A presentation on various routes of radioisotope production, basic calculations involved and applications of radioisotopes

1. Production and Application of
Radioisotopes
Madhava B Mallia
Radiopharmaceuticals Chemistry Section
Radiochemistry and Isotope Group

2. Syllabus
1. Production of radioisotopes
2. Application of radioisotopes in medicine
(12 lectures)

3. Uses of Radioisotopes
Radioisotopes are useful in,
• Medicine
• Agriculture
• Industry
• Hydrology etc..

4. Tracer

6. Gamma ray detector

7. Tracer application in medicine
Gamma camera

8. Radioactivity
Radioactivity is the spontaneous 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 a radioisotope
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 or stability island

13. What is the need for the production of
isotopes?

14. Nuclear reactor Cyclotron

15. Radioisotope production in a
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 of the 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
Thermal neutron
Natural molybdenum target composition
Contributes towards
activity
Contributes towards
weight of the isotope

19. Calculation of irradiation yield
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 neutron capture 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 capture followed 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 Bond breakage
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 specific activity is important?

27. Antibody Low specific activity
radioisotope
Low specific activity
radiolabeled tracer

28. Some medically important radioisotopes
produced in a reactor

29. Molybdenum-99 as sodium molybdate
(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 sodium iodide (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 740C 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 samarium chloride
(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 Lutetium chloride (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 isotope in 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 equilibrium is a condition where the ratio of activity
of long lived parent isotope and short-lived daughter isotope
remain constant

35. Net rate of formation 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 B C 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 C D 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 C D
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
1 2 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 radionuclide generator 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 of a 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:
Percentage of 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:
Percentage of 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
Solvent extraction generator
Sublimation generator

47. Alumina column generator
Normal alumina
H+
Acidic alumina

48. Acidic alumina
99MoO4
-
Acidic alumina
loaded with 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 a column 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 simple operation 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 produced molybdenum 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.

54. Sublimation generator

55. Electrochemical generator
(concept only)
Parent/daughter
equilibrium solution

56. Applications of radiation in
Nuclear Medicine

57. Nuclear medicine
Medical specialty which 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 vivo In 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
• 131I as 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 radiopharmaceuticals are 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
Intra venous administration
of radiopharmaceutical
Typical gamma camera
Typical procedure for scanning

64. SPECT Vs PET
SPECT PET
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 a diagnostic 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 and Effective 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 background ratio
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)123Cs123Xe123I
124Te(p,2n) 123I
131I 8.0 d β 364 (81%), 637 (7%) 130Te(n,)131Te131I
235U(n,f)131I

69. SOME IMPORTANT PET RADIOISOTOPES
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 radiopharmaceuticals are 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 cell killing
Particulate radiations can damage cell direct
effect or indirect effect

72. Choice of therapeutic radioisotope
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,) 131Te131I
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 of particulate radiation
Energy of particulate radiation
Radioisotope
Cross-fire effect

74. Diagnostic Vs Therapeutic
radiopharmaceuticals
Diagnostic Radiopharmaceuticals 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
(Biologically active 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 radiopharmaceutical design
(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-
tetraacetic acid
NOTA -1,4,7-triazacyclononane-1,4,7-triacetic
acid

79. Radiolabeling techniques
Isotopic labeling Non-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 specific activity radiopharmaceutical

81. Non-isotopic labeling with non-metal
High specific activity radiopharmaceutical
Iodogen or chloramin-T
Na131I

82. Non-isotopic labeling with transition 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)

83. 99mTc-Tetrofosmin
ECD + 99mTcO4
-

84. Hynic (Hydrazino nicotinic acid): A
bifunctional chelator for 99mTc
HYNIC-TOC
Do not disturb!!
NHS-ester of Hydrazino nicotinic
acid (HYNIC)
TOC

85. 99mTc-HYNIC-TOCHYNIC-TOC
Na99mTcO4, EDDA, Tricine
SnCl2.2H2O
100oC, 20 min

86. Non-isotopic labeling with lanthanides

87. Radiolabeling antibodies/proteins:
Pre-labeling approach
177LuCl3
Post-labeling approach
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).