wk3 radiopharmacy basics

Atomic Structure and Fundamental Terminology

• Composition of Matter: All elements are composed of atoms. Atoms are spherical and consisting of two primary components:     * Nucleus: A small central core containing protons and neutrons.     * Extranuclear Space: The region surrounding the nucleus where electrons reside.     * Chemical Integrity: An atom cannot be broken down further without changing its fundamental chemical nature.

• Subatomic Particles and Charge:     * Electrons: Negatively charged particles.     * Protons: Positively charged particles.     * Neutrons: Neutrally charged particles (no electrical charge).

• Atomic Notation:     * Mass Number ($A$): The sum of the number of protons and the number of neutrons ($A = Z + N$).     * Atomic Number ($Z$): The number of protons, which determines the element's identity.     * Neutron Number ($N$): The number of neutrons in the nucleus.     * Symbolic Representation: ${^A_Z X}$, where $X$ is the chemical element symbol.

• Definitions:     * Element: An atom defined by a specific number of protons.     * Isotope: Nuclides that belong to the same element (same number of protons) but possess a different number of neutrons.     * Nuclide: A distinct nuclear species characterized by its specific mass number ($A$).     * Example (Carbon): Carbon-12 and Carbon-14 are both the element Carbon, but Carbon-14 is an isotope of Carbon and a specific Carbon-14 nuclide.

Radioactive Decay and Nuclear Stability

• Nuclear Stability: A nucleus is stable when it maintains an optimal ratio of protons to neutrons. If this ratio is disturbed, the nucleus becomes unstable (radioactive).

• Radioactivity Mechanism: Unstable nuclei seek stability by:     * Ejecting portions of the nucleus (particulate radiation).     * Emitting energy in the form of photons (gamma rays).

• Radionuclides vs. Radioisotopes:     * Radionuclide: An unstable nucleus.     * Radioisotope: Radioactive versions of a specific element.     * Iodine Examples:         * $127 ext{I}$: Stable (53 protons, 74 neutrons).         * $123 ext{I}$: Unstable (53 protons, 70 neutrons).         * $131 ext{I}$: Unstable (53 protons, 78 neutrons).

• Decay Process:     * Parent: The initial radionuclide.     * Daughter: The resultant radionuclide after decay.     * Shedding Energy: Energy is emitted in the form of alpha, beta, or gamma rays. The type of decay is determined by which rule for nuclear stability is violated.

• Types of Radioactive Decay:     * Alpha Radiation: Emission of two protons and two neutrons.     * Beta Radiation: Emission of a high-energy electron.     * Gamma Radiation: Emission of a high-energy electromagnetic photon.

Half-Life and Radioactive Measurement

• Half-Life ($T_{1/2}$): The unique time period required for half of the radioactivity of a radionuclide to decay.

• Physical Half-Life ($T_p$): The time for a radionuclide to be reduced by half of its existing radioactivity. It is unique to every radionuclide and independent of external conditions.

• Biological Half-Life ($T_b$): The time required for an organism to eliminate half of the administered radiopharmaceutical via physiological processes.

• Effective Half-Life ($T_e$): The time taken for the radionuclide activity to decrease to half its initial value within the body, accounting for both biological elimination and radioactive decay. It is always shorter than either $T_p$ or $T_b$.     * Formula: $T_e = rac{T_p imes T_b}{T_p + T_b}$

• Units of Radioactivity:     * Becquerel (Bq): SI unit; $1 ext{ Bq} = 1 ext{ radioactive decay per second}$.     * Prefixes:         * $1 ext{ MBq} = 1,000,000 ext{ decays per second}$.         * $1 ext{ GBq} = 1000 ext{ MBq}$.     * Curie (Ci): Historical unit; $1 ext{ mCi} = 37 ext{ MBq}$.

• Standard Clinical Doses:     * Typical 99mTc MDP Bone Scan: $740 - 900 ext{ MBq}$.     * Typical $131 ext{I}$ Thyroid Cancer Therapy: $3 - 5 ext{ GBq}$.

Clinical Applications of Radionuclides

• Diagnostic Imaging Requirements:     * Primarily emit gamma rays; should not emit alpha or beta rays to minimize patient dose.     * Gamma emission must be strong enough to exit the patient’s body.     * Ideal energy range: $100 - 300 ext{ keV}$ (best suited for gamma camera detection).

• Therapeutic Requirements:     * High energy emission.     * Particulate emission (alpha and beta rays) to deposit energy locally.     * Suitable biodistribution for targeted therapy.     * Long physical and biological half-lives preferred to maintain treatment intensity.

• Theranostics: A field combining specific targeted therapy with specific diagnostic tests in a "precision medicine" approach.

• Commonly Used Diagnostic Radionuclides:     * 99mTc (Technetium): $6 ext{ hrs}$ half-life; $140 ext{ keV}$ gamma.     * 123I (Iodine): $13 ext{ hrs}$ half-life; $159 ext{ keV}$ gamma.     * 201Tl (Thallium): $73 ext{ hrs}$ half-life; $135 ext{ and } 167 ext{ keV}$ gamma.     * 67Ga (Gallium): $78 ext{ hrs}$ half-life; $93, 184, 300, ext{ and } 384 ext{ keV}$ gamma.     * 68Ga (Gallium): $68 ext{ mins}$ half-life; positron emission.     * 18F (Fluorine): $110 ext{ mins}$ half-life; positron emission.

• Commonly Used Therapeutic/Other Radionuclides:     * 99Mo (Molybdenum): $66 ext{ hrs}$ half-life; used in generators.     * 131I (Iodine): $8 ext{ days}$ half-life; $364 ext{ keV}$ gamma + beta (used for imaging and therapy).     * 235U (Uranium): $703 ext{ million years}$ half-life; used for production.     * 68Ge (Germanium): $271 ext{ days}$ half-life; used in generators.     * 137Cs (Caesium): $30 ext{ years}$ half-life; used for Quality Control.     * 60Co (Cobalt): $5.27 ext{ years}$ half-life; used for Quality Control.     * 89Sr (Strontium): $50 ext{ days}$ half-life; radionuclide therapy.     * 177Lu (Lutetium): $6 ext{ days}$ half-life; radionuclide therapy.     * 90Y (Yttrium): $2.6 ext{ days}$ half-life; radionuclide therapy.

Radionuclide Production Methods

• Natural Radionuclides: Heavy elements like $235 ext{U}$ with long half-lives ($704 ext{ million years}$) are unsuitable for direct human use.

• Artificial Production Approaches:     * Nuclear Reactor Produced: Particulate bombardment (activation) or fission.     * Accelerator Produced (Cyclotron).     * Generator Produced.

• Nuclear Fission (Reactor):     * Process: Fission involves splitting a heavy nucleus (e.g., $235 ext{U}$) into two smaller nuclei after adding a neutron to form very unstable $236 ext{U}$.     * Byproducts: Free neutrons and heat energy.     * Chain Reaction: Produced neutrons can be "thermalized" (slowed down) to initiate further fission. Uncontrolled reactions lead to reactor meltdowns.     * Moderator: Slows down fission neutrons using heavy water or graphite, as slow neutrons are more efficient at starting fission.     * Control Rods: Strong neutron absorbers used to manage or shut down the chain reaction.

• ANSTO OPAL Reactor:     * Specifications: Open Pool Australian Lightwater research reactor, opened in 2007.     * Power: $20 ext{ Megawatts}$.     * Fuel: Low enriched uranium (LEU) containing approx. $20\% ext{ } 235 ext{U}$.     * Design: Core ($35 ext{ cm}$ square, $60 ext{ cm}$ high) composed of 16 fuel assemblies, submerged in a $12.9 ext{ metre}$ deep pool of demineralised water for cooling, moderation, and shielding.     * Isotopes Produced: $131 ext{I}, 177 ext{Lu}, 99 ext{Mo}, 137 ext{Cs}$.

• Cyclotron Production:     * Mechanism: Accelerates charged particles in spiral paths inside two semicircular metallic cylinders called "Dees" within a magnetic field.     * Reactions: High-energy particles impact a target to enable a nuclear reaction.     * Energy Levels:         * 9-11 MeV: Small cyclotrons, can only produce $18 ext{F}$.         * 30 MeV: Larger cyclotrons, produce other medical radioisotopes like $123 ext{I}$.     * Availability: There are 17 cyclotrons in Australia (NSW: 5, VIC: 5, QLD: 4, SA: 1, WA: 1, NT: 1).

Radionuclide Generator Systems

• Purpose: Provides on-site, convenient access to short-lived isotopes for departments located far from reactors or cyclotrons.

• Operation: A long-lived parent radionuclide decays into a short-lived daughter. They are different elements, allowing for chemical separation.

• Elution: The process of chemically separating and extracting the daughter radionuclide from the parent.

• Equilibrium States:     * Transient Equilibrium: Parent half-life is $10 - 100$ times greater than the daughter half-life (e.g., $99 ext{Mo} - 99m ext{Tc}$).     * Secular Equilibrium: Parent half-life is $100 - 1000$ times greater than the daughter half-life.

• Generator Components:     * Lead shielding for safety.     * Glass or plastic column containing adsorbent material (e.g., aluminium oxide/alumina).     * Parent radionuclide is fixed to the column.     * Wet vs. Dry Systems: Uses saline vials and vacuum collection vials. Elution must be sterile and pyrogen-free.

• 99Mo - 99mTc Generator Specifics:     * Parent: $99 ext{Mo}$ ($T_{1/2} = 66 ext{ hrs}$) adsorbed onto alumina.     * Daughter: $99m ext{Tc}$ ($T_{1/2} = 6 ext{ hrs}$) is less tightly bound.     * Eluent: Normal saline washed over the column to produce $99m ext{Tc} ext{-sodium pertechnetate}$.     * Regrowth: Maximum daughter activity is reached approx. 4 daughter half-lives after elution ($24 ext{ hours}$ for $99m ext{Tc}$).

Quality Control in Radiopharmacy

• Radionuclide Purity: Proportion of total radioactivity present as the stated radionuclide.     * Test: $99 ext{Mo} ext{ breakthrough test}$.     * Limit: < 0.1\% total activity or no more than $1 ext{ MBq } 99 ext{Mo} ext{ per } 1 ext{ GBq } 99m ext{Tc}$.

• Chemical Purity: Measures non-radioactive chemical levels (e.g., aluminium from the column).     * Test: Aluminium ion breakthrough test (paper colourimetric test).     * Limit: < 10 ext{ } \mu ext{g/mL}.     * Consequences of Excess Aluminium: Cloudiness in eluate, hepatic uptake on images, and poor quality due to labeling problems.

• Radiochemical Purity: The ratio of the radionuclide in the desired bound form (radiopharmaceutical) versus its unbound form ("free" radionuclide).     * Impact: Affects patient radiation dose, biological distribution, and image quality.

99mTc-Sodium Pertechnetate (99mTcO4)

• Characteristics: Ideal radionuclide with no particulate emissions, $6 ext{ hr}$ half-life, and $98\%$ photon yield at $140 ext{ keV}$.

• Metastable State ("m"): Indicates a daughter nucleus remains in an excited state for a considerable time (> 1 ext{ } \mu ext{s}) before emitting a gamma ray via isomeric transition.

• Chemistry: Eluted as $+7$ valence state. To bond with other pharmaceuticals, it must be reduced to a lower state (usually $+4$) using a reducing agent like stannous chloride (tin).

• Biodistribution: Acts similarly to iodide. Concentrates in thyroid, salivary glands, choroid plexus, and gastric mucosa. Crosses the placental barrier. Excreted via kidneys and GI tract.

Radiopharmaceutical Design and Localization

• Design Criteria: Must be sterile, pyrogen-free, inexpensive, and provide a high target-to-non-target activity ratio.

• Common Radiopharmaceuticals and Targets:     * 99mTc HDP/MDP: Bone.     * 99mTc DTPA: Kidneys.     * 99mTc DISIDA/HIDA: Gall Bladder.     * 99mTc Sestamibi: Heart.     * 99mTc MAA: Lung perfusion.     * 99mTc Neurolite/ECD: Brain.     * 99mTc Nanoscan: Lymph drainage.

• Methods of Localization: Passive diffusion, Ion exchange, Active transport, Phagocytosis, Capillary blockade, Metabolism, Receptor binding, Compartment localisation, Antigen-antibody complex, and Chemotaxis.

• Adverse Reactions: Extremely rare unanticipated responses to the non-radioactive pharmaceutical component (approx. $1:100,000$). Typically allergic: rash, hives, vomiting, occurring $5 ext{ mins to } 48 ext{ hrs}$ post-injection.