•
Azedra® (I-131 iobenguane): Was FDA-approved (2018); production was discontinued in 2024
•
Dose: Therapeutic doses usually 200-800 mCi (7.4-29.6 GBq)
•
Before treatment: Tumour uptake must be confirmed with diagnostic I-123 MIBG or I-131 MIBG
•
Thyroid blockade: SSKI or potassium iodide → started 24-48 hours before treatment, continued for 10-14 days
•
Drug interactions: Drugs that reduce MIBG uptake must be stopped (→ see 12.3.8)
12.5.8 Ho-166 Microspheres (QuiremSpheres®)
•
Holmium-166-labelled poly-L-lactic acid microspheres
•
β⁻ emitter (Emax = 1.85 MeV) + gamma (81 keV → SPECT imaging)
•
T½ = 26.8 hours
•
Advantage over Y-90 microspheres: Can be imaged with SPECT and MR → dosimetric verification is possible
•
Can also be used as a scout dose (instead of Tc-99m MAA → more accurate prediction of dose distribution)
•
Indications: Liver tumours (HCC, metastases)
12.5.9 Y-90 Ibritumomab Tiuxetan (Zevalin®)
•
Radioimmunotherapy (RIT) → CD20-positive non-Hodgkin lymphoma
•
Anti-CD20 monoclonal antibody (ibritumomab) + Y-90
•
Pre-treatment In-111 biodistribution imaging is no longer mandatory (2011)
•
Dose: 14.8 MBq/kg (0.4 mCi/kg), maximum 1184 MBq (32 mCi)
•
Platelet count ≥150,000 → full dose; 100,000-149,000 → 11.1 MBq/kg (0.3 mCi/kg)
•
Platelets <100,000 → contraindicated
•
Details: → See Chapter 20 (Haematology and Lymphoma) and Chapter 26 (Radionuclide Therapy)
12.5.10 Radiosynovectomy Agents2 questions
•
Intra-articular injection → treatment of synovial hypertrophy (rheumatoid arthritis, haemophilic arthropathy)
•
Choice of agent according to joint size:
•
Y-90 silicate/citrate: Large joints (knee) → β⁻, T½ = 64.1 hours, penetration 11 mm
•
Re-186 sulphide: Medium joints (shoulder, hip, elbow) → β⁻, T½ = 3.7 days, penetration 3.6 mm
•
Er-169 citrate: Small joints (finger) → β⁻, T½ = 9.4 days, penetration 1 mm
BOARD TIP
▸
"Choice of agent in radiosynovectomy?"
→ According to joint size: large joint = Y-90 (long penetration), medium joint = Re-186, small joint = Er-169 (short penetration). Logic: large joint = thick synovium → deep penetration needed → high-energy beta.
Figure 12.10: Tissue penetration of radiosynovectomy agents and their selection by joint size.
Did this figure help you understand the topic?
12.6 Biodistribution and Pharmacokinetics
12.6.1 Factors Affecting Biodistribution
Physicochemical properties:
•
Particle size:
–
20-60 µm → embolisation at arteriole level (Y-90 microspheres)
–
10-100 nm → sentinel lymph node mapping (filtered sulphur colloid)
–
100-1000 nm → RES phagocytosis (sulphur colloid → liver, spleen)
–
10-100 µm → capillary blockade (MAA → pulmonary arterioles)
–
<10 nm → passage into blood capillaries (not retained in the lymph node)
•
Electric charge: Positively charged → affinity for the cell membrane (MIBI, tetrofosmin)
•
Lipophilicity: Lipophilic agents → cross the BBB (HMPAO, ECD) and cell membranes
•
Protein binding: High protein binding → not glomerularly filtered (MAG3 is 90% bound)
Biological factors:
•
Blood flow: Blood flow to the target organ → determines radiopharmaceutical distribution
•
Receptor density: Determines the amount of uptake for receptor-based agents
•
Metabolic activity: FDG uptake is proportional to glucose metabolism
•
Organ function: Renal/hepatic function → affects the rate of clearance
Figure 12.11: In vivo fate of radiopharmaceuticals by particle size (logarithmic scale).
Did this figure help you understand the topic?
12.6.2 Routes of Excretion
•
Renal excretion: The most common route → Tc-99m DTPA, Tc-99m MAG3, FDG, Ga-68 PSMA-11
•
Hepatobiliary excretion: Tc-99m HIDA/mebrofenin, Tc-99m MIBI (partly), In-111 OctreoScan
•
Pulmonary excretion: Xe-133, Kr-81m (in gas form)
•
Saliva/GI tract: Tc-99m pertechnetate, I-131 (salivary glands)
•
Lactation: Many radiopharmaceuticals pass into breast milk → breastfeeding restrictions are needed
12.6.3 Effective Half-Life2 questions
It determines the rate at which the total activity of the radiopharmaceutical in the body decreases:
•
Tphys: Physical half-life (radioactive decay)
•
Tbiol: Biological half-life (metabolic elimination)
•
Teff: Effective half-life → always shorter than the shortest half-life
1/Teff = 1/Tphys + 1/Tbiol or Teff = (Tphys × Tbiol) / (Tphys + Tbiol)
BOARD TIP
▸
"The effective half-life is always shorter than both the physical and the biological half-life." Example: Tphys = 6 hours, Tbiol = 3 hours → Teff = (6×3)/(6+3) = 2 hours.
▸
"Which half-life is used in dose calculation?"
→ The effective half-life (MIRD formalism).
12.7 Adverse Effects and Interactions of Radiopharmaceuticals
12.7.1 General Safety Profile
Diagnostic radiopharmaceuticals are extremely safe → the incidence of adverse reactions is very low (~1-6/100,000 injections). The reasons are:
•
Tracer principle → the pharmacological dose is very low (microgram–nanogram)
•
Allergic reactions are rare (unlike iodinated contrast agents)
•
Anaphylaxis is extremely rare
12.7.2 Specific Adverse Effects
Tc-99m MAA:
•
Pulmonary capillary blockade → usually asymptomatic
•
In severe pulmonary hypertension: The number of particles should be reduced (risk of haemodynamic compromise)
•
In a right-to-left shunt: Risk of systemic embolisation
Tc-99m Sulphur Colloid:
•
Rare allergic reactions
•
Contains gelatin → caution in patients with gelatin allergy
Tc-99m MIBI:
•
Metallic taste (transient)
•
Headache (rare)
FDG:
•
Pain/redness at the injection site (rare)
•
No serious adverse effects reported
Ga-67 Citrate:
•
Allergic reactions (rare)
I-131 (therapeutic doses):
•
Sialadenitis: The most common adverse effect → inflammation of the salivary glands → pain, swelling, dry mouth
•
Prevention: Sour sweets/lemon (increase salivary flow → controversial; some centres start 24 hours after treatment)
•
Nausea/vomiting: Especially at high doses
•
Bone marrow suppression: Dose-dependent, usually transient
•
Hypothyroidism: An expected outcome (in thyroid cancer treatment)
•
Transient thyrotoxicosis: Radiation thyroiditis → release of stored hormone
•
Secondary malignancy: Risk of leukaemia (cumulative dose >600-800 mCi)
•
Gonadal damage: Transient oligospermia/azoospermia (in men), transient amenorrhoea (in women)
•
Pulmonary fibrosis: In treatment of diffuse lung metastases (risk increases if lung retention at 48 hours is >80 mCi)
Ra-223:
•
Bone marrow suppression (thrombocytopenia)
•
Diarrhoea, nausea
•
Fracture risk (increased in combination with abiraterone + prednisone → this combination is contraindicated; ERA-223)
12.7.3 Drug Interactions4 questions
Some drugs can alter radiopharmaceutical uptake → may cause false results:
Thyroid scintigraphy/RAI therapy:
•
Iodine-containing drugs/contrast agents: Saturate the iodine pool → reduce RAI uptake
•
IV iodinated contrast: 6-8 weeks wait
•
Amiodarone: 3-6 months (or longer) wait (long T½)
•
Antithyroid drugs (PTU, methimazole): Block organification → methimazole is stopped 2-5 days before treatment; PTU is stopped earlier because its effect lasts longer
•
Lithium: Increases RAI uptake (blocks iodine release)
•
Levothyroxine: Suppresses TSH → reduces RAI uptake → stopped before treatment (3-4 weeks) or rhTSH is used
MIBG scintigraphy:
•
Labetalol: stop 10 days before; longest: antipsychotics (~3-4 weeks, depot ~1 month)
•
Tricyclic antidepressants: Block the uptake-1 mechanism → stop 1-3 days before (EANM/SNMMI 2019)
•
Calcium channel blockers: stop 48 hours before
•
Cocaine, amphetamine: Uptake-1 inhibition
•
Reserpine: Impairs vesicular storage
FDG PET:
•
Insulin: Increases muscle and fat uptake → reduces tumour uptake → should be given at least 4 hours before injection
•
Corticosteroids: Raise blood glucose → may reduce FDG uptake
•
G-CSF (filgrastim): Increases bone marrow and splenic FDG uptake → image 2-4 weeks after treatment
•
Chemotherapy: At least 2-3 weeks after treatment (to let the inflammatory response subside)
•
Radiotherapy: At least 2-3 months after treatment (to let radiation pneumonitis/inflammation subside)
Bone scintigraphy:
•
Bisphosphonates: May reduce bone uptake (competition)
•
Iron preparations: May form a complex with Tc-99m MDP → low bone uptake
•
Aluminium antacids: Interaction with Tc-99m
BOARD TIP
▸
"Which drug must be stopped for the longest time before RAI therapy?"
→ Amiodarone (3-6 months or longer → very long T½, high iodine content).
▸
"When should G-CSF be stopped before FDG PET?"
→ At least 2-4 weeks before (to let bone marrow activation subside).
▸
"Which drug must be stopped for the longest time before MIBG?"
→ Antipsychotics (~3-4 weeks; depot form ~1 month).
12.8 Radiopharmaceutical Quality Control
12.8.1 Quality Control Parameters8 questions
Radiopharmaceuticals must meet defined quality standards before administration to the patient:
1. Radionuclidic purity:
–
Radionuclidic purity is the fraction of total radioactivity that belongs to the desired radionuclide.
–
Contaminant radionuclides: Unwanted radionuclides arising from the production process
–
In the Tc-99m generator: Mo-99 breakthrough → the most important contaminant
–
Limit: ≤0.15 µCi Mo-99 / mCi Tc-99m (NRC limit) = ≤0.15 kBq/MBq
–
Measurement: Lead container (6 mm lead) → absorbs the 140 keV gamma of Tc-99m, while the 740-780 keV gamma of Mo-99 passes through → measured in the dose calibrator
–
In I-123: I-124 and I-125 contamination may occur
2. Radiochemical purity (RCP):
–
Radiochemical purity is the fraction of radioactivity bound in the desired chemical form.
–
Unwanted forms: Free pertechnetate (TcO₄⁻), colloidal/hydrolysed Tc-99m
–
Acceptance limit: ≥90% for most Tc-99m kits (pertechnetate ≥95%; varies by kit type)
–
Method: Thin-layer chromatography (TLC) or paper chromatography
TLC method:
•
Stationary phase: ITLC-SG (silica gel-impregnated glass fibre strip) or ITLC-SA (silicic acid)
•
Mobile phase: Solvent system (acetone, saline, MEK, etc.)
•
Principle: Different Tc-99m forms have different Rf values
Common TLC systems:
•
ITLC-SG + acetone:
–
Free TcO₄⁻ → migrates with the front (Rf = 1.0)
–
Tc-99m complex + colloidal Tc → stay at the origin (Rf = 0)
–
This system determines the percentage of free pertechnetate
•
ITLC-SG + saline (or 85% methanol):
–
Free TcO₄⁻ + Tc-99m complex → migrate with the front (Rf = 1.0)
–
Colloidal/hydrolysed Tc → stays at the origin (Rf = 0)
–
This system determines the percentage of colloidal Tc
•
Percentage of desired complex = 100% - (free TcO₄⁻ %) - (colloidal Tc %)
BOARD TIP
▸
"What is measured when acetone is used in TLC?"
→ Free pertechnetate (migrates with the front).
▸
"What is measured when saline is used?"
→ Colloidal Tc (stays at the origin).
▸
"How is RCP calculated?"
→ RCP = 100 - free TcO₄⁻ (%) - colloidal Tc (%). Example: acetone TLC → 96% at origin, 4% at front → free TcO₄⁻ = 4%. Saline TLC → 2% at origin, 98% at front → colloidal Tc = 2%. RCP = 100 - 4 - 2 = 94% → above the limit for most kits (≥90%) → usable.
An ITLC-SG strip is developed first in acetone, then in saline: as the solvent rises, free pertechnetate (and in saline the Tc complex) moves to the front while the rest stays at the origin; the strip is cut and the halves counted. In the last step radiochemical purity is calculated from both results and compared with the 90% limit; three preparation scenarios can be chosen.
Continuous stream · no seeking
Key point: acetone measures free pertechnetate (moves to the front), saline measures colloidal Tc (stays at the origin); RCP = 100 − free TcO₄⁻ − colloidal Tc, and for most kits it must be at least 90%.
Source: book (ITLC-SG + acetone: TcO₄⁻ Rf 1, complex and colloid Rf 0; ITLC-SG + saline or 85% methanol: TcO₄⁻ and complex Rf 1, colloid Rf 0; RCP = 100 − free − colloid; limit ≥90%; example 4% / 2% → 94%). Percentages of the other two scenarios illustrative. Lipophilic complexes (e.g. MIBI, HMPAO) need different solvent systems.
How to use: a single click on the drawing pauses and resumes; ↑ ↓ or the buttons below change the preparation scenario; ← → change steps.
Did this animation help you understand the topic?
Figure 12.12: Radiochemical purity calculation with two-system ITLC: a worked example on acetone and saline strips (schematic).
3. Radiopharmaceutical purity:
–
Freedom of the desired radiopharmaceutical from other chemical compounds
–
Assessed by HPLC
4. Chemical purity:
–
Chemical purity assesses the amount of non-radioactive chemical impurities in the preparation.
–
Aluminium test: Al³⁺ breakthrough in the Mo-99/Tc-99m generator
–
Leakage of aluminium from the alumina column
–
Limit: ≤10 µg Al/mL eluate
–
Measurement: Colorimetric test (aurin tricarboxylic acid/aluminon test paper)
–
Lead container: ~6 mm thick → almost completely absorbs the 140 keV gamma of Tc-99m
5. pH:
–
Should usually be between 4.5 and 7.5
–
Varies by kit type
6. Sterility and apyrogenicity:
–
Mandatory for IV administration
–
Sterility test: Bacterial culture (retrospective → result in 14 days)
–
Pyrogen test: LAL (Limulus Amoebocyte Lysate) test → endotoxin detection
–
Because of the short shelf life of radiopharmaceuticals, they are used before the sterility result is available → aseptic technique is critical
7. Particle size (for particulate agents):
–
Tc-99m MAA: 10-100 µm (>90%), no particles >150 µm
–
Tc-99m sulphur colloid: 100-1000 nm
–
Assessed with a haemocytometer or microscope
Regulatory framework for production and release:
•
GLP (Good Laboratory Practice) governs the reliability of non-clinical research data, whereas GMP (Good Manufacturing Practice) governs the production and quality assurance of products given to patients
•
The EU GMP guide consists of three parts and 19 annexes. For radiopharmaceuticals, Annex 1 (sterile products), Annex 3 (radiopharmaceuticals), Annex 13 (investigational products) and Annex 15 (qualification/validation) are particularly important; EANM also provides guidance for small-scale (hospital/PET centre) preparation
•
A short half-life or heat sensitivity of the product may make terminal sterilisation (autoclaving) impossible; in that case aseptic production and sterile filtration are used
•
Sterile operations, filtration and filling require a high-grade cleanroom; steps carried out in closed systems may be performed under less strict conditions. Cleanrooms are monitored regularly by particle counting and hygiene monitoring
•
Because of the short half-life, results of sterility (and sometimes radionuclidic purity) tests are usually obtained after the batch has been released (retrospectively); tests and limits are defined in the European Pharmacopoeia
•
The Head of Production and the Head of Quality Control must be independent of each other; the Qualified Person who releases the batch may be one of the two
•
After production, quality control samples and retention (reference) samples are taken
12.8.2 Mo-99/Tc-99m Generator Quality Control2 questions
Mo-99 breakthrough test:
•
Should be performed at every elution (especially the first elution and after a long interval)
•
Method: The eluate is placed in a lead container → measured in the dose calibrator on the Mo-99 setting
•
First elution: ~80-90%
•
Limit: ≤0.15 µCi Mo-99 / mCi Tc-99m (at the time of administration)
•
If Mo-99 contamination is high → not used (Mo-99 has a long T½ = 66 hours → high patient dose)
Al³⁺ breakthrough test:
•
Colorimetric test → comparison with an aurin tricarboxylic acid standard
•
Limit: ≤10 µg/mL
•
High aluminium → colloid formation, impaired kit labelling
Elution efficiency:
•
The fraction of theoretical activity that is eluted
•
Excess aluminium → flocculation in sulphur colloid → lung uptake; colloid formation in MDP → liver uptake
•
Subsequent elutions: >90% (with regular elution)
•
Elution every 24 hours is optimal
BOARD TIP
▸
"The two most important tests in generator quality control?"
→ Mo-99 breakthrough and Al³⁺ breakthrough.
▸
"Mo-99 breakthrough limit?"
→ ≤0.15 µCi Mo-99 / mCi Tc-99m.
▸
"Al³⁺ limit?"
→ ≤10 µg/mL.
▸
"How is Mo-99 breakthrough measured?"
→ The eluate is placed in a lead container (6 mm lead → absorbs the 140 keV Tc-99m gamma) → measured in the dose calibrator on the Mo-99 setting.
▸
"How is Al³⁺ measured?"
→ Colorimetric test (aurin tricarboxylic acid paper).
12.8.3 Radiopharmaceutical Quality Control Summary Table
| Parameter | Method | Acceptance Limit |
|---|---|---|
| Radionuclidic purity (Mo-99) | Lead container + dose calibrator | ≤0.15 µCi Mo-99/mCi Tc-99m |
| Radiochemical purity (RCP) | TLC (thin-layer chromatography) | ≥90% (most kits) |
| Chemical purity (Al³⁺) | Colorimetric test | ≤10 µg Al/mL |
| pH | pH paper/meter | 4.5-7.5 (by kit type) |
| Sterility | Bacterial culture (retrospective) | No growth |
| Apyrogenicity | LAL test | Below the endotoxin limit |
| Particle size (MAA) | Haemocytometer/microscope | 10-100 µm (>90%) |
Key Points for the Board
Radiopharmacology and Production – Additional Points
•
<40 kDa → capillary extravasation; ≤60 kDa → glomerular filtration; IgG → long blood half-life via FcRn
•
EPR → non-specific accumulation of large molecules in tumour
•
DRL → recommended typical diagnostic activity in a standard patient
•
GLP (non-clinical) vs GMP (production); if terminal sterilisation is not possible, aseptic production + 0.22 µm filtration
•
Sterility testing is mostly retrospective; Heads of Production and QC are independent; the Qualified Person releases the batch
Radiopharmaceutical Design and Labelling
•
Reducing agent in Tc-99m kits = stannous chloride (SnCl₂) → reduces pertechnetate from +7 to a lower oxidation state → forms a complex with ligands
•
Excess SnCl₂ → colloidal Tc formation; insufficient SnCl₂ → free pertechnetate remains
•
Tc-99m MIBI and MAG3 kits require boiling; other kits are usually prepared at room temperature
•
Presence of oxygen → SnCl₂ oxidation → labelling efficiency falls → kits are stored under nitrogen
•
Tc-99m sulphur colloid: Tc is not reduced → precipitates as Tc₂S₇ (+7)
•
Transchelation intermediate ligands: tetrofosmin (gluconate), MAG3 (tartrate), MIBI (citrate)
•
MAG3 kit: ~2 mL filtered air into the vial (excess Sn²⁺ is oxidised) + 10 min boiling water bath (benzoyl group is cleaved)
•
HMPAO: eluate must be ≤2 hours old and the generator eluted within the last 24 hours (Tc-99 build-up impairs labelling); without stabiliser use within 30 min
Localisation Mechanisms – Comparison
•
Capillary blockade: Tc-99m MAA (pulmonary arterioles, 10-100 µm)
•
Phagocytosis (RES): Tc-99m sulphur colloid (hepatic Kupffer cells)
•
Active transport: Tl-201 (Na⁺/K⁺-ATPase), I-131/I-123 (NIS); FDG enters by GLUT-facilitated diffusion (metabolic trapping)
•
Mitochondrial membrane potential: Tc-99m MIBI, Tc-99m tetrofosmin
•
Chemisorption: Tc-99m MDP/HDP, F-18 NaF (bone surface)
•
Metabolic trapping: FDG (hexokinase), Tc-99m HMPAO (glutathione → conversion to hydrophilic form)
•
Compartmental distribution: Tc-99m DTPA (GFR), Tc-99m labelled red cells (blood pool)
•
Receptor binding: DOTATATE (SSTR2), PSMA, MIBG (uptake-1/NET), OctreoScan (SSTR2)
•
Tubular secretion: Tc-99m MAG3 (98% tubular secretion)
•
Tubular binding (cortical fixation): Tc-99m DMSA (proximal tubule)
Red Cell Labelling Efficiencies
•
In vivo: 75-80% (lowest, most free pertechnetate)
•
Modified in vivo (in vivtro): 85-90%
•
In vitro (UltraTag®): >95% (gold standard → preferred for MUGA and GI bleeding)
FDG PET – Critical Facts
•
Metabolic trapping: GLUT → hexokinase → FDG-6-phosphate (low glucose-6-phosphatase → trapping)
•
Patient preparation: 4-6 hours fasting, blood glucose <150-200 mg/dL, ≥4 hours after insulin
•
Insulin-sensitive GLUT-4 in myocardium/skeletal muscle → the fed state/insulin increases muscle and myocardial uptake, leaving less FDG for the tumour
•
False-negative tumours: Lepidic adenocarcinoma, RCC, HCC, prostate Ca, low-grade lymphoma, well-differentiated NET, mucinous tumours
•
False positives: Infection/inflammation, sarcoidosis, granulomatous disease, brown fat, muscle activity, postoperative changes
•
Reducing brown fat uptake: Warm environment, propranolol (20 mg orally, 1 hour before), diazepam
PET Radiopharmaceuticals – Theranostic Pairs
•
Ga-68 DOTATATE (diagnosis) → Lu-177 DOTATATE (therapy/PRRT) → NET
•
Ga-68/F-18 PSMA (diagnosis) → Lu-177 PSMA (therapy) → mCRPC
•
Theranostics = diagnostic + therapeutic pair using the same molecular target
Therapeutic Radiopharmaceuticals – Comparison
•
I-131: β⁻ + gamma, T½ = 8 days → thyroid cancer, hyperthyroidism
•
Lu-177: β⁻ + gamma, T½ = 6.65 days → PRRT (DOTATATE), PSMA therapy
•
Y-90: Pure β⁻ (no gamma), T½ = 64.1 hours → radioembolisation, radioimmunotherapy (Zevalin)
•
Ra-223: Alpha, T½ = 11.4 days → mCRPC with bone metastases (survival benefit!)
•
Sr-89: Almost pure β⁻, T½ = 50.5 days → bone pain palliation (long T½ → more toxicity)
•
Sm-153: β⁻ + gamma, T½ = 46.3 hours → bone pain palliation (short T½ → less toxicity)
Bone Palliation Agents – Survival
•
Only Ra-223 has shown a survival benefit (ALSYMPCA trial)
•
Sr-89 and Sm-153 → palliative only, no survival benefit
•
Ra-223 → alpha emitter (high LET, short range 100 µm)
•
Ra-223 → indicated only in mCRPC with bone metastases (visceral metastases → contraindicated)
Y-90 Radioembolisation – Critical Thresholds
•
Pre-treatment Tc-99m MAA shunt study is mandatory
•
Lung shunt >20% → contraindicated
•
Lung shunt 10-20% → dose reduction
•
GI shunt → prophylactic coil embolisation
•
TheraSphere® (glass) vs SIR-Spheres® (resin) → resin has a greater embolic effect
Drug Interactions – Longest Withdrawal Times
•
RAI: Amiodarone → 3-6 months (longest); levothyroxine → 3-4 weeks; methimazole → 2-5 days
•
MIBG: Antipsychotics → ~3-4 weeks (longest); labetalol → 10 days; TCA → 1-3 days
•
FDG PET: G-CSF → 2-4 weeks; chemotherapy → 2-3 weeks; radiotherapy → 2-3 months
Quality Control – Critical Limits
•
Mo-99 breakthrough: ≤0.15 µCi Mo-99/mCi Tc-99m → lead container + dose calibrator
•
Al³⁺ breakthrough: ≤10 µg/mL → colorimetric test
•
Radiochemical purity (RCP): ≥90% for most Tc-99m kits → measured by TLC
•
TLC + acetone → measures free pertechnetate (migrates with the front)
•
TLC + saline → measures colloidal Tc (stays at the origin)
•
RCP = 100 - free TcO₄⁻ (%) - colloidal Tc (%)
Radiosynovectomy – Agent by Joint Size
•
Large joint (knee): Y-90 (penetration 11 mm)
•
Medium joint (shoulder, hip): Re-186 (penetration 3.6 mm)
•
Small joint (finger): Er-169 (penetration 1 mm)
Effective Half-Life
Teff = (Tphys × Tbiol) / (Tphys + Tbiol)
•
Always shorter than both the physical and the biological half-life
•
The effective half-life is used in dose calculations (MIRD)
Particle Size and Biodistribution
•
<10 nm → blood capillaries (10-100 nm → lymph nodes)
•
10-100 nm → sentinel lymph node (filtered sulphur colloid)
•
100-1000 nm → RES phagocytosis (sulphur colloid)
•
10-100 µm → capillary blockade (MAA)
•
20-60 µm → microsphere embolisation (Y-90 SIR-Spheres)
Tc-99m Pertechnetate vs Iodine – Thyroid
•
Pertechnetate → trapping only (entry via NIS, no organification)
•
Iodine (I-123, I-131) → trapping + organification
•
Discordant nodule: hot on Tc-99m, cold on iodine → malignancy risk → biopsy
PRRT (Lu-177 DOTATATE) – Critical Facts
•
NETTER-1 trial → PFS benefit
•
Dose: 7.4 GBq × 4 cycles (8 weeks apart)
•
Renal protection: Amino acid infusion (lysine + arginine) → reduces tubular reabsorption
•
Dose-limiting organs: Kidneys and bone marrow
Lu-177 PSMA – Critical Facts
•
VISION trial → OS and PFS benefit
•
Dose: 7.4 GBq × 6 cycles (6 weeks apart)
•
Patient selection: Positivity must be confirmed by PSMA PET
•
Dose-limiting: Salivary glands (xerostomia), kidneys, bone marrow
Current guidelines on this chapter's topics
The latest guidelines and consensus documents on the procedures covered in this chapter (official EANM index and primary sources, November 2026). Comparison of the text with these versions is in progress; consult the guideline itself for details.
- 2022EANM guideline on quality risk management for radiopharmaceuticals (opens in a new tab)
- 2021Guideline on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals (opens in a new tab)
- 2020EANM guideline on the validation of analytical methods for radiopharmaceuticals (opens in a new tab)
- 2010Guidelines for Labelling of Leukocytes with 111In-Oxine (opens in a new tab)
- 2010Guidelines for Labelling of Leukocytes with 99mTc-HMPAO (opens in a new tab)
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