This course is an introduction to the applications of modern pharmacochemical aspects in drug design and in the successful confrontation of pathologic conditions (incurable, insufficiently cured diseases, toxicity of chemicals), using contemporary pharmacochemical methods. Relations of chemical structure, physicochemical properties and activity are studied. Another aim is the acquisition of satisfactory knowledge of the medicinal chemistry of free radicals, role of oxygen in life, free radical reactions in biological systems, reactive oxygen species and mechanisms of radical attack to lipids, proteins and DNA. Knowledge of physiological defensive mechanisms against free radicals, as well as explanation of oxidative stress are among the aims of this course. Comprehension of the blood-brain barrier, construction, function and physiologic role, in relation to drug action, is another aim.
Furthermore, the course aims at providing basic knowledge on the properties and medical applications of ionizing radiation, as well as the nuclear properties requirements of radionuclides used in radiopharmacy. In a deeper scope, this course covers the pharmaceutical radiochemistry of commonly used radionuclides in radiopharmacy. The design and mechanism of action of common radiopharmaceuticals at the target site is discussed. Finally, the course covers methods of evaluation of the radiochemical purity of radiopharmaceuticals.
Course Content (Syllabus)
This course presents some modern aspects in the broad field of bioactive molecules (drugs, poisons) and the molecular approach to pathologic conditions, aiming to a rational confrontation of them through drug design. The effect of the chemical characteristic groups on activity and toxicity of drug molecules is studied and an approximation in physicochemical properties/chemical structure/activity relationships is performed. Further topics are: Pharmacochemistry of free radicals. Role of oxygen in aerobic life, free radical reactions in biological systems. Reactive oxygen species. Mechanisms of radical attack on lipids, proteins, DNA. Defence of the body against radical offence, the involved mechanisms. Structure, function of blood brain barrier and drug permeability.
Radioactivity: Radioactive decay, α, β-, β+, particle emissions, electron capture, γ ray emission, isomeric transition, internal conversion, Auger electrons. Law of radioactivity, Half-life, Successive decay equations, transient and secular equilibrium. Interaction of radiation with matter: ionization, bremsstrahlung, annihilation, photoelectric effect, Compton scattering, pair production. Radiolysis of water, effect of radiation on macromolecules, DNA strand breaks, oxygen effect. Radionuclide generator: Principles of a generator. 99Mo/99mTc generator. Yield of 99mTc. Radionuclide, radiochemical and chemical purity of 99Μο/99mTc generator eluate. Labeled compounds: Radionuclide, radiochemical and chemical purity of labeled compounds. Methods of radiochemical yield calculation (radiochromatography). Radiopharmaceuticals: general principles, diagnostic and therapeutic
radiopharmaceuticals. Properties of 99mTc. Chemistry of 99mTc. Labeling with 99mTc
(Labeling with reduced 99mTc, Formation of 99mTc-complexes by ligands exchange,
reducing agents). Techentium(V), oxo core, isomerism. Methods of radioiodination of
proteins (iodine chloride, iodogen, chloramin-T, enzymatic methods)
Radiopharmaceuticals of 99mTc and other radionuclides (preparation, clinical
applications, pharmacokinetic data). Sodium pertechnetate, technetium-sulfur colloid,
technetium-human albumin macroaggregates, technetium-DTPA, technetiumglucoheptate,
technetium-succimer, trivalent and pentavalent, technetiummethylendiphosphonate,
technetium-iminodiacetic acid derivatives, technetiumhexamethylene
amine oxime, technetium- ethyl cysteinate dimmer, technetiummercaptoacetyltriglycine,
rhenium-(hydroxiethylidine diphosphonate). [111In]-Indium-tris (oxine). [123/131Ι]-
Sodium Iodide, [123/131Ι]-metaiodobenzyl-guanidine. [18F]-2-fluorodeoxyglucose.
Thallium-201. Labeling monoclonal antibodies-advantages and disadvantages. Direct
labeling of mAbs with radio-iodine and technetium. Red blood cell labeling with
technetium and indium.