Radiopharmaceutics Lecture Slides 2023 PDF

RADIOPHARMACEUTICALS Pharmaceutics III 2023 Presented by: Unami Sibanda Lecturer: Pharmaceutics...

RADIOPHARMACEUTICALS Pharmaceutics III 2023 Presented by: Unami Sibanda Lecturer: Pharmaceutics M.Pharm (Radiopharmacy) Acknowledgements The notes for this course have been developed by: Miss Unami Sibanda and Prof S.M. Khamanga  LECTURE 1 Outline Definition of radiation, radioactivity, radioisotope, ionization and excitation Electromagnetic radiation and corpuscular or particulate radiation Ionizing (directly and indirectly) and Non-Ionizing radiation Radiation Quantities and units, e.g Exposure (X), Activity (A) Biological effects of radiation Early and Late effects of radiation exposure  Definitions Radiation – transport of energy by electromagnetic (EM) waves or atomic particles Radioactivity – a spontaneous process by which an unstable parent nucleus emits a particle or EM radiation and transforms into a more stable daughter nucleus that may or may not be stable Radioisotope - atoms that contain an unstable combination of neutrons and protons, or excess energy in their nucleus Ionization – energy required to remove an electron from an atom Excitation – energy required to excite an atom from its ground state to a higher level  Did you know? Radiation is all around us Natural, there is radiation in the earth, rocks, water, air Radon - from the decay of Uranium (naturally present) Light is a form of Radiation Beneficial aspects of radiation include the following: Sun, it is a major source of radiation Clean source of energy for power generation Irradiated food Medical  High Frequency Electromagnetic Radiation Electromagnetic radiation is formed from oscillations of the electric and magnetic field Electromagnetic waves are massless and, unlike sound waves, they can travel through a vacuum. High frequency types of electromagnetic radiation such as UVA, UVB, X-rays and gamma rays are forms of ionizing radiation.  Corpuscular radiation Corpuscular radiation (also known as particulate radiation) is an ionizing form of radiation that consists of a stream of atomic or subatomic particles. These particles may be positively/negatively charged or neutral. These particles are emitted during nuclear decay. They have mass and can travel through a vacuum.  Ionizing and non-ionizing radiation Ionizing radiation can ionize matter either directly or indirectly because its quantum energy exceeds the ionizing potential of atoms Radiation that carries enough energy per quantum to remove an electron from an atom or a molecule Introduces a reactive and potentially damaging ion into the environment of the irradiated medium Non-Ionizing radiation cannot ionize matter because its energy per quantum is below the ionization potential of atoms  Directly Ionizing radiation Consists of charged particles such as electrons, protons, α particles and heavy ions Deposits energy into the medium through Coulomb Interaction between the charged particle and orbital electrons of atoms in the absorber  Indirectly Ionizing radiation Consists of uncharged (neutral) particles which deposit energy into the medium through a two- step process: The neutral particle releases or produces a charged particle in the medium The released charged particle deposits ionizes the medium through Coulomb interactions with orbital electrons of the medium Indirectly ionizing photon radiation Consists of following main categories Ultraviolet X-rays, characteristic x- rays and bremsstrahlung γ- rays Annihilation Quanta (β+ or positron annihilation)  Radiation Quantities and units Exposure Kerma Dose (also referred to as Absorbed dose) Equivalent dose Effective dose Activity  Biological effects of Radiation Direct Effects If radiation interacts with atoms of DNA molecule, or some other cellular component critical to survival of cell, it is referred to as a direct effect Results in the breakdown of the cell sequence Indirect Radiation causes the formation of free radicals When radiation interacts with water, it may break bonds that hold water molecule together, producing fragments such as hydrogen (H+) and hydroxyls (OH-) ions These fragments may combine to form toxic substances, such as H2O2, which can contribute to the destruction of the cell  Early and late effects of radiation exposure Human whole-body exposures above 50 rads may result in a variety of symptoms called radiation sickness. These include anorexia, vomiting, diarrhea, dizziness, leukopenia and headaches. In humans three organ systems are critical. Hematopoietic system (≤ 500 rads), gastrointestinal system (500 to 1000 rads) and central nervous system (several thousands rads and above) Early (acute) effects appear within days, weeks or months of irradiation and are associated with fast proliferated epithelial cells. Late effects appear months or years after irradiation and appear in structures which proliferate slowly. Late effects may become evident years after a single dose of radiation or after chronic exposure to relatively low dose rates of radiation.  Self-study Sections to be covered before Lecture 2 Atoms Bohr’s theory Electronic structure Quantum theory Chemical bonds Ionic bonds Covalent bonds Complex formation Structure of nucleus Nomenclature of a nuclide  LECTURE 2 Outline Medical Imaging Modalities Nuclear medicine Radiopharmaceuticals Nuclear medicine vs other imaging modalities Radioactive decay  Nuclear medicine Nuclear medicine is a specialized area of radiology that uses very small amounts of radioactive materials, or radiopharmaceuticals to assess bodily functions and structure and to diagnose and treat disease. Uses unsealed sources of radioactivity Non-invasive, safe and painless Cost-effective Advantages; Early detection, Sensitivity Specificity Nuclear medicine vs other imaging modalities  Radiopharmaceuticals Radiopharmaceuticals are radioisotopes bound to biological molecules able to target specific organs, tissues or cells within the human body. These radioactive drugs can be used for the diagnosis and, increasingly, for the therapy of diseases.  Radioactive decay Atoms that exist with unstable nuclei are called radioactive nuclides or radioisotopes Radionuclides may decay by any one or a combination of six processes: spontaneous fission, α decay, β decay, β+ decay, electron capture, and isomeric transition (IT) in order to achieve stability. In radioactive decay, particle emission or electron capture may be followed by isomeric transition. In all decay processes, the energy, mass, and charge of radionuclides must be conserved.  More than 1,000 radioactive isotopes of the various elements are known. There are 253 nuclides that have not been known to decay using current equipment – we consider these “stable isotopes” e.g. Carbon-12 Radio-active decay is not linear but occurs exponentially.  The half-life is the time it takes for 50% of the original amount to degrade. The half-life of an element can take anything from minutes, to days, to years. For example: Fluorine-18 half-life = 109.7 minutes Carbon-14 half-life = 5730 years  Decay of Fluorine-18 : half life = 109.7mins (just under 2hrs) By Cburnett - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12042656  Radioactive decay: spontaneous fission Fission is a process in which a heavy nucleus breaks down into two fragments typically in the ratio of 60:40 and releases neutrons in the process. Fission in heavy nuclei can occur spontaneously or by bombardment with energetic particles. The half-life for spontaneous fission is 2x1017 years for 235U and only 55 days for 254Cf. Spontaneous fission is an alternative to α decay or γ emission.  Radioactive decay: α decay Usually heavy nuclei such as radon, uranium, neptunium, and so forth decay by α-particle emission. The α particle is a helium ion with two electrons stripped off the atom and contains two protons and two neutrons bound together in the nucleus. In a decay, the atomic number of the parent nuclide is therefore reduced by 2 and the mass number by 4  Alpha particles emitted during alpha decay are an ionizing form of radiation and therefore destructive to the molecules they interact with. However, because of their relatively large size they collide frequently with other molecules, thus slowing them down. This makes them very poorly penetrative. Skin or even a piece of paper can stop their movement.  Radioactive decay: β decay (β- emission) When the neutron to proton ratio is too high, a neutron "transforms" into a proton and electron, with the electron being ejected from the nucleus. The ejected electron is called a “beta minus particle” or just "beta particle“ After β decay, the atomic number of the daughter nuclide is one more than that of the parent nuclide; however, the mass number remains the same for both nuclides.  The β particle is emitted with variable energy from zero up to the decay energy. The decay or transition energy is the difference in energy between the parent and daughter nuclides. Beta particles are also destructive to the molecules they interact with, however, they have a much better ability to penetrate substances because of their tiny mass. Paper Aluminium  Radioactive decay: β decay + (β or positron emission) Nuclei that are “neutron deficient” or “proton rich” (i.e., have an N/Z ratio less than that of the stable nuclei) can decay by β +-particle emission accompanied by the emission of a neutrino (v), which is an opposite entity of the antineutrino After β +-particle emission, the daughter nuclide has an atomic number that is 1 less than that of the parent  At the end of the path of β + particles, positrons combine with electrons and are thus annihilated, each event giving rise to two photons of 511 keV that are emitted in opposite directions. These photons are referred to as annihilation radiations.  Radioactive decay: Electron capture When a nucleus has a smaller N/Z ratio compared to the stable nucleus, as an alternative to β + decay, it may also decay by the so-called electron capture process, in which an electron is captured from the extranuclear electron shells, thus transforming a proton into a neutron and emitting a neutrino The atomic number of the parent is reduced by 1 in this process X + e- z-1Y + ve  Radioactive decay: Isomeric transition A nucleus can remain in several excited energy states above the ground state that are defined by quantum mechanics. The decay of an upper excited state to a lower excited state is called the isomeric transition In isomeric transition, the energy difference between the energy states may appear as γ rays  Gamma radiation is high frequency electromagnetic ionizing radiation. Gamma rays carry no mass and move easily through substances without much interaction with molecules. Lead or thick metal is needed to stop gamma radiation.  Lecture 3 Outline Production of Radionuclides Properties of Ideal radioisotope Technicium chemistry and radiopharmaceutical kits Dosing of Radiopharmaceuticals Radiopharmaceutical quality control  Production of Radionuclides Radionuclides for use in radiopharmaceutical preparations are manufactured in the following ways; Nuclear fission - Nuclides with high atomic number are fissionable and a common reaction is the fission of uranium- 235 by neutrons in a nuclear reactor. For example,iodine- 131, molybdenum-99 and xenon-133 can be produced in this way. Radionuclides from such a process must be carefully controlled in order to minimize the radionuclidic impurities. Charged particle bombardment - Radionuclides may be produced by bombarding target materials with charged particles in particle accelerators such as cyclotrons.  Neutron bombardment - Radionuclides may be produced by bombarding target materials with neutrons in nuclear reactors. Radionuclide generator systems - Radionuclides of short half-life may be produced by means of a radionuclide generator system involving separation of the daughter radionuclide from a long-lived parent by chemical or physical separation. Cyclotrons A cyclotron consists of two flat hollow objects called dees. The dees are part of an electrical circuit. On the other side of the dees are large magnets that steer the injected charged particles (protons, deutrons, alpha and helium) in a circular path The charged particle follows a circular path until the particle has sufficient energy that it passes out of the field and interact with the target nucleus.  Examples of cyclotron produced radionuclides Gallium-67, Iodine-123, Indium-111, Thalium-201 Short-lived radionuclides include; Carbon-11, Nitrogen- 13,Oxygen-15 and Fluorine 18 Nuclear Reactors A nuclear reactor contains fuel rods of enriched fissionable 235U positioned in the reactor core Fuel rods are surrounded by a moderator such as heavy water (D2O) Each uranium fissioning uranium atom releases fast neutrons that are slowed to thermal energy by their interactions with D2O Thermal neutrons are easily captured other uranium atoms. When the uranium atoms fission, they release more neutrons that sustain the chain reaction The fission process generates heat that is carried off by water or other coolants through heat exchangers  Nuclear reactors are designed for different purposes Power reactors convert the heat generated from the fission process into electricity Isotope reactors have specialized ports where target material may be introduced into the neutron flux, causing neutron activation of stable nuclides into radioactive nuclides Examples of reactor produced radionuclides include; Iodine-131 and Molybdenum 99 MEDICAL ISOTOPE PRODUCTION REACTOR Radionuclide Generators Radionuclide generators were introduced into nuclear medicine practice because of the need to administer large amounts of radioactivity for better-quality images A long-lived parent radionuclide is allowed to decay to its short-lived daughter radionuclide and the latter is chemically separated in a physiological solution. A generator provides a fresh supply of short-lived daughter nuclides as needed until parent activity is depleted  The generator most prominent is 99mTc generator. The 99Mo parent has a 2.75day half-life and provides a useful generator life of about 2 weeks. Typically, a new generator is received weekly to meet the activity needs of a hospital or nuclear pharmacy 99Mo/99mTc Generator  The majority of Mo-99 is produced in five nuclear research reactors around the world using highly enriched uranium targets. One of these reactors, SAFARI-1, is owned and operated by the South African Nuclear Energy Corporation (NECSA) in Pelindaba, South Africa.  Normal saline is forced through the generator under vacuum pressure resulting in a saline solution containing the Tc-99m as pertechnetate in a process called elution. The Tc-99m pertechnetate enriched saline that comes out the other side is collected in a vial shielded by a lead cover and is called the eluate. The required dose of the eluate is removed and used to reconstitute the radiopharmaceutical product. All of this must be done under sterile conditions using aseptic technique!  Ideal properties of a radiopharmaceutical Types of Emission Energy of Gamma Rays Photon Abundance Easy availability Target to Non target Ratio Effective Half-life Patient Safety Preparation and Quality Control  Technicium chemistry and Radiopharmaceutical kits Technetium is a transition metal of silvery gray colour belonging to group VIIB (Mn, Tc, and Re) and has the atomic number 43 Technetium can exist in eight oxidation states, namely, - 1 to 7+ The chemical form of 99mTc obtained from the Moly generator is sodium pertechnetate (99mTc-NaTcO4) In 99mTc-labeling of many compounds, prior reduction of 99mTc from the 7+ state to a lower oxidation state is required Stannous chloride is the commonly used reducing agent in most preparations of 99mTc-labeled compounds Kits for 99mTc-Labeling Kits for most 99mTc-radiopharmaceuticals are prepared from a “master” solution consisting of the compound to be labelled mixed with an acidic solution of a stannous compound in appropriate proportions The pH of the solution is adjusted to 5 to 7 with dilute NaOH, purged with nitrogen, and aliquots of the solution are dispensed into individual kit vials  The solution is then lyophilized (freeze-dried) and the vial flushed and filled with sterile nitrogen. Lyophilization renders the dried material in the vial readily soluble in aqueous solution and thus aids in labelling by chelation. In the kit preparation, when the acidic solution of Sn2+ is added, a complex is formed between Sn2+ and the chelating agent The reduced 99mTc species are chemically reactive and combine with a wide variety of chelating agents  Dosing of Radiopharmaceuticals The amount of radioactivity that can be administered for scintigraphic procedures performed in clinical nuclear medicine is limited by the amount of radiation exposure received by the patient The patient radiation exposure is determined by the percent localization of the administered dose in each organ of the body, the time course of retention in each organ, and the size and relative distribution of the organs in the body  Radioactivity is measured in Becquerels (Bq) or Curies (Ci) 1 Bq = 1 disintegration (atom decaying) per second 1 Curie (Ci) = 3.7 x 1010 disintegrations per second The dose of radiation administered to a patient (the administered dose) is usually measured in mCi or MBq. Marie Curie was the first woman to receive the Nobel Prize in physics for her work on radioactivity. She died from leukemia, caused by exposure to high-energy radiation from her research. The label on the outer package should include: a statement that the product is radioactive or the international symbol for radioactivity the name of the radiopharmaceutical preparation; the preparation is for diagnostic or for therapeutic use; the route of administration; the total radioactivity present (for example, in MBq per ml of the solution) the expiry date the batch (lot) number for solutions, the total volume; any special storage requirements with respect to temperature and light; the name and concentration of any added microbial preservative  The radioactivity of the initial eluate is measured using a dose calibrator  The radioactivity concentration of the eluate and expiry period must be calculated at the time of preparation. The radioactivity concentration can be calculated using the following formula: At = activity in 1 ml eluate at the present time A0 = activity in 1 ml eluate at the time of elution λ = decay constant in seconds-1 (Tc 99m: λ= 0.1151 hr-1) t = time interval Absorbed doses The amount of radiation absorbed by tissue in the body in which a radioactive substance resides is called the radiation absorbed dose (rad), measured in units of rads or Grays(Gy). rad = 1 x 10-5 Joule/g of tissue 1 Gy = 100 rads (1 Joule/kg of tissue) The extent of the damage caused by the absorbed radiation depends on: The type of tissue absorbing the radiation Power of radioactive source Duration of exposure Age of the person Health status of the person  The physical quantity of the absorbed dose, taking into account the biological effectiveness of the radiation is termed the dose equivalent Dose equivalent is measured in sievert (Sv) or Roentgen Equivalent Man (REM) 1 Sievert = Damage done by 1 Joule per kg (1 Gy) 1 rem = 0.01 Sievert Absorbed Dose Radioactivity Dose Equivalent Common Units curie (Ci) rad rem SI Units Becquerel (Bq) Gray (Gy) Sievert (Sv) Radiopharmaceutical Quality Control Radionuclide Purity The only desired radionuclide in the Mo-99/Tc-99m generator eluate is Tc-99m Any other radionuclide in the sample is considered a radionuclide impurity and is undesirable because it will result in additional radiation expo-sure to the patient without clinical benefit. The most common radionuclide contaminant in the generator eluate is the parent radionuclide, Mo-99 Chemical Purity A routine quality assurance step is to measure the generator eluate for the presence of the column packing material, Al2O3 Colorimetric qualitative spot testing determines if unacceptable levels are present. Excessive aluminium levels may interfere with the normal distribution of certain radiopharmaceuticals Radiochemical Purity When Tc-99m is eluted from the generator, its expected valence state is +7, in the chemical form of pertechnetate(TcO−4). The clinical use of sodium pertechnetate as a radiopharmaceutical and the preparation of Tc-99m- labelled pharmaceuticals from commercial kits are based on the 7+ oxidation state Reduction states at +4, +5, or +6 result in impurities. These reduction states can be detected by thin-layer chromatography Other quality control tests include: Identity tests - The radionuclide is generally identified by its half-life or by the nature and energy of its radiation or by both pH Sterility Bacterial endotoxins/ pyrogens LECTURE 4 Outline Scintigraphy Single-Photon Emission Computed Tomography (SPECT) Positron Emission Tomography (PET) Hospital Radiopharmacy Radiation Therapy Radiation Protection Role of a Radiopharmacist as part of Inter-disciplinary team  Scintigraphy Scintigraphy is a diagnostic technique that uses radiopharmaceuticals (radiotracers) for internal imaging. Radiopharmaceuticals are introduced into the body, usually by injection. The pharmaceutical molecule includes a radioactive element (radiotracer) and delivers this element to target organs or tissues. The radiation released from the radio-isotope is recorded on external cameras which are able to create an image depicting where the radiopharmaceutical has concentrated.  Radioisotopes used for diagnosis emit gamma rays and have a short half-life and reach a relatively stable form soon after imaging is completed. Gamma rays are able to pass through the body tissue easily without causing much damage. A short half life is requires so that the patient does not remain “radioactive” for an extensive period. Single-Photon Emission Computed Tomography (SPECT) Single-Photon Emission Computed Tomography (SPECT) makes use of radiopharmaceuticals that release gamma radiation when they decay. The gamma rays emitted as the radioisotope decays is seen by a gamma camera and put together to create a 3D image. Examples of radio-isomers used for SPECT scans are Technetium-99m and Iodine-123 Technetium-99m (Tc-99m) Tc-99m is widely used because: When it decays to Tc-99 it releases gamma rays with a photon energy of 140 keV It has a half-life of six hours which is long enough to examine metabolic processes yet short enough to minimise the radiation dose to the patient. It is relatively cheap and readily available It is eluted from molybdenum-99 (Mo-99) which has a half- life of 66 hours, allowing it to be transported over fairly long distances. Iodine-123 Iodine-123 is used for iodine uptake tests to detect thyroid tumours and pathologies Iodine-123 decays to tellurium-123 by electron capture and emits gamma radiation with an energy of 159 keV It has a half-life is 13.22 hrs Iodine-123 for medical use is manufactured for the local market by iThemba Labs in Somerset West  It is usually supplied to hospitals in the form of a basic solution and is administered to patients via injection or sometimes orally as capsules or a drink  Positron Emission Tomography (PET) A positron-emitting radioisotope is attached to a specific ligand to create a radiotracer that binds to a particular tissues. The radiotracer is administered into the patient, normally via IV. As the radioisotope decays it emits a positron, which almost immediately combines with a nearby electron resulting in simultaneous emission of two identifiable gamma rays in opposite directions. The gamma rays are seen by a gamma camera.  The molecule most commonly used for this purpose is 18-fluorodeoxyglucose (FDG), a sugar molecule carrying the radioactive isomer Flourine-18 that collects in highly metabolic cells. The solution is injected and after an hour the patient is placed in the imaging scanner that detects both gamma rays as they are emitted simultaneously. PET's most important clinical role is in oncology and Flourine-18 it has proven to be the most accurate non-invasive method of detecting and evaluating most cancers. It is also used in cardiac and brain imaging. In South Africa 18F-FDG injection solution is produced for the local market by iThemba labs PET/CT scan of a patient with breast cancer. A trace amount of radiolabeled glucose ( 18 F- Fluorodeoxyglucose) was injected intravenously 1 h prior to the scan. https://www.researchgate.net/figure/PET-CT-scan-of-a-patient-with-breast-cancer-A-trace-amount-of-radiolabeled-glucose-18_fig1_233918959  Radiation Therapy Nuclear medicine uses radio-isotopes to destroy cancerous cells. The isotopes used emit destructive α-or β- particles as they decay. The radiopharmaceutical concentrates at the target tissue and emits destructive ionizing radiation. Because α-or β- particles do not penetrate deeply the effect is localised and negative effects on healthy tissue is avoided. Examples include: 131I, Iodine, emits β-particles and a small amount of gamma-rays 90Y, Yttrium, which emits β-particles, available as Yttrium ibritumonab tiuxetan (Zevalin) for non Hodgkin’s lymphoma 32P, phosphorus 32, which emits β-particles, available as Sodium phosphate injection for the treatment of hemoproliferative disease 89Sr, strontium-89, which emits β-particles, available as Strontium chloride injection (metastron) for palliation of bone pain Hospital Radiopharmacy Radiation Protection  For radioprotection, the production area should be at negative pressure while pharmaceutical aseptic units are at positive pressure. The compromise is a negative pressure isolator within a positive pressure room. Some other unique elements in the radiopharmacy include: Staff preparing and handling radioactive materials must wear a personal dosimeter, Thermoluminescent dosimeter (TLD) which measures full body radiation exposure and a finger monitor to monitor extremity dose. The protection of the operator from radiation is of paramount importance. Protective equipment includes protected lead lined garments, tools for maximizing the distance from the source (e.g. tongs and forceps), lead syringe and vial shields, drip trays decontamination kits for spills. Unshielded syringes or vials should never be used during manipulation of radiopharmaceuticals.  All personnel exposed to radiation from Radiopharmaceuticals should be informed and trained on radiation protection The National Nuclear Regulator prescribes radiation dose limits for radiation workers, pregnant radiation workers, non-radiation workers and members of the public, the aim of the dose limits is as follows: To keep the chance of contracting a stochastic effect acceptably small To prevent anyone from suffering threshold effects of radiation All radiation workers should apply the ALARA principle when working with radioactive substances  Role of a Radiopharmacist as part of Inter-disciplinary team Nuclear Medicine is a multidisciplinary speciality Medicine Patient care Physics Pharmacy Medical Nuclear Medical Pharmacists doctors Medicine Physicists Technicians Physicians Technologists Technologists Chemists Oncologists Nurses Cardiologists Radiographers Surgeons Radiologists The Radiopharmacist Registered speciality by the SAPC The roles of a Radiopharmacist include; Manufacture/procurement; preparation and supply of safe and effective Radiopharmaceuticals. Labelling (RBC & WBC) Quality Control Advice and support on the use of Radiopharmaceuticals (possible drug interactions; causes of altered biodistribution etc.) Research and development of new radiopharmaceuticals, including clinical trials and development of new dispensing techniques The end!