Everything Radionuclides - Nuclear Medicine

Presentation includes info on the properties, production, usage and quality control of radionuclides / radiopharmaceuticals. By Victor Ekpo, et al.

1. EVERYTHING RADIONUCLIDES PROPERTIES, PRODUCTION, COMPARISONS EKPO Victor , ADEDOKUN Aderonke , ADEWA Dare, ADEDEWE Nusirat , DAVID Dorathy , AJIBADE Oluwafemi . A M.SC MEDICAL PHYSICS PRESENTATION COURSE ON NUCLEAR MEDICINE (2017) COLLEGE OF MEDICINE, UNIVERSITY OF LAGOS (CMUL), NIGERIA

2. OVERVIEW Definitions Properties Activity Half-Life Energy Decay Process Production Cyclotron Nuclear Reactor Generator Radiopharmaceuticals Characteristics Applications Quality Control 2

3. DEFINITION A radionuclide is a radioactive nuclide with an unstable nucleus that dissipate its excess energy by spontaneously emitting ionizing radiation (e.g. alpha, beta or gamma rays). It is also called radioisotope, radioactive isotope or radioactive nuclide. In Nuclear Medicine (NM), radionuclides are used for diagnosis, treatment and research. 3

4. What causes radioactivity? Radioactivity is caused by instability in the nucleus due to either: Imbalance in the number of neutrons (N) and protons (Z) – Natural Radionuclides Excitation due to bombardment of particles – Artificial Radionuclides 4

5. STABLE & UNSTABLE NUCLIDES Odd Z - Odd N nuclei are usually unstable (exceptions are: 2 H, 6 Li, 10 B, 14 N). For A<20, Z = N nuclei are usually stable . For A>20, Z = N nuclei are usually unstable . These nuclei require N>Z for stability . There are no stable nuclei with Z>83. 5

6. PROPERTIES Radionuclides are characterized by: Activity Half – Life Energy Decay scheme Production method 6

7. ACTIVITY Radioactive materials experience an exponential decay. The decay rate (called activity) is the number of disintegrations occurring each second. Activity (A) is the change in number of radioactive atoms ( dN ) per unit time ( dt ). A = – dN / dt , and, can be expressed as: A = λ N After time t, A (t) = A o e - λ t or N (t) = N o e - λ t where A o , N o = initial activity, number of radioactive atoms resp. λ = decay constant 7

8. ACTIVITY (UNITS) SI Unit: Becquerel 1 Becquerel ( Bq ) = 1 disintegration per second ( dps ) 1 milliCurie ( mCi ) = 37 MBq Typical values of Activity in Nuclear Medicine: 0.1 – 30mCi for diagnostics, and up to 300mCi for therapy. 8

9. CUMULATIVE ACTIVITY The total number of nuclear transformations in an organ or tissue is called cumulative activity ( Ā ). Cumulative activity values are often different for healthy patients and patients with certain diseases. where A o = initial activity in the organ T e = effective half-life Organ Dose , D = Ā x S-factor (in Gy ) Total Body / Eff. Dose , E = ∑D (for all organs) (in mSv ) Ā = 1.44 x A o x T e 9

10. SPECIFIC ACTIVITY Specific Activity (a) is the Activity of a given radionuclide per unit mass. It is a physical property of the radionuclide. where N A is Avogadro’s constant, and M is molar mass Its unit is in Bq /g or Ci/g. Relatively h igh specific activity is preferred in NM. 99m Tc is considered to have high a of 5.2x10 6 Ci/g . a a   10

11. HALF-LIFE (T ½ ) Half-Life is the time taken for number of radioactive atoms to decay by half. It is a constant for each radionuclide, and given by the equation. N (t) = N o e - λ t At half-life (t=T 1/2 ), N (t) = ½ N o , We can thus show that: T ½ = In 2/ λ T ½ =   11

12. Half-Life (contd.) There are 3 types of Half-Lives Physical Half-Life ( T p or T 1/2 ) : The time taken for number of radioactive atoms to decay by half. Biological Half-Life (T b ) : The time required for the body to biologically eliminate half of a radionuclide’s activity or amount (through metabolic turnover and excretion). Effective Half-Life ( T e ) : The time required for radioactivity distributed in organs to decrease to half its original value due to radioactive decay and biological elimination. T e < T p , T b =   12

13. Half-Life (contd.) Effective Half-Life depends on the: Radiopharmaceutical Organ involved Personal variation Health state of the organ 13

14. 14 :

15. Half – Life of 99m Tc 15 99m Tc with half-life of 6 hours, will reduce to only 6.25% of its original value within 24 hours (4 half-lives). :

16. ENERGY Preferred radionuclides should emit gamma rays of energy 50 – 300 keV . This energy range is high enough to exit the patient but low enough to be collimated and easily measured. Radionuclides emitting mono-energetic gamma rays are preferred. 16

17. MODES OF DECAY 17 There are four main modes of radioactive decay: Alpha decay Beta decay Beta plus decay Beta minus decay Electron capture Gamma decay Pure gamma decay Internal conversion Spontaneous fission

18. MODES OF DECAY (CONTD.) 18 DECAY EMITTED PARTICLE α decay α particle β - decay β - , anti-neutrino β + decay β + , neutrino Electron Capture Neutrino Pure Gamma Decay Gamma rays Internal Conversion Orbital Electron Spontaneous fission Fission products

19. CHART OF NUCLIDES 19 Z N

20. CHART OF NUCLIDES Neutron-poor nuclides Neutron-rich nuclides

21. DESIRABLE PROPERTIES OF RADIONUCLIDES Physical half-life of a few hours. Decay to a stable daughter (or one with very long T 1/2 ). Emit γ -rays but no α & β – rays. Decay by isomeric transition and electron capture is preferred. Emit γ -rays of energy 50 – 300 keV . Emit mono-energetic γ -rays. Have high specific activity. Be easily and firmly attached to the radiopharmaceutical at room temperature, and does not affect its metabolism. Be affordable and readily available at hospital site. 21

22. COMMONLY USED RADIONUCLIDES The primary radionuclide used for diagnostic nuclear medicine is Technetium-99m . The primary radionuclide used for therapeutic nuclear medicine is Iodine-131 . The primary radionuclide used for Positron Emission Tomography ( PET ) is Fluorine-18 -labelled De- oxyglucose ( FDG ). 22

23. PRODUCTION OF RADIONUCLIDES 3 METHODS Cyclotrons / Particle Accelerators Nuclear Reactors Generators 23

24. CYCLOTRON-PRODUCED RADIONUCLIDES Radionuclides can be produced in cyclotrons (or other particle accelerators) by accelerating heavy charged particles (e.g. p, α , d ) to bombard stable nuclei. Examples of cyclotron-produced radionuclides are: 18 F, 67 Ga, 123 I, 57 Co, 201 Tl. 68 Zn + p  67 Ga + 2n Protons are accelerated to approx. 20MeV to bombard 68 Zn nuclei. i.e. 68 Zn (p, 2n) 67 Ga 24

25. CYCLOTRON-PRODUCED RADIONUCLIDES ( contd.) Some radionuclides produced by cyclotrons (such as 123 Cs) decay further to the more clinically useful radionuclide ( 123 I). Most cyclotron-produced radionuclides are neutron-poor , and thus decay by β + decay or electron capture (EC). 25

26. Schematic diagram of a Cyclotron 26

27. WORKING PRINCIPLE OF A CYCLOTRON A cyclotron is a circular accelerator with semi-circular electrodes (called D’s or dees because of their shape). An ion source (hydrogen ion, i.e. proton) is introduced at the centre between the ‘D’s and accelerated to very high energy. The accelerated proton hits the target with a very high speed releasing neutron and the desired daughter radionuclide . 18 O + p  18 F + n 27

28. CYCLOTRON-PRODUCED RADIONUCLIDES ( contd.) As cyclotron-produced radionuclides are very expensive. there are now smaller specialized hospital-based cyclotrons to produce clinically used radionuclides, such as 18 F for PET. 28 Industrial cyclotron Medical Cyclotron

29. CYCLOTRON-PRODUCED RADIONUCLIDES ( contd.) 29

30. NUCLEAR REACTOR-PRODUCED RADIONUCLIDES 2 methods: Nuclear Fission Neutron Activation Here, radionuclides are produced using neutrons to bombard either: Unstable target nuclei, leading to nuclear fission , OR Stable target material, via neutron activation Nuclear reactor-produced radionuclides are usually neutron-rich, and thus decay mainly by β - decay. 30

31. NUCLEAR FISSION-PRODUCED RADIONUCLIDES: Most common target fissile material is 235 U. When bombarded by neutrons, it splits into smaller nuclei called fission fragments. The desired radionuclide can be separated from the other fissile fragments using chemical separation techniques. 31 NUCLEAR REACTOR PRODUCED RADIONUCLIDES (contd.)

32. CHARACTERISTICS OF NUCLEAR FISSION–PRODUCED RADIONUCLIDES Radionuclide Gamma ray energy ( keV ) Physical half-life 99 Mo 740 66 h 133 Xe 364 8.1 d 131 I 81 5.27 d 137 Cs 662 30 y 32 Commonly NM radionuclides produced by fission are: 99 Mo, 133 Xe, 131 I, 137 Cs .

33. NEUTRON ACTIVATED – PRODUCED RADIONUCLIDES: In Neutron Activation , an accelerated neutron is captured by a stable nuclide, inducing radioactivity. Reactions are usually (n, γ ); (n,p) or (n, α ). (n, γ ) is the most common, thus producing isotopes of the target material. 33 NUCLEAR REACTOR PRODUCED NUCLIDES (contd.)

34. Thus, since their chemistry are alike, the daughter radionuclide CANNOT be separated from its parent ( carrier ) using chemical techniques. The produced daughter radionuclide is NOT carrier-free . 34 NUCLEAR REACTOR PRODUCED NUCLIDES (contd.)

35. The presence of carrier in the mixture limits the ability to concentrate the radionuclide of interest and therefore lowers the specific activity. Because of this, nuclear fission is mainly preferred to neutron activation. An exception is 125 I. 35 NUCLEAR REACTOR PRODUCED NUCLIDES (contd.)

36. CHARACTERISTICS OF NEUTRON ACTIVATION–PRODUCED RADIONUCLIDES RADIONUCLIDE GAMMA RAY ENERGY (KEV) PHYSICAL HALF-LIFE 51 Cr 320 27.7 d 59 Fe 1099 44.5 d 99 Mo 740 66 h 131 I 364 8.1 d 36

37. 99m Tc is produced using a radionuclide generator. Because of the relatively low half-life of 99m Tc (6 hours), it cannot be feasibly stored for days ( 93.75 % of it decays within 24 hours ). Therefore, its parent nuclide 99 Mo (T 1/2 = 66 hours) is stored and transported in the form of portable lead-shielded radionuclide generators, and supplied to hospitals. The 99 Mo / 99m Tc generators are fondly called moly cows . GENERATORS 37

38. Technetium – 99m Generator 38 Fig: Different generators

39. Radionuclide generators :- are constructed on the principle of the decay-growth relationship between a long-lived parent and its short-lived daughter radionuclide. i.e. a long-lived parent nuclide is allowed to decay to its short-lived daughter nuclide and the latter is then chemically separated . 99 Mo  99m Tc + β - (T 1/2 = 66hrs ) (T 1/2 = 6hrs) GENERATORS (contd.) 39

40. 99m Tc Decay Processes 235 U  99 Mo  99m Tc  99 Tc  99 Ru Process Nuclear Fission Beta decay Isomeric Transition Beta decay Location 235 U + 1 n  99 Mo + 134 Sn + 3 1 n [Nuclear Reactor] 99 Mo  99m Tc + e - + ṽ [ Generator] 99m Tc  99 Tc + γ (140keV) [Inside the body ] 99 Tc  99 Ru + e - [Inside the body] 40

41. 99 Mo - 99m Tc process 99 Mo 87.6% 99m Tc  140 keV T½ = 6 h 99 Tc ß - T ½ = 2*10 5 y 99 Ru (stable) 12.4% ß - , ṽ T ½ = 66 h 41 ß - , ṽ T½ = 66 h Isomeric Transition

42. PROCEDURE FOR PRODUCTION OF 99m Tc Nuclear Fission : Molybdenum produced as nuclear fission product of 235 U in nuclear reactor. Molybdenum in compound form as Ammonium Molybdenate (NH 4 + )(MoO 4 - ) is loaded to column of inorganic alumina (Al 2 O 3 ) resin in the generator, and shipped. Adsorption Occurs : Molybdenum compound attaches to the surface of the alumina molecules. The generator makes use of the fact that Molybdenum likes to bond with Alumina, but Technetium does not. 42

43. PROCEDURE FOR PRODUCTION OF 99m Tc Elution : 99 Mo decays to 99m Tc, and an isotonic saline* (called “ eluant ”, e.g. NaCl ) is added to the column to remove the 99m Tc (“eluate”) when it is needed . Chemical technique mainly used for separation is Column Chromatography . The 99 Mo is not soluble in saline and therefore remains in the column, while the 99m Tc is soluble and thus extracted. 43

44. THE PROCESS OF ELUTION 44

45. As air filter is opened, atmospheric pressure forces saline into the column. Saline passes through the column to elute (wash off). The Cl - ions exchange with the 99m TcO 4 - forming Sodium Pertechnetate (Na 93m TcO 4 ). A 99m Tc generator is eluted once daily for one week (or as need be) and then replaced . The half-life of 99 Mo is 66 hours, which allows the generator to remain useful for approximately 1 week (about 2.5 half-lives ). 45 PROCEDURE FOR PRODUCTION OF 99m Tc

46. TRANSIENT vs SECULAR EQUILIBRIUM (TE) (SE) Equilibrium occurs when ratio of activity of parent and daughter reach a constant. 99m Tc is produced as 99 Mo decays. For TE, T p > T d e.g. 99 Mo – 99m Tc generator For SE, T p >>> T d e.g. 81 Rb – 81m Kr generator 46 For 99m Tc, TE occurs at ~ 22-23 hours (~4 half-lives of 99m Tc). Elution is done at this time.

47. TRANSIENT AND SECULAR EQUILIBRIUM Secular Equilibrium (SE) For T 1/2 (parent) >> T 1/2 (daughter ), e.g. 81 Rb – 81m Kr generator T ½ (4.58 hr) (13 secs ) SE occurs at approx. 5 to 6 half-lives of the daughter. SE lasts longer. 47

48. Recall that activity, A = λ N The formula that governs the ratios of the activities is: where A P , λ P are activity and decay constant of the parent, and A D , λ D are activity and decay constant of the daughter Maximum activity of daughter nuclide occurs at time, t max given by: 48 TRANSIENT vs SECULAR EQUILIBRIUM (contd.)

49. For TRANSIENT EQUILIBRIUM , t ½D < t ½P and λ D > λ P , For SECULAR EQUILIBRIUM , t ½D << t ½P and λ D >> λ P , A D / A P ≈ 1 49 TRANSIENT vs SECULAR EQUILIBRIUM (contd.)

50. Types of Generators 2 types of generators: Dry type : this has a separate container of saline solution that is changed every time a new elution will be made. The column is thus dry between elutions. Wet type : it has a built-in container with enough volume of saline solution for all elutions. Transient Equilibrium generators and Secular Equilibrium generators are also sometimes considered types of generators. 50

51. ACTIVITY OF DAUGHTER The activity of the daughter (e.g. 99m Tc) at the time of elution depends on the following : 1. The activity of the parent. 2. The rate of formation of the daughter, which is equal to the rate of decay of the parent (i.e . A o e - λ t ). 3. The time since the last elution. 4. The elution efficiency (typically 80% to 90%). 51

52. GENERATOR-PRODUCED NUCLIDES 52

53. 53 SUMMARY OF RADIONUCLIDE PRODUCTION METHODS

54. ADVANTAGES AND DISADVANTAGES OF DIFFERENT PRODUCTION METHODS METHOD OF RADIONUCLIDE PRODUCTION ADVANTAGES DISADVANTAGES Cyclotron High specific activity Fewer radioisotopes are produced It is easily accessible than nuclear reactor Expensive to purchase and operate Nuclear fission The fission process is a source of a number of widely used radioisotopes ( 90 Sr, 99 Mo, 131 I and 133 Xe) High specific activity Large quantities of radioactive materials generated Neutron activation - It is difficult to separate chemically Low specific activity Generator It is cheap It is portable High specific activity It is easy to operate It cannot be stored for future use. 54

55. Physical half-life: 6 hours; Biological half-life: 24 hours; the absence of β radiation permits the administration of GBq activities for diagnostic purposes without significant radiation dose to the patient. emits 140 keV photons which can be readily collimated to give images of superior spatial resolution; Readily available in a sterile, pyrogen free and carrier free state from 99 Mo - 99m Tc generators . 99m Tc can easily be labelled with several radiopharmaceuticals, as shown in table later. Technetium-99m Properties 99m Tc has the following favorable characteristics: 55

56. RADIOPHARMACEUTICALS Pharmaceuticals are attached (labelled) to the radionuclide in order to send it to desired target within the body. The resultant mixture is called radiopharmaceuticals. They compose of a radionuclide bond to an organic molecule. Radiopharmaceuticals are designed to concentrate on a particular organ /tissue. They mimic a natural physiologic process. They evaluate function rather than anatomy. 56

57. DESIRABLE PROPERTIES OF RADIOPHARMACEUTICALS Localize largely and quickly in target organ. Eliminated from the body with effective T 1/2 similar to duration of examination. Effective T1/2 should be long enough to complete the study, but short enough to minimize patient dose. Have low toxicity. Form stable product in vivo and in vitro . Minimal electron contamination. Contain no chemical or radionuclide contaminants. Be readily and cheaply available. 57

58. MIXING OF RADIOPHARMACEUTICALS Radiopharmaceuticals can be produced by simple mixing and shaking at room temperature . e.g. 99m Tc + MDP + other chemicals. Room is under positive pressure of sterile air. The radiopharmaceutical is usually sterilized and anti-microbial preservatives added. 58

59. Technetium-99m RADIOPHARMACEUTICALS 59 S/N COMPOUND ORGAN 1. Hexamethyl propylene amine oxime (HMPAO) Cerebral imaging 2. Dimercaptosuccinic acid (DMSA) - Mercaptoacetyletriglycine (MAG3), DTPA Renal study 3. Human serum albumin (HSA) colloidal particles / Sulfur Colloid Liver, spleen, red bone marrow imaging 4. Iminodiacetic acid (HIDA) Biliary studies 5. HSA Macroaggregates Lung perfusion imaging 6. Diethylene Triamine Pentacetic Acid (DTPA) Lung ventilation studies 7. Methylene diphosphonate (MDP) Bone imaging 8. Autologous red cells Cardiac function 9. Heat-damaged autologous red cells Spleen imaging 10. Sestamibi (MIBI) or tetrofosmin Cardiac perfusion imaging, for parathyroid adenoma, breast

60. OTHER RADIOPHARMACEUTICALS AND ORGANS S/N COMPOUND ORGAN 1. 133 Xe Lung ventilation imaging 2. 201 Thallium Cardiac (myocardial perfusion) 3. Radioiodine or 99m Tc-NaI Thyroid imaging 4. 123 I or 131 I- labelled hippuran Renal study 5. 51 Cr – labelled RBC Liver, spleen, kidneys 6. 67 Ga – labelled citrate Tumour detection and infection 7. 111 In-labelled leukocytes Detect acute infection 8. 75 Se- selenomethionine Pancreas localization 9. 75 Se – Cholesterol Suprarenal cortex localization 10. 81m Krypton- gas Lung ventilation 60

61. RADIONUCLIDES FOR THERAPY 61 131 I treatment of thyroid cancer, 131 I treatment of hyperthyroidism Radioimmunotherapy with 90 Y ibritumomab tiuxetan ( Zevalin ) & 131 I tositumomab ( Bexxar ) therapy of low-grade non-Hodgkin's lymphoma. They can be administered in capsule or liquid solution form.

62. QC FOR RADIOPHARMACEUTICALS Physical tests pH Ionic strength Osmolality Particle size Radiochemical tests; Radionuclide purity Radiochemical purity Chemical purity Specific activity Biological test; Sterility Apyrogenicity Toxicity 62

63. PHYSICAL TESTS pH and Ionic Strength Ideal pH of radiopharmaceutical should be 7.4 The pH of radiopharmaceutical is measured by a pH meter Correct ionic strength is achieved by the addition of acid or alkali. Particle Size The size of particles aid to determine the site where radiopharmaceutical will get localized. 63

64. CHEMICAL TESTS RADIONUCLIDE PURITY It is the percentage of the total radioactivity in the form of the desired radionuclide present in the radiopharmaceutical. Impurities arise from fission of heavy elements in the reactor. Multi-Channel Analyser (MCA) or well counter is used for test. Beta Spectrometer or a liquid scintillator may also be used to test in pure beta emission radionuclides. 64

65. CHEMICAL TEST (CONTD.) Radionuclide impurities could give rise to instability of radiopharmaceutical, increasing the dose and degrading the image quality. Sodium ascorbate , sodium sulphite, and ascorbic acid are often added to maintain stability. 65

66. CHEMICAL TEST (CONTD.) RADIOCHEMICAL PURITY It refers to the percentage of total radioactivity in a sample that is present in the desired chemical form . Radiochemical impurities may arise from decomposition due to change in temperature or pH, and light. Presence of radiochemical impurities could alter the bio-distribution of radiopharmaceutical . 66

67. CHEMICAL TEST (CONTD.) Methods used to detect radiochemical impurities in a given radiopharmaceutical include; Gel chromatography Precipitation Solvent extraction High performance liquid chromatography (HPLC) Distillation 67

68. CHEMICAL TEST (CONTD.) CHEMICAL PURITY Whereas radiochemical purity deals with the purity of the starting materials for radiopharmaceuticals, chemical purity checks the final material , to ascertain it has not been affected by the process (milking). e.g. Presence of Al ions in Tc radiopharms , gotten from the alumina in the 99m Tc generator. A simple colorimetric limit test (spot colour test) is used for alumina. 68

69. CHEMICAL TEST (CONTD.) ACTIVITY Measures the amount of radioactivity of a radiopharm of each dose before administration to patients. The determination of activity is carried out by means of an isotope dose calibrator . The Dose Calibrator is used to determine content of Mo each time the 99m Tc generator is eluted. 69

70. BIOLOGICAL TEST To examine the sterility, apyrogenicity and toxicity. STERILITY It indicates the absence of micro-organisms in a radiopharmaceutical preparation. 70

71. BIOLOGICAL TEST (CONTD.) METHODS OF STERILIZATION Autoclaving Radiopharmaceutical is sterilized by heating steam at 121 o c under a pressure of 18 psi for 15-20 minutes. Suitable for thermostable radiopharmaceutical (such as 99m Tc - pertechnetate , 111 In-indium chloride ). Not suitable for heat labile radiopharms (e.g. I-131) and short- lived radionuclides (e.g. F-18) because it takes too long . 71

72. BIOLOGICAL TEST (CONTD.) Membrane filtration Radiopharmaceutical is filtered through a membrane filter that remove various organisms by sieving mechanism. It is suitable for short lived radionuclides and heat-labile radiopharmaceutical. 72

73. BIOLOGICAL TEST (CONTD.) 73 Fig: Millipore Filter – a type of Membrane Filter

74. BIOLOGICAL TEST (CONTD.) STERILITY TEST It is performed by incubating the radiopharmaceutical sample in fluid Thioglycollate medium or soybean-casein digest at 30 C to 35 C and 20 C to 25 C for 14 days respectively. 74

75. BIOLOGICAL TEST (CONTD.) APYROGENICITY TEST All radiopharmaceuticals for human administration are required to be pyrogen -free . Pyrogens are either polysaccharides or proteins produced by metabolism of microorganism . Pyrogenic contamination may be prevented by the use of sterile glassware, solutions, and equipment under aseptic conditions in any preparation procedure . 75

76. BIOLOGICAL TEST (CONTD.) Apyrogenicity test (contd.) Tested by injecting rabbits with test material and monitoring their rectal temperature over 3 hours. If the total temperature rise is less than 1.4 o C , and none of the animals shows a temperature rise over 0.6 C , then the material is considered to be non- pyrogenic . 76

77. BIOLOGICAL TEST (CONTD.) Toxicity test Toxicity arises from the pharmaceutical part of the radiopharmaceutical, however it is minimal since the quantity of radiopharmaceutical used is usually small. The toxic effect of radiopharmaceutical is described by L50/60 , which describes the dose required to produce mortality of 50% of a species in 60 days after administration of a radiopharmaceutical dose. Toxicity is preferably studied using cell culture and computer modelling. 77

78. SUMMARY Radionuclides are produced with cyclotrons, nuclear reactors or generators. Their QA involve a Physical test (pH, ionic, etc.), Chemical test (radionuclide purity, radiochemical purity, etc.) and Biological test (sterility, apyrogenicity , toxicity tests). 78

79. REFERENCES B. Saha . Fundamentals of Nuclear Pharmacy . 4 th ed. New York: Springer, 2013. D. L. Bailey. Nuclear Medicine Physics : a handbook for students and teachers . — Vienna: International Atomic Energy Agency, 2014. E. B. Podgorsak . Radiation Oncology Physics: A Handbook for Teachers and Students . Vienna: IAEA, 2005. E. Forster. Equipment for Diagnostic Radiography. New York: Springer, 2012. IAEA. Nuclear Medicine Resources Manual . Vienna : International Atomic Energy Agency, 2006. J. A. Pope. Medical Physics Imaging. Heinemann Advanced Science, 1999. J. T. Bushberg , et al. The Essential Physics of Medical Imaging. 2 nd ed. Philadelphia: Lippincott Williams & Wilkins, 2002. Marco Silari . Radionuclide Production. African School of Physics, 2010 P. Allisy -Roberts, J. R. Williams. Farr’s Physics of Medical Imaging. Edinburg: Elsevier Health Sciences, 2007 S. Webb. The Physics of Medical Imaging . 2 nd ed. Florida: CRC Press, 2012. W. Huda, R. Sloan. Review of Radiologic Physics . 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

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