Radiopharmaceuticals

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Radiopharmaceuticals

  1. 1. Presented By:Lone Vidya R.Government College OfPharmacy, Aurangabad. 12/26/12 1
  2. 2. Outline ofpresentation 12/26/12 2 Page 2
  3. 3. Radiopharmacy studies related to the Radiopharmacy studies related to thepharmaceutical, chemical, pharmaceutical, chemical,physical,biochemical, and biological physical,biochemical, and biologicalaspects of radiopharmaceuticals. aspects of radiopharmaceuticals. A Radiopharmaceuticala special class of A Radiopharmaceuticala special class of radiochemical formulation having high radiochemical formulation having high purity, sterility and apyrogenicity, purity, sterility and apyrogenicity, suitable for administration to human suitable for administration to human patients either orally or intravenously, patients either orally or intravenously, either for diagnosis or therapy either for diagnosis or therapy 12/26/12 3
  4. 4. Evolution Of Nuclear Medicine 12/26/12 4
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  7. 7. TERMINOLOGY TERMINOLOGYIsotopes IsotopesAtoms of the same element with different atomic mass Atoms of the same element with different atomic massnumbers numberse.g. carbon-12, carbon-13 and carbon-14 e.g. carbon-12, carbon-13 and carbon-14Nuclide Nuclideis a type of atom whose nuclei have specific numbers of is a type of atom whose nuclei have specific numbers ofprotons and neutrons protons and neutronsNotation of a nuclide= AAEZ Notation of a nuclide= EZe.g. = 235U92 e.g. = 235U92 12/26/12 7
  8. 8. Types Of Nuclides 12/26/12 8
  9. 9. RADIONUCLIDERADIONUCLIDE (Radioisotopes)) (Radioisotopes An atom with an unstable nucleus, An atom with an unstable nucleus, characterized by excess energy characterized by excess energy available to be imparted either to available to be imparted either to A newly created radiation particle A newly created radiation particle within the nucleus or via internal within the nucleus or via internal conversion. conversion. 12/26/12 9
  10. 10. CLASSIFICATION OF RADIONUCLIDE Stability class No. of nuclidesRadioactive non-primordial, but naturally occurring on 51EarthRadioactive synthetic (half-life < 1 hour) >2400Theoretically stable to all but proton decay 90Radioactive synthetic (half-life > 1 hour). Includes most 562useful radiotracersEnergetically unstable to one or more known decay 163modes.Radioactive primordial nuclides 35 12/26/12 10
  11. 11. Radioactivity The process in which an unstable isotope undergoes changes until a stable state is reached and in the transformation emits energy in the form of radiation (alpha particles, beta particles and gamma rays). 12/26/12 11
  12. 12. 12/26/12 12
  13. 13. RADIATION MEASUREMENTThe basic unit for quantifying radioactivity (i.e. describes the rate atwhich the nuclei decay). Curie (Ci):Curie (Ci), named for the famed scientist Marie Curie Curie = 3.7 x 1010 atoms disintegrate per second (dps) Millicurie (mCi) = 3.7 x 107 dps Microcurie (μCi) = 3.7 x 104 dps Becquerel (Bq): A unit of radioactivity. One Becquerel is equal to 1disintegration per second. 12/26/12 13
  14. 14. Radioactive decay Radioactive decay The process in which an unstable atomic nucleus spontaneously loses energy by emitting ionizing particles and radiation.Mode Of Radioactive Decay Naturally……….combination of α, β and γ emission. Artificially……….spontaneous fission, neutron emission and even proton and heavy-ion emission. 12/26/12 14
  15. 15. RADIOACTIVE DECAY LAWRADIOACTIVE DECAY LAWThe rate of decay (number of disintegrations per unit time) The rate of decay (number of disintegrations per unit time)is proportional to N, the number of radioactive nuclei in the is proportional to N, the number of radioactive nuclei in thesample …… sample …… dN/ dt ∞ -λN…… dN/ dt ∞ -λN……Large λ =rapid decay; Large λ =rapid decay;small λ =slow decay. small λ =slow decay. 12/26/12 15
  16. 16. Types of decay 1- Alpha particle 2- Beta particle 3- Gamma ray 12/26/12 16
  17. 17. Type of Radiation Alpha particle Beta particle Gamma raySymbol orCharge +2 -1 0Speed slow fast Very fastIonising ability high medium 0Penetrating power low medium highStopped by: paper aluminium lead 12/26/12 17
  18. 18. Properties of an Ideal Diagnostic Properties of an Ideal Diagnostic Radioisotope Radioisotope Easy Availability Easy Availability Types of Emission Types of Emission Energy of Gamma Rays Energy of Gamma Rays Photon Abundance Photon Abundance Target to Non target Ratio Target to Non target Ratio Effective Half-life Effective Half-life Patient Safety Patient Safety 12/26/12 18
  19. 19. EASY EASYAVAILABILITYAVAILABILITY The radiopharmaceutical should be easily The radiopharmaceutical should be easily produced, inexpensive, and readily produced, inexpensive, and readily available in any nuclear medicine available in any nuclear medicine facility facilityTYPES OF Pure Gamma Emitter Pure Gamma EmitterEMISSION (Alpha & Beta Particles are non (Alpha & Beta Particles are non imageable & Deliver High Radiation imageable & Deliver High Radiation Dose.) Dose.) 12/26/12 19
  20. 20. ENERGY OF ENERGY OF GAMMA GAMMA RAYS RAYS For diagnostic studies the radionuclide must emit aaƔ radiation with an For diagnostic studies the radionuclide must emit Ɣ radiation with an energy preferably between 30 and 300 kev. Below 30 kev, Ɣ rays are energy preferably between 30 and 300 kev. Below 30 kev, Ɣ rays are absorbed by tissue absorbed by tissue Ideal: 100-250 kev Ideal: 100-250 kev e.g. 99mTc, 123I, 111In e.g. 99mTc, 123I, 111In 12/26/12 20
  21. 21. PHOTON PHOTON ABUNDANCE ABUNDANCEShould be high Should be highto minimize to minimizeimaging time. imaging time. 12/26/12 21
  22. 22. Target to Non Target to Non It should be high to: Maximize the target Ratio target Ratio efficacy of diagnosis. Minimize the radiation dose to the patient.An ideal radiopharmaceutical should haveAn ideal radiopharmaceutical should have all the above characteristics to provide all the above characteristics to provide maximum effcacy in the diagnosis of maximum effcacy in the diagnosis of diseases and aaminimum radiation diseases and minimum radiation dose to the patient. dose to the patient. 12/26/12 22
  23. 23. EFFECTIVE HALF-LIFE1. It should be short enough to minimize the radiation dose to patients and long enough to perform the procedure.2. Ideally 1.5 times the duration of the diagnostic procedure.3. Example: For a Bone Scan which is a 4-h procedure, 99mTc- phosphate compounds with an effective half-life of 6 h are the ideal radiopharmaceuticals. 12/26/12 23
  24. 24. DESIGN OF NEW RADIOPHARMACEUTICALS GeneralConsiderations 1. The method of preparation should be simple, easy, and 1. The method of preparation should be simple, easy, and reproducible, and should not alter the desired property of the reproducible, and should not alter the desired property of the labeled compound. labeled compound. 2. Optimum conditions of temperature, pH, ionic strength, and molar 2. Optimum conditions of temperature, pH, ionic strength, and molar ratios should be established and maintained for maximum effcacy ratios should be established and maintained for maximum effcacy of the radiopharmaceutical. of the radiopharmaceutical. 12/26/12 24
  25. 25. Factors Influencing the Design of NewFactors Influencing the Design of New Radiopharmaceuticals Radiopharmaceuticals 12/26/12 25
  26. 26. COMPATIBILITYWhen aalabeled compound is to be prepared, the first criterion to consider isWhen labeled compound is to be prepared, the first criterion to consider iswhether the label can be incorporated into the molecule to be labeled.whether the label can be incorporated into the molecule to be labeled. This may be assessed from aaknowledge of the chemical properties of the two  This may be assessed from knowledge of the chemical properties of the twopartners. partners. For example, 111In ion can form coordinate covalent bonds, and DTPA is aa  For example, 111In ion can form coordinate covalent bonds, and DTPA ischelating agent containing nitrogen and oxygen atoms with lone pairs of chelating agent containing nitrogen and oxygen atoms with lone pairs ofelectrons that can be donated to form coordinated covalent bonds. electrons that can be donated to form coordinated covalent bonds.Therefore, when 111In ion and DTPA are mixed under appropriate Therefore, when 111In ion and DTPA are mixed under appropriatephysicochemical conditions, 111In-DTPA is formed and remains stable for aa physicochemical conditions, 111In-DTPA is formed and remains stable forlong time. long time. 12/26/12 26
  27. 27. CHARGE OF THE MOLECULEThe charge on aaradiopharmaceutical The charge on radiopharmaceuticaldetermines its solubility in various determines its solubility in varioussolvents. solvents. The greater the charge, the higher the  The greater the charge, the higher thesolubility in aqueous solution. solubility in aqueous solution.Nonpolar molecules tend to be more Nonpolar molecules tend to be moresoluble in organic solvents and lipids soluble in organic solvents and lipids 12/26/12 27
  28. 28. SIZE OF THE SIZE OF THEMOLECULE MOLECULE It is an important determinant in its It is an important determinant in its absorption in the biologic system. absorption in the biologic system.  Larger molecules (mol. wt. >~60, 000)  Larger molecules (mol. wt. >~60, 000) are not filtered by the glomeruli in the are not filtered by the glomeruli in the kidney. kidney.  This information should give some clue  This information should give some clue as to the range of molecular weights of the as to the range of molecular weights of the desired radiopharmaceutical that should be desired radiopharmaceutical that should be chosen for aagiven study. chosen for given study. 12/26/12 28
  29. 29. PROTEIN BINDINGAlmost all drugs, radioactive or not, bind to plasma proteins to variabledegrees.Protein binding is greatly influenced by a number of factors, such as thecharge on the radiopharmaceutical molecule, the pH, the nature of protein,and the concentration of anions in plasma.111In-chelates exchange 111In with transferrin to form 111In-transferrin.Protein binding the tissue distribution and plasma clearance of aradiopharmaceutical and its uptake by the organ of interest 12/26/12 29
  30. 30. SOLUBILITY SOLUBILITYFor injection, the radiopharmaceutical should be inaqueous solution at a pH compatible with blood pH (7.4).The ionic strength and osmolality of the agent shouldalso be appropriate for blood.The radiopharmaceutical 111In-oxine is highly soluble inlipid and is therefore used specifically for labelingleukocytes and platelets. 12/26/12 30
  31. 31. STABILITY STABILITYIt must be stable both in vitro and in vivo.It must be stable both in vitro and in vivo. In vivo breakdown of aaradiopharmaceutical results in undesirable  In vivo breakdown of radiopharmaceutical results in undesirablebiodistribution of radioactivity. biodistribution of radioactivity.For example, dehalogenation of radioiodinated compounds gives For example, dehalogenation of radioiodinated compounds givesfree radioiodide, which raises the background activity in the clinical free radioiodide, which raises the background activity in the clinicalstudy. study. Temperature, pH, and light the stability of many compounds and  Temperature, pH, and light the stability of many compounds andthe optimal range of these physicochemical conditions must be the optimal range of these physicochemical conditions must beestablished for the preparation and storage of labeled compounds. established for the preparation and storage of labeled compounds. 12/26/12 31
  32. 32. PRODUCTION OFRADIOISOTOPES 12/26/12 32
  33. 33. Nuclides with a mass largerNuclear than about 130 amu spontaneously split apart toFission form lighter, more stable, nuclides. The half-life for the spontaneous fission of 238U is 1016 years By irradiating samples of heavy nuclides with slow- moving thermal neutrons it is possible to induce fission reactions. E.g:-99Mo (which decays to 99 Tcm), 131I, and 133Xe. 12/26/12 33
  34. 34. More than 370 daughter nuclides with atomic masses between 72 and 161 amu areformed in the thermal-neutron- induced fission of 235U, including the two products 12/26/12 34
  35. 35. NEUTRONACTIVATION Neutrons produced by the fission of uranium Neutrons produced by the fission of uranium in aanuclear reactor can be used to create in nuclear reactor can be used to create radionuclides by bombarding stable target radionuclides by bombarding stable target material placed in the reactor. material placed in the reactor. Process involves capture of neutrons by Process involves capture of neutrons by stable nuclei stable nuclei 98 Mo + n → 99Mo + γ 50 Cr + n → 51Cr + γ 31 P + n → 32P + γ 32 S + n → 32P + p 12/26/12 35
  36. 36. The produced radioisotope is typically anisotope of the target element, thereforechemical separation is not possible.This means that the (N,γ) producedradionuclide are not carrier-free. 12/26/12 36
  37. 37. CHARGEDPARTICLE INDUCED REACTIONS •Radionuclides may be produced by bombarding target materials with charged particles in particle accelerators such as cyclotrons. •Based on the use of accelerators. Charged particles like protons, deuterons or alphas are accelerated to energies between 1 to 100 MeV and bombard a target material. 12/26/12 37
  38. 38. Cyclotron Cyclotron 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(drive) steer the injected charged particles (protons,deutrons, alpha and helium) in a circular path.The charged particle follows a circular path untilthe particle has sufficient energy that it passes out ofthe field and interact with the target nucleus. 12/26/12 38
  39. 39. RADIONUCLIDE RADIONUCLIDEA system for holding A system for holding GENERATORS GENERATORSthe parent in such aaway the parent in such waythat the daughter can be that the daughter can beeasily separated for easily separated forclinical use is called aa clinical use is calledradionuclide generator radionuclide generator Principle: Principle: A long-lived parent A long-lived parent radionuclide is allowed to radionuclide is allowed to decay to its short-lived decay to its short-lived daughter radionuclide and the daughter radionuclide and the latter is chemically separated in latter is chemically separated in aaphysiological solution. physiological solution. Example: Example: technetium-99m, obtained from technetium-99m, obtained from aagenerator constructed of generator constructed of molybdenum-99 absorbed to an molybdenum-99 absorbed to an alumina column alumina column 12/26/12 39
  40. 40. 99Mo/99mTc Generator 12/26/12 40
  41. 41. Various techniques, for the preparation of radionuclide generators 12/26/12 41
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  45. 45. List Of Radiopharmaceuticals Radiopharmaceutical Trade Name Primary UsesCarbon-14 Urea Pytest Detection of H PyloriCobalt-57 cyanocobalamin Rubratope Schilling testCobalt -57 & -58 Dicopac Schilling testcyanocobalaminChromium-51sodium chromate Chromitope (Bracco) Mallinckrodt Cr-51 for labeling RBCsFluorine-18 FDG positron emission tomography imagingFluorine-18 Florbetapir Amyvid Beta amyloid plaque PET imaging for Alzheimers diseaseGallium-67 Neoscan (GE) soft-tissue tumor and inflammatory process DuPont Ga-67 imaging Mallinckrodt Ga-67Indium-111 chloride Indiclor (Nycomed) for labeling monoclonal antibodies and Mallinckrodt In-111Cl peptides (OncoScint & Octreoscan) 12/26/12 45
  46. 46. Indium-111 pentetate (DTPA) Indium DTPA In 111 imaging of CSF kineticsIndium-111 oxyquinoline Indium-111 oxine for labeling leukocytes and platelets(oxine)Indium-111 Capromab monoclonal antibody for imaging prostate ProstaScintpendetide cancerIndium-111 Imciromab monoclonal antibody for diagnosis of Myoscintnot on marketpentetate myocardial necrosisIndium-111 pentetreotide Octreoscan imaging of neuroendocrine tumorsIndium-111 satumomab OncoScint CR/OV imaging of metastatic disease associatedpendetide not on market with colorectal and ovarian cancerI-123 sodium iodide thyroid imaging & uptake MallinckrodtAmershamI-123 Iobenguane (MIBG) neuroendocrine tumor imaging AdreviewI-125 iothalamate Glofil measurement of glomerular filtrationI-125 human serum albumin Isojex plasma volume determinations(RISA) 12/26/12 46
  47. 47. Tositumomab & Iodine I 131 Bexxar Treatment of Non-Hodgkins LymphomaTositumomabI-131 iodohippurate Hippuran; renal imaging and function studies HipputopeDiscontinued productsI-131 (Univ of Michigan) adrenal imagingiodomethylnorcholesterol(NP-59)I-131 I-131 MIBG imaging of pheochromocytomas andmetaiodobenzylguanidine(MIB neuroblastomasG)Krypton-81m gas (from Rb-81 Discontinued pulmonary ventilation imaginggenerator)P-32 chromic phosphate Phosphocol�P32 therapy of intracavitary malignanciesP-32 sodium phosphate therapy of polycythemia veraRubidium-82 (from Sr-82/Rb- Cardio-Gen-82 positron emission tomography imaging82 generator) 12/26/12 47
  48. 48. Tc-99m Arcitumomab CEA-Scanoff the market monoclonal antibody for colorectal cancerTc-99m albumin colloid Microlite discontinued imaging of RES (liver/spleen)Tc-99m bicisate (ECD) Neurolite cerebral perfusion imagingTc-99m Depreotide Neotectoff the market somatostatin receptor-bearing pulmonary massesTc-99m disofenin (DISIDA) Hepatolite - CIS hepatobiliary imagingTc-99m exametazine (HMPAO) Ceretec cerebral perfusion imagingTc-99m Gluceptate DraximageMallinckrodt renal imaging off the marketTc-99m Human Serum Albumin imaging of cardiac chambers(HSA)Tc-99m Fanolesomab Tc-99m NeutroSpecoff monoclonal antibody for infectious imaging the market 12/26/12 48
  49. 49. Applications Of Radiopharmaceuticals As an aid in the diagnosis of Treatment of disease diseaseRadiolabelled Molecules DiseaseChromic Phosphate P32 For Lung, Ovarian, Uterine, And Prostate CancersSodium Iodide I 131 Thyroid CancerSamarium Sm 153 Cancerous Bone TissueSodium Phosphate P 32 Cancerous Bone Tissue And Other Types Of CancersStrontium Chloride Sr 89 Cancerous Bone Tissue 12/26/12 49
  50. 50. As an aid in the diagnosis of disease (diagnostic radiopharmaceuticals) e.g. e.g.1.51 Cr-EDTA for measuring glomerular filtration 1.51 Cr-EDTA for measuring glomerular filtrationrate. rate.2. e.g.99m TC-methylene di phosphonate (MDP) used 2. e.g.99m TC-methylene di phosphonate (MDP) usedin bone scanning). in bone scanning). 12/26/12 50
  51. 51. 1. Radiopharmaceuticals; final text for addition to the international pharmacopoeia 1. Radiopharmaceuticals; final text for addition to the international pharmacopoeia (november 2008) (november 2008)2. The radiopharmacy;a technologist’s guide; editors by 2. The radiopharmacy;a technologist’s guide; editors bySuzanne dennan; chapter 1; ppno. 2-12 Suzanne dennan; chapter 1; no. 2-123. Advances in medical radiation imaging for cancer diagnosis and treatment, 3. Advances in medical radiation imaging for cancer diagnosis and treatment,Nuclear technology review 2006, IAEA, (2006) pp. 110-127.Nuclear technology review 2006, IAEA, (2006) pp. 110-127.4. Beneficial uses and production of radioisotopes. 2004 update. Nea/iaea 4. Beneficial uses and production of radioisotopes. 2004 update. Nea/iaeaJoint publication. Oecd 2005. Joint publication. Oecd 2005.5. Development of radionuclide generators for biomedical applications, by 5. Development of radionuclide generators for biomedical applications, byRubel chakravarty bhabha atomic research centre Rubel chakravarty bhabha atomic research centre6. www. Wikipedia.com 6. www. Wikipedia.com 12/26/12 51
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