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Radioisotope production and application
- 1. Production and Applicationof Radioisotopes Madhava B Mallia Radiopharmaceuticals Chemistry Section Radiochemistry and Isotope Group
- 2. Syllabus 1. Production ofradioisotopes 2. Application of radioisotopes in medicine (12 lectures)
- 3. Uses of Radioisotopes Radioisotopesare useful in, • Medicine • Agriculture • Industry • Hydrology etc..
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- 7. Tracer application inmedicine Gamma camera
- 8. Radioactivity Radioactivity is thespontaneous disintegration of a nucleus with emission of radiation(s)
- 9. • Alpha decay •Beta- decay • Beta+ decay and Electron capture decay 223 88Ra 219 86Rn + 4 2He 223 88Ra87Fr219 86Rn 131 53I 131 54Xe + β- 131 54Xe131 53I 18 9F 18 8O + β+ 125 53I 125 52Te + X-rays 18 9F18 8O 125 53Te125 52Te
- 10. Units of radioactivity •Activity – Activity of a radioactive sample is the number of disintegration happening per second in that sample • SI unit – Bq (Bequerels) • 1 Bq = 1 dps (disintegrations per second) • 1 Curie – 3.7 x 1010 dps (Bq) • I millicurie – 37 MBq
- 11. Half-life of aradioisotope Half-life (t1/2) – Time taken to reduce the activity of a radioactive sample to half the initial value Half-life is a constant for a given radioisotope Decay constant (λ) is the probability of disintegration of a radioactive atom λ = 0.693 / t1/2
- 12. Stability belt orstability island
- 13. What is theneed for the production of isotopes?
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- 15. Radioisotope production ina reactor Target + Projectile Radioisotope + Ejectile Neutron Gamma
- 16. Neutron induced reactions 1.(n, γ) reaction (Radiative neutron capture) Target + Neutron Radioisotope + gamma ray Other example: 59Co (n, ) 60Co Thermal neutron Low specific activity radioisotopes are formed Prompt gamma ray 98Mo (n, ) 99Mo
- 17. Specific activity ofthe radioisotope Specific activity = Activity/total weight of the isotope Mass can be expressed in the units of gram, milligram, microgram etc or mol, millimol, micromol etc…
- 18. Understanding specific activity Thermalneutron Natural molybdenum target composition Contributes towards activity Contributes towards weight of the isotope
- 19. Calculation of irradiationyield A = Nσφ (1 – e-λtirr) e-λtc A is the activity produced in Bq at the end of irradiation N is the total number of atoms is the abundance of target isotope σ is the reaction cross section (probability of reaction) in barn (1 barn = 10-24 cm2) Φ is the neutron flux (n/cm2/s) in the reactor λ is the decay constant of the radioisotope produced tirr is the time of irradiation of the target in the reactor tc is the cooling time ie. the time lapsed after end of irradiation till present
- 20. 2. (n, γ)followed by β- emission Target + Neutron Intermediate radioisotope + gamma Radioisotope of interest 130 Te (n, ) 131 Te - , 25 min 131 I 124 Xe (n, ) 125 Xe 125 I EC High specific activity radioisotopes are formed
- 21. 3. (n, γ)followed by charged particle emission Target + Neutron + Charged particles Radioisotope (n, p) reaction 32S (n, p) 32P 14N (n, p) 14C (n, ) reaction 27Al (n, ) 24Na High specific activity radioisotopes are formed
- 22. 4. Multi-stage neutroncapture or successive neutron capture 186 W (n, ) 187 W (n, ) 188 W - 69.4 days 188 Re Low specific activity radioisotopes are formed • Successive neutron capture reactions are rare • Usually carried out in high flux reactors using enriched targets
- 23. 5. Neutron capturefollowed by fission Important fission products: 137Cs, 90Sr, 85Kr, 147Pm, 99Mo, 89Sr, 131I etc Separation of radioisotopes is a tedious task High specific activity radioisotopes are formed
- 24. The szilard-Chalmers process:Chemical effect of nuclear reaction IH H H HH H H C2H5 127 I 127I 128I Compound nucleus 128I
- 25. 128I Bond elongation Bondbreakage Conditions for S-C process to be useful for radioisotope production • The radioactive atom should break away during the process • The breakaway atom should not combine back with the target molecule • There should not be any exchange between the recoiled radioactive atom and its isotopic atom in the target molecule • The target should be stable and should not decompose during irradiation • Enrichment factor should be high (The enrichment factor in this case is defined as the ratio of specific activity of recoiled chemical form to that of the target at the end of irradiation) High specific activity radioisotopes are formed
- 26. Why high specificactivity is important?
- 27. Antibody Low specificactivity radioisotope Low specific activity radiolabeled tracer
- 28. Some medically importantradioisotopes produced in a reactor
- 29. Molybdenum-99 as sodiummolybdate (Na2MoO4) • Natural MoO3 irradiated for 7 days • 98Mo enrichment ~24% • Cross section ‘’ of 98Mo for (n, γ) reaction – 130 milli barn • Irradiated MoO3 dissolved in 4N NaOH to obtain Na2MoO4 • After quality control, Na2MoO4 is dispatched to various nuclear medicine centers
- 30. Iodine-131 as sodiumiodide (NaI) • Natural TeO2 irradiated for ~ 30 days • 130Te enrichment is ~34% • Cross section ‘’ of 130Te for (n, γ) reaction – 290 milli barn • Irradiated 130Te is heated at 740C for 3 h in a stream of argon • 131I evolved is trapped in alkaline sodium sulphite (Na2SO3) to obtain NaI • After quality control, 131I in the form of NaI is dispatched to various nuclear medicine centers
- 31. Samarium-153 as samariumchloride (SmCl3) • Enriched Sm2O3 irradiated for 7 days • 152Sm enrichment is ~98% • Cross section ‘’ of 152Sm for (n, γ) reaction – 260 milli barn • Irradiated Sm2O3 dissolved in 0.1N HCl to obtain 153Sm as SmCl3 • After quality control, SmCl3 is dispatched to various nuclear medicine centers
- 32. Lutetium-177 as Lutetiumchloride (LuCl3) • Enriched Lu2O3 irradiated for 21 days • 176Lu enrichment is ~82% • Cross section ‘’ of 176Lu for (n, γ) reaction – 2020 milli barn • Irradiated Lu2O3 dissolved in dilute HCl to obtain 177Lu as LuCl3 • After quality control, LuCl3 is dispatched to various nuclear medicine centers
- 33. Production of isotopein cyclotron A = 6.242 x 1018 N I z-1 (1-e-tirr)e-tc A is the activity produced in Bq at the end of irradiation N is the total number of atoms/cm2 is the abundance of target isotope σ is the reaction cross section (probability of reaction) in barn (1 barn = 10-24 cm2) I is the beam current in ampere z is the charge on the projectile λ is the decay constant of the radioisotope produced tirr is the time of irradiation of the target in the reactor tc is the cooling time ie. the time lapsed after end of irradiation till present
- 34. Radioactive equilibrium Radioactive equilibriumis a condition where the ratio of activity of long lived parent isotope and short-lived daughter isotope remain constant
- 35. Net rate offormation of N2, dN2 / dt = 1N1 - 2N2 A B C 1 2 N1 N2 Rate of formation of N2 = 1N1 Rate of decay of N2 = 2N2 A1 0 2 2 1- e- t 1 e- t 2-A2 = If B is present initially, A1 0 2 2 1- e- t 1 e- t 2-A2 = + A2 0 e- t 2
- 36. Transient equilibrium λd /λp ~ 10 Secular equilibrium λd / λp ~ 100 A1 0 2 2 1- e- t 1 e- t 2-A2 =
- 37. Bateman equation A BC D E F λ1 λ2 λ3 λ4 λ5 Nm = C1e- 1 t + C2e- 2 t + …………………+ Cme- m t Where, m-1 (((m N1 0C1 = m-1 (((m N1 0C2 =
- 38. A B CD E F λ1 λ2 λ3 λ4 λ5 2 43 61 5 m = 2 m-1 (((m N1 0C1 = m-1 (((m N1 0C2 = Nm = C1e- 1 t + C2e- 2 t + …+ Cme- m t
- 39. A B CD E F G H λ1 λ2 λ3 λ4 λ5 λ6 λ7 Nm = C1e- 1 t + C2e- 2 t + …………………+ Cme- m t m-1 ( (( m N1 0C1 = m-1 N1 0C2 = ( (( m λ* is partial decay constant leading to m th member Λis the total decay constant of 1 to m th member
- 40. λ1 λ2 λ2’ λ3 12 3 m = 3 Nm = C1e- 1 t + C2e- 2 t + C3e- 3 t m-1 ( (( m N1 0C1 = m-1 N1 0C2 = ( (( m λ1 * = λ1 λ2 * = λ2 Λ1 = λ1 Λ2 = λ2 + λ2’
- 41. Radionuclide generator A radionuclidegenerator is a system where a long lived parent and short lived daughter is in a state of radioactive equilibrium and the daughter radionuclide can be separated from that of the parent in a radionuclidically as well as radiochemically pure form by using simple separation procedure
- 42. Desirable characteristics ofa radionuclide generator High separation efficiency of the daughter radionuclide from the parent High selectivity of separation and hence high radionuclidic purity High radiochemical purity Simple and rapid operation Adequate radiological safety to the operator
- 43. Radiochemical purity (RCP) Definition: Percentageof activity in the sample due to desirable chemical form Example: Possible species in 99mTc eluate: 99mTcO2 ----- reduced technetium 99mTcO4 - ----- pertechnetate
- 44. Radionuclidic purity (RNP) Definition: Percentageof activity in the sample due to desirable radionuclide Example: Possible radionuclide in 99mTc eluate: 99mTc, 99Tc, 99Mo
- 45. Examples: 99Mo-99mTc generator –Transient equilibrium 68Ge-68Ga generator – Secular equilibrium 188W-188Re generator – Secular equilibrium 90Sr-90Y generator – Secular equilibrium
- 46. Alumina column generator Solventextraction generator Sublimation generator
- 47. Alumina column generator Normalalumina H+ Acidic alumina
- 48. Acidic alumina 99MoO4 - Acidic alumina loadedwith 99MoO4 -
- 49. MoO4 2- Mo7O24 6- Mo3O28 4- higher polymer MoO3. H2O MoO3.H2O pH 4 -5pH > 7 pH 2 -3 pH <1 Capacity of acidic alumina – 20 mg of Mo / gram of alumina
- 50. Construction of acolumn generator 1. Determination of maximum activity that can be loaded 2. pH adjustment of 99Mo solution 3. Washing alumina column with HCl solution of pH 4 4. Loading of activity 5. Washing the column with 100 mL saline
- 51. Advantages: 1. Very simpleoperation and handling – ideal for hospital radiopharmacy 2. High radioactive concentration of the daughter. 3. High radionuclidic, radiochemical and chemical purity of the daughter 4. Ensures radiological safety of the user. Disadvatages: This generator requires high specific activity (preferably fission produced) 99Mo, if at all we want to get high activity of technetium. In other words, the loading capacity of (n, ) molybdenum on alumina is very low due to the limited capacity of alumina to hold molybdenum.
- 52. Solvent extraction generator •Based on selective extraction of 99mTcO4 - by methyl ethyl ketone 99MoO4 - solution at pH >10 MEK layer containing 99mTcO4- • Remove MEK layer containing 99mTcO4- • Pass it through basic alumina to remove traces of 99MoO4 - • Remove MEK by gentle warming • Reconstitute in physiological saline
- 53. Advantages: 1. Reactor producedmolybdenum with moderate specific activity can be utilized. 2. 99mTc can be obtained in high radioactive concentration. 3. High radionuclidic and radiochemical purity. Disadvantages: 1. Operation is complicated as well as time consuming compared to column generator. Also trained personnel required for the generator operation. 2. Possibility of chemical contamination from polymeric organic species. 3. Possible fire hazard from the use of flammable organic solvent. 4. Not very convenient from radiological safety point of view.
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- 56. Applications of radiationin Nuclear Medicine
- 57. Nuclear medicine Medical specialtywhich uses radiopharmaceuticals for diagnosis or therapy of various diseases Diagnosis – detection of disease Therapy – Treatment of disease Radiopharmaceutical Molecule tagged with a radioisotope used for diagnosis or therapy
- 58. Radioisotope Applications Diagnostic In vivoIn vitro Analysis of hormones, proteins, enzymes etc in blood Radiopharmaceuticals Brachy therapy Therapeutic •Simple radiochemicals •Radiopharmaceuticals with non-metallic radioisotope (covalent compounds) •Radiopharmaceuticals with metallic radioisotope (coordination compounds or complexes) •Radioactive particulate preparations (colloids)
- 59. Simple radiochemicals • 131Ias NaI – Active form 131I- - uptake in Thyroid • 32P as Na32PO4 - uptake in bone • 89SrCl2 – Active form 89Sr2+ - uptake in bone (mimics Ca2+) • 201TlCl – Active form 201Tl+ - uptake in heart (mimics Ca2+)
- 60. Radiopharmaceuticals with non-metallic radioisotope(covalent compounds)
- 61. Radiopharmaceuticals with metallic radioisotope(coordination compounds)
- 62. Diagnostic radiopharmaceuticals Diagnostic radiopharmaceuticalsare used for detecting presence or absence of a disease/abnormality in the body, imaging the morphology of various organs in the body or evaluating the function of various organs in the body. Information is obtained through scan of the body using gamma camera
- 63. Oral administration of radiopharmaceutical Intravenous administration of radiopharmaceutical Typical gamma camera Typical procedure for scanning
- 64. SPECT Vs PET SPECTPET Single photon emitting radioisotope Positron emitting radioisotope Low resolution images High resolution images Longer time duration per scan Shorter time duration per scan Widely available Limited availability Economical Costly
- 65. Characteristics of adiagnostic radioisotope • Radionuclide decay mode and decay energy – pure gamma emitter – Energy between 100 – 200 keV • Half-life – Long enough to allow radiopharmaceutical preparation, quality control and imaging • Availability and cost – Should be easily available – Should be economical • Simple chemistry – Should allow simple chemistry for radiopharmaceutical preparation Above considerations are also applicable for a diagnostic radiopharmaceutical
- 66. Physical, Biological andEffective half-life Physical half-life: Time required to reduce the activity to half the initial value Biological half-life: Time required to reduce the activity in the body by half-the initial value Effective half-life: 1/(teffective) = 1/(tphysical) + 1/(tbiological) Effective half-life should be atleast 1.5 times the test duration
- 67. Target to backgroundratio It is the ratio of counts from target to counts from background Target Background
- 68. SPECT RADIOISOTOPES Radionuclide t1/2(h) Decay mode Main E (keV) (%) Production route 111In 67.9 EC (100%) 245, 172 111Cd(p,n)111In 99mTc 6.1 IT (100%) 141 99Mo/99mTc generator 201Tl 72.0 EC (100%), Hg X-rays 135, 167 203Tl(p,3n)201Pb(p,n)201Tl 123I 13.2 EC 159 (83%) 124Xe(p,2n)123Cs123Xe123I 124Te(p,2n) 123I 131I 8.0 d β 364 (81%), 637 (7%) 130Te(n,)131Te131I 235U(n,f)131I
- 69. SOME IMPORTANT PETRADIOISOTOPES Radionuclide t1/2 (min) Production route 11C 20.3 14N (p,) 13N 9.9 16O (p,) 15O 2.0 14N (d,n) 15N (p,n) 16O (p,pn) 18F 109.8 18O (p,n) 20Ne (d,) 64Cu 12.7 h 64Ni (p,n) 68Ga 68.3 68Ge/68Ga generator
- 70. Therapeutic radiopharmaceuticals Therapeutic radiopharmaceuticalsare drugs tagged with a therapeutic radioisotope used to deliver therapeutic dose of radiation to the target site Therapeutic radioisotopes can be: alpha emitters Beta emitters Auger electron emitters Particulate emitters are high LET radiations
- 71. Therapy or cellkilling Particulate radiations can damage cell direct effect or indirect effect
- 72. Choice of therapeuticradioisotope Radionuclide t1/2 (d) max Eβ (MeV) Main E (MeV) (%) Production route 117mSn 13.6 0.13 0.158 (87%) 116Sn (n,) 117mSn 117Sn (n,n’) 117mSn 177Lu 6.7 0.50 0.113 (6.4%), 0.208 (11%) 176Lu (n,) 177Lu 153Sm 1.9 0.80 0.103 (29%) 152Sm (n,) 153Sm 131I 8.0 0.81 0.364 (81%) 130Te (n,) 131Te131I 235U (n,f) 131I 186Re 3.8 1.07 0.137 (9%) 185Re (n,) 186Re 89Sr 50.5 1.46 88Sr (n,) 89Sr 89Y (n,p) 89Sr 166Ho 1.1 1.60 0.810 (6.3%) 165Ho (n,) 166Ho 32P 14.3 1.71 31 P (n,) 32P 32 S (n,p) 32 P 188Re 0.7 2.11 0.155 (15%) 187Re (n,) 188Re 90Y 2.7 2.27 89Y (n,) 90Y 235U (n,f) 90Sr 90Y
- 73. Tumor/organ size Range ofparticulate radiation Energy of particulate radiation Radioisotope Cross-fire effect
- 74. Diagnostic Vs Therapeutic radiopharmaceuticals DiagnosticRadiopharmaceuticals Therapeutic Radiopharmaceuticals Used for diagnosis Used for therapy Pure gamma emitting radioisotopes preferred Particulate emitting radioisotopes with or without associated gamma emissions Relatively short half-life Relatively long half-life Low LET radiations High LET radiations Does not kill cells Kills cells
- 75. Radiopharmaceutical design Target specific (Biologicallyactive molecule like antibody, peptide or small molecule which can specifically target an organ or tissue) Metal essential (Molecule itself do not have any targeting action, but upon forming a complex with radiometal show targeting action)
- 76. Target specific radiopharmaceuticaldesign (a) Absence of suitable functional groups for radiolabeling (b) Radiochemistry is difficult resulting in very low radiolabeling yield (c) loss of biological/targeting activity on radiolabeling
- 77. Bifunctional chelating agent Chelator– its function is to hold the radioisotope through coordinate bond Linker – its function is to keep the chelator sufficiently away from the biomolecule such that biological activity of the molecule is not lost due to steric hindrance Functional group – the biomolecule is attached to the BFCA through functional group. Chelator ChelatorFunctional group Functional group
- 78. p-NCS-bezyl-DOTA p-NCS-bezyl-NOTA p-NH2-bezyl-DOTA DOTA -1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraaceticacid NOTA -1,4,7-triazacyclononane-1,4,7-triacetic acid
- 79. Radiolabeling techniques Isotopic labelingNon-isotopic labeling Radiolabeling is the process of tagging a radioisotope to a molecule Metal labeling Non-metal labeling Lanthanide labeling Transition metal labeling
- 80. Isotopic labeling Low specificactivity radiopharmaceutical
- 81. Non-isotopic labeling withnon-metal High specific activity radiopharmaceutical Iodogen or chloramin-T Na131I
- 82. Non-isotopic labeling withtransition metal Medically important transition and post-transition metals: 99mTc, 188Re, 68Ga, 111In DOTA-peptide 68Ga-DOTA-peptide 68Ga-NOTA-peptideNOTA-peptide DTPA also can be used for 68Ga, 111In (Macrocyclic complexes have higher stability)
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- 84. Hynic (Hydrazino nicotinicacid): A bifunctional chelator for 99mTc HYNIC-TOC Do not disturb!! NHS-ester of Hydrazino nicotinic acid (HYNIC) TOC
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- 86. Non-isotopic labeling withlanthanides
- 87. Radiolabeling antibodies/proteins: Pre-labeling approach 177LuCl3 Post-labelingapproach Pre-labeling approach 177LuCl3 177Lu-p-NH2-benzyl-DOTA complex Antibody/protein 177Lu-p-NH2-benzyl-DOTA- antibody/protein complex
- 88. Quality control (QC)of radiopharmaceuticals QC of radiopharmaceuticals can be divided into three categories • Physical tests Appearance, pH, radioactivity content, radionuclide identification and radionuclidic purity (RNP) • Radiochemical purity (RCP) and chemical purity • Biological control tests such as Bacterial endotoxin test (BET) and Sterility test (ST).