Nuclear Medicine: Introduction to Radiochemistry (PDF)

Nuclear medicine  https://www.pok.polimi.it/mod/page/view.php?id=5612 Radioisotopes used in medicine are produced by: Linear Particle Accelerator (LINAC) Currently more than 80% of the...

Nuclear medicine  https://www.pok.polimi.it/mod/page/view.php?id=5612 Radioisotopes used in medicine are produced by: Linear Particle Accelerator (LINAC) Currently more than 80% of the medical radioisotopes are CYCLOTRONS produced by research reactors. The remaining radioisotopes are GENERATORS made with particle accelerators Production of medical radioisotopes Currently more than 80% of the medical radioisotopes are produced by research reactors. The remaining radioisotopes are made with particle accelerators. Research reactors – production of artificial radioisotopes Produce radioisotops by fission of highly enriched uranium, where URANIUM 235 is more than 20%. Nucleus transformed with nuclear reactions are often radioactive and are called the artificial radionuclides. Fission product yields from neutron fission of U-235 Prominent radioisotopes: Technetium -99m 80% of all diagnostic imaging mainly produced in research reactors Technetium-99m is a daughter product of molybdenum-99 Tc-99m decays to aTc-99g by emitting a gamma rays The Tc-99g further decays to stable ruthenium-99.  Rays (6h) β-, (220 000y) 99gTc 99Ru (STABLE) β-, (67h) (g – ground state) Many radioisotopes are produced by accelerators due to production on large scale. Advantages of accelerators over nuclear reactors (fission reactions) Accelerators powered by electricity are Safer, simple and reliable to operate Produces few radioisotopes at a time More economical Generates less than 10% of the waste of research reactors Waste is less hazardous Linear particle accelerator (LINAC) used to obtain 99Mo/99mTc LINAC could be used to obtain molybdenum-99, necessary for Tc-99 production, from a Low Enriched Uranium target where less than 20% of uranium-235 is present. Linear particle accelerator (LINAC) used to obtain 99Mo/99mTc RECYCLATION of Mo-100 The LINAC produces a mix of Mo-100 and Mo-99 in solution from the Mo-100 target. The Mo-100/Mo-99 is shipped to radio-pharmacies and hospitals, where Tc-99m is extracted and can be used to create Diagnostic injections. Benefit: Mo-100 can be recycled and reused as a target to make more Tc-99m LINAC production of 99Mo/99mTc via Photon-induced reaction Generators are devices where radionuclide decay λ photons into the daughter radioisotop of interest. The generator is transported to the hospital, where Tc-99m (half life 6h) is extracted. The generator can be used for 2 weeks after which fresh Mo-99 is required. The molybdenum-technetium generator The separation and elution of the daughter radionuclide 99mTc from the parent radionuclide 99Mo. The column, usually glass, containing a bed of aluminium oxide (alumina) as a support for the parent radionuclide.99Mo will bind strongly to this support media and is not washed off during the subsequent elution of the daughter radionuclide 99mTc. A system of tubing allows the column to be washed with a sterile saline solution. The tubing will be medically approved since the liquids that contact this material may be injected into humans. Filters in the form of porous frits, usually a 0.22 µm filter which serves to remove any small particles from the eluted sample. Technetium generators are typically eluted once or twice per day for 1 to 2 weeks. https://www.google.com/search?sca_esv=581685960&sxsrf=AM9HkKlGuMzuzU23R8_DaPU9BV HTpGjvdw:1699787824202&q=The+molybdenum- technetium+generator+system&tbm=vid&source=lnms&sa=X&ved=2ahUKEwjlzNGLq76CAxWdgf 0HHSY5Aj0Q0pQJegQIChAB&biw=1280&bih=587&dpr=1.5#fpstate=ive&vld=cid:064ef515,vid:sF dmpBIWlik,st:0 Linear particle accelerator (LINAC) LINAC accelerates charged particles or ions to a high speed passing thorough a series of oscillating electric potentials along a linear beamline. Particle Source (S) Target of charged particles or ions TARGET (production: High energy X rays, Radiofrequency Neutrons (3H, D), source Drift tubes Electrons (from β-) - changing voltage Atmosphere in the drift tubes is source VACUUM Charged particles are accelerated across the gaps between electrodes. The particles are accelerated by the electric field in the gap between electrodes connected alternatively to the poles of an AC generator. Accelaration of charged particles in LINAC Particle is accelerated between gap of drift tubes by charging the closes drift tube to the opposite charge. Other important isotopes produced using LINAC are germanium-68 and actinium-225. Germanium-68 is produced by proton irradiation of Gallium metal target, purified by organic extraction and used in a medical isotope generator to produce Gallium-68 PET imaging agents. Ga-68 has a half-life of 67.7 min and it is among the shortest half-life radioisotopes. Actinium-225 1. The neutron is kicked out of the nucleus (226Ra) 2. Transmutation: β- decay, (Z+1, Z=89) 225Ac The world’s longest superconducting LINAC The European X-ray Free Electron Laser (European XFEL), 3.4 km long, operates at Hamburg in Germany and generates ultrashort X-ray flashes at a rate of 27,000 per second which is one billion times higher than the best conventional X-ray sources. New capabilities to explore chemistry, e.g. - track chemical processes, - track atomic and electronic behaviour of substances as they react, - determination of structures from crystals and - recording images and movies of biological interactions between substances such as enzymes and potential drugs. Stanford Linear Accelerator (SLAC) in Menlo Park, California has 3.2 km. It is the 2nd largest accelerator in the world. SLAC consists of 80 000 accelerating electrodes which accelerate ion particles to 50 GeV. Based on this SLAC, the researchers gain 3 Nobel prices.  Another type of particle accelerator is the Cyclotron. Cyclotrons are circular in shape, as opposed to the linear shape of the LINAC. The particle moves in a circular motion under the influence of electromagnetic field perpendicular to its plane of motion. ADVANTAGES of Cyclotrons: Cyclotrons are located hospital-based, by which the delivery of pharmaceuticals to patients is much more secured. In addition, the risk of transport accidents is practically zero. DISADVANTAGE of Cyclotrons: Cyclotron only produces one major radioisotope  Which will be easier separate? Which will be easier separate? Isotopes of the same element have chemical and physical properties indistinguishable and thus react identically.  Typical purification methods include distillation, extraction and chromatography. Depending on the type of ions to be separated, the stationary phase can be set up to separate cations and anions. For example, in generators the parent radionuclide ions are trapped in the stationary phase using strong ionic interactions and the daughter radionuclide ions are eluted using appropriate buffers. The purity of the radioisotope can be determined using a gamma spectrometer. Radioisotop purity is 100% while Radionuclide purity is around 99.7% due to presence other radionuclides.  True ALL C C  True B B, D, D, E D A False  Shor lived radiosisotopes are produced in generators in the same location. The long lived radioisotopes can be transported for radiochemistry to distant locations. Synthesis of radiopharmaceutics - Radiosynthesis The radiosynthesis is restricted by the specific half-life of the radioisotope. Moreover, the transportation from the production site to the radiochemistry lab. has to be taken into account. These two steps cannot be longer than 3 half-lives of the radioisotope itself. The synthetic technique used for radiolabeling depends on physical or chemical state of the radioisotope. Radioisotopes from cyclotron could be obtained in solid, liquid or gas form. The radioisotope is chemically bonded to a pharmacologically active agent to form the radiotracer.  between radioisotope and the element forming the bond Radioactive metals or radiometals are generally bound to organic ligands using ionic bonds. The electrophilic metal ions bind to electron rich donors, such as carboxylic acids (COOH) or amines (NH2). The number of donor groups in a single ligand which bind to a metal ion is referred to as denticity, and can be mono, bi or polydentate. The radioisotope is chemically bonded to a pharmacologically active agent to form the radiotracer. Formation of multiple bonds between a metal ion and donors within the same ligand gives additional stability to the metal complex. The process is referred to the chelation and the metal complex is called a chelate. An example of metal chelates is the gallium-68 labeled PSMA-11 molecule which is used for prostate cancer imaging. The PSMA-11 molecule has two specific regions, one for binding to PSMA,which is overexpressed in prostate cancer, and the other to bind with gallium-68. The molecule contains three donor groups forming the metal complex. The rate of formation of the metal chelate, i.e, kinetics of the reactions, is also an important parameter for radiometal chemistry, especially for short lived isotopes such as gallium-68 that has a half-life of 68 minutes. Here, the reaction of PISMA-11 takes about 2 minutes, which is advantageous for a radioisotope with such short half-life. Another example of metal chelates is the antibody tacatuzumab conjugated with the macrocycle DOTA. DOTA is a very common chelator for therapeutic radiometals, such as yttrium-90 and lutetium-177. The antibody targets the cancer cells and the therapeutic radiometal causes damage to the tissue and eventually cell death. DOTA is a good chelator also for binding some diagnostic radiometals, such as indium-111 and gallium-68. Other types of chelators (chelating macromolecules) A common feature of these chelators is that the carboxylic functional groups -COOH Or –NH bind to the radiometals. Each radiometal prefers a certain number of carboxylic acid functionalities and hence a variety of chelators are required for different radiometals. The chelation chemistry is fairly standardized. But, the disadvantage is that the chelating macromolecule sterically hinders the biological activity of pharmaceutical. Carrier: The problem is greater for smaller Antibody Peptide pharmaceuticals such as a peptid where the ratio between the chelator and pharmaceutical size is large. However, attaching a chelator to an antibody does not significantly hinder its binding efficacy. Effective binding Lower affinity or specificity Easier preparation due to the large changes in the size and polarity etc... ACTIVE SITE TARGETING VECTOR ANTIBODY or PEPTIDE Targeting vector´s specificity or affinity for its biological target Radio-decay of Lutéciu-177 characteristics have specific advantages for radiotherapy. TARGETS: Schematics of Lutetium-177 radiopharmaceutical design Today, there are around 180 ongoing clinical trials based on 177Lu labelled molecules. https://www.iaea.org/newscenter/news/new-crp-development-of-potential-lutetium-177-radiopharmaceuticals-design- radiolabelling-and-nonclinical-evaluation-f22078 Using ANTIBODY SPECIFIC for treatment of cancer cells https://www.google.com/search?q=the+antibody+conjugated+with+the+macrocycle+DOTA,+damage+of+cancer+ cells&source=lmns&tbm=vid&bih=547&biw=1255&hl=en&sa=X&ved=2ahUKEwj169L9- b2CAxWhU6QEHQDoCTsQ0pQJKAN6BAgBEAg#fpstate=ive&vld=cid:58fb5619,vid:VyUVO6JLejs,st:0 PREPARATION OF TRACERS, pharmaceuticals TYPES OF REACTIONS Substitutional Reactions – radioisotopes form covalent bonds Nucleaophilic substitution is the chemical reaction in which an electron-rich nucleophile (18F-) replaces a functional group within electron-deficient molecule electrophile (i.e. living group: OTf) Aliphatic nucleophilic substitution. Aliphatic electrophilic substitution. is use to synthesize iodine-124 labeled dopamine transporter. The substitution of the electropositive tributyltin functional group with an iodine-124 cation. Another type of Substitution. can be performed by prosthetic groups that have been pre-functionalized with the radioisotope. A good example of such reaction is the synthesis of a Bolton-Hunter reagent. Synthesis of a Bolton-Hunter reagent Used for the preparation of a peptide or an antibody. Electrophilic aromatic substitution with radioiodine. Benefit: - This strategy isolates the harsh oxidative reaction conditions from sensitive biologics like a peptide or an antibody. Advantages of substitutional reaction Radiotracer where a hydroxyl ion (OH-) is replaced by a fluorine-18 ion The radiotracer is very similar to the parent molecule and hence it is able to mimic its biological activity. Pharmaceuticals with fluorine in their structure,which can be isotopically replaced with fluorine-18 for imaging. Afatinib - Cancer treatment - PET imaging The development of a new radiopharmaceutical follows a specific protocol. The radiochemists together with medicinal chemists select the candidates among group of compounds with desired pharmacological activity and feasible pharmacokinetics. The most promising variants of the radiotracers are passed through several pharmacokinetic, preclinical and clinical experimental phases to be finally approved as a radiopharmaceutical for clinical use.  B D True C B D False False True C D B,D 11. 11. 2024