1. RADIOACTIVITY & RADIONUCLIDE PRODUCTION
Dr. Mohammed Alnafea

2. History of Radiopharmacy
Medicinal applications since the discovery of Radioactivity Early 1900’s
Limited understanding of Radioactivity and dose

3. 1912 — George de Hevesy Father of the “radiotracer” experiment.
Used a lead (Pb) radioisotope to prove the recycling of meat by his landlady.
Received the Nobel Prize in chemistry in 1943 for his concept of “radiotracers”

4. Early use of radiotracers in medicine
1926: Hermann Blumgart, MD injected 1-6 mCi of “Radium C” to monitor blood flow (1st clinical use of a radiotracer)
1937: John Lawrence, MD used phosphorus-32 (P- 32) to treat leukemia (1st use of artificial radioactivity to treat patients)
1937: Technetium discovered by E. Segre and C. Perrier

5. Early Uses continued
1939: Joe Hamilton, MD used radioiodine (I-131) for diagnosis
1939: Charles Pecher, MD used strontium-89 (Sr-89) for treatment of bone metastases.
1946: Samuel Seidlin, MD used I-131 to completely cure all metastases associated with thyroid cancer. This was the first and remains the only true “magic bullet”.
1960: Powell Richards developed the Mo-99/Tc-99m generator
1963: Paul Harper, MD injected Tc-99m pertechnetate for human brain tumor imaging

6. Part 1: Characteristics of a Radiopharmaceutical
What is a radiopharmaceutical?
A radioactive compound used for the diagnosis and therapeutic treatment of human diseases.
Radionuclide + Pharmaceutical

7. Radioactive Materials
N → ↑ Z
Chart of the Nuclides
Unstable nuclides
Combination of neutron and protons
Emits particles and energy to become a more stable isotope

8. Radiation decay emissions
Alpha (a or 4He2+)
Beta (b- or e-)
Positron (b+)
Gamma (g)
Neutrons (n)

9. Radioactivity
In 1896 Henri Becquerel -> find that the photographic plate had been darkened in the part nearest to uranium compounds. He called this phenomenon radioactivity.
Radioactivity (radioactive decay) is the spontaneous break up (decay) of atoms.
Marie Curie (student of Becquerel) examined the radioactivity of uranium
compound and she discovered that:
1. All uranium compounds are radioactive
2. Impure uranium sulphide contains two other elements which are more radioactive
than uranium.
3. Marie named these elements radium & polonium.
4. Radium is about two million times more radioactive than uranium.

10. Alpha, Beta & gamma radiation
When the radioactive atoms break up, they release energy and lose three kinds of radiation (Alpha, Beta & gamma radiation).
Alpha & Beta are particles where as gamma-rays are electromagnetic wave with the greatest penetrating power.
These radiation

11. Interactions of Emissions
Alpha (a or 4He)
High energy over short linear range
Charged 2+
Beta (b- or e-)
Various energy, random motion
negative
Gamma (g)
No mass, hv
Positron (b+)
Energy >1022 MeV, random motion
Anihilation ( KeV ~180°)
Neutrons (n)
No charge, light elements

12. Physical Half Life and Activity
Radioactive decay is a statistical phenomenon
t1/2
l= decay constant
Activity is the amount of radioactive material
Half-life is time needed to decrease nuclides by 50%
decay constant is the Number of atoms decaying per unit time is proportional to the number of unstable
atoms

13. Measured Activity
In practicality, activity (A) is used instead of the number of atoms (N).
A= ct, m
where c is the detection coefficient
A=AOe-t
Units
Curie (Ci),
3.7E10 decay/s
1 g Ra
Becquerel (Bq)
1 decay/s
The quantity of radioactive material, expressed as the number of radioactive atoms undergoing nuclear transformation per unit time, is called activity (A)
Traditionally expressed in units of curies (Ci), where 1 Ci = 3.70 x 1010 disintegrations per second (dps)
The SI unit is the becquerel (Bq)
1 mCi = 37 MBq

14. Half Life and decay constant
Half-life is time needed to decrease nuclides by 50%
Relationship between t1/2 and l
N/No=1/2=e-t
ln(1/2)=-t1/2
ln 2= t1/2
t1/2=(ln 2)/
NB: Physical half-life and decay constant are inversely related and unique for each radionuclide

15. Why use radioactive materials ?
Radiotracers
High sensitivity
Radioactive emission (no interferences)
Nuclear decay process
Independent reaction
No external effect (chemical or biochemical)
Active Agent
Monitor ongoing processes

16. Applications in Nuclear Medicine
Imaging
Gamma or positron emitting isotopes
99mTc, 111In, 18F, 11C, 64Cu
Visualization of a biological process
Cancer, myocardial perfusion agents
Therapy
Particle emitters
Alpha, beta, conversion/auger electrons
188Re, 166Ho, 89Sr, 90Y, 212Bi, 225Ac, 131I
Treatment of disease
Cancer, restenosis, hyperthyroidism

17. Ideal Characteristics of a Radiopharmaceutical
Nuclear Properties
Wide Availability
Effective Half life (Radio and biological)
High target to non target ratio
Simple preparation
Biological stability
Cost

18. Ideal Nuclear Properties for Imagining Agents
Reasonable energy emissions.
Radiation must be able to penetrate several layers of tissue.
No particle emission (Gamma only)
Isomeric transition, positron (b+), electron capture
High abundance or “Yield”
Effective half life
Cost

19. Detection Energy Requirements
Best images between KeV
Limitations
Detectors (NaI)
Personnel (shielding)
Patient dose
What else happens at higher energies?
Lower photoelectric peak abundance, due to the Compton effect
Cs-137 decay (662 KeV)
Energy →

20. Gamma Isotopes Radionuclide T1/2 g (%) Tc-99m 6.02 hr 140 KeV (89)
Tl hr 167 KeV (9.4)
In d 171(90), 245(94)
Ga hr 93 (40), 184 (20), (17)
I hr 159(83)
I d 284(6), 364(81), (7)
Xe d 81(37)

21. Radioactive Decay Kinetics

22. Basic decay equations Probability of decay: p=Dt
The radioactive process is a subatomic change within the atom
The probability of disintegration of a particular atom of a radioactive element in a specific time interval is independent of its past history and present circumstances
The probability of disintegration depends only on the length of the time interval.
Probability of decay: p=Dt
Probability of not decaying: 1-p=1- Dt

23. Summary: The Radioactive Decay Law
The radioactive decay law in equation form;
Radioactivity is the number of radioactive decays per unit time;
The decay constant is defined as the fraction of the initial number of radioactive nuclei which decay in unit time;
Half Life: The time taken for the number of radioactive nuclei in the sample to reduce by a factor of two;
Half Life = (0.693)/(Decay Constant);
The SI Unit of radioactivity is the becquerel (Bq)
1 Bq = one radioactive decay per second;
The traditional unit of radioactivity is the curie (Ci);
1 Ci = 3.7 x 1010 radioactive decays per second

24. ATOMIC STRUCTURE number of protons in nucleus
Atomic number (Z):
number of protons in nucleus
Mass number (A):
Number of protons + neutrons
Neutron number (N):
Nuclear forces:
"Strong" attractive force
electrostatic repulsive force  
Radioactive decay caused by nuclear instability
Due to p-p electrostatic repulsion

25. RADIONUCLIDE DECAY MODES
Number of protons (Z)
Number of neutrons (A-Z)
Stable nuclei
Unstable – radioactive : half-life < 1ms
Unstable – radioactive : half-life > 1000 years
No stable nuclei when Z > 83 or N > 126

26. Nuclear Transformation
When the atomic nucleus undergoes spontaneous transformation, called radioactive decay, radiation is emitted
If the daughter nucleus is stable, this spontaneous transformation ends
If the daughter is unstable, the process continues until a stable nuclide is reached
Most radionuclides decay in one or more of the following ways: (a) alpha decay, (b) beta-minus emission, (c) beta-plus (positron) emission, (d) electron capture, or (e) isomeric transition.

27. No stable nuclei when Z > 83 or N > 126
RADIONUCLIDE DECAY MODES
No stable nuclei when Z > 83 or N > 126

28. Alpha Decay
Alpha () decay is the spontaneous emission of an alpha particle (identical to a helium nucleus) from the nucleus.
Typically occurs with heavy nuclides (A > 150) and is often followed by gamma and characteristic x-ray emission

29. RADIONUCLIDE DECAY MODES
Nuclei with  Z > 83

30. Beta-Minus (Negatron) Decay
Beta-minus (-) decay characteristically occurs with radionuclides that have an excess number of neutrons compared with the number of protons (i.e., high N/Z ratio)
Any excess energy in the nucleus after beta decay is emitted as gamma rays, internal conversion electrons or other associated radiations

32. RADIONUCLIDE DECAY MODES
Occurs in nuclei with high neutron:proton ratio

33. Beta-Plus Decay (Positron Emission)
Beta-plus (+) decay characteristically occurs with radionuclides that are “neutron poor” (i.e., low N/Z ratio)
Eventual fate of positron is to annihilate with its antiparticle (an electron), yielding two 511-keV photons emitted in opposite directions

35. RADIONUCLIDE DECAY MODES
Occurs in nuclei with a low neutron:proton ratio

36. Electron Capture Decay
Alternative to positron decay for neutron-deficient radionuclides.
Nucleus captures an orbital (usually K- or L-shell) electron
Electron capture radionuclides used in medical imaging decay to atoms in excited states that subsequently emit detectable gamma rays

37. RADIONUCLIDE DECAY MODES
Electron capture
Occurs in nuclei with a low neutron:proton ratio

38. RADIONUCLIDE DECAY MODES
 emission
Generally accompanies other radioactive decay
associated with energy loss from changes in nuclear energy states

39. RADIONUCLIDE DECAY MODES
Spontaneous fission
Used by high Z nuclei
2 nuclei of approximately equal mass produced
Accompanied by release of energy and neutrons

40. Summary: Radioactive Decay
Fission: Some heavy nuclei decay by splitting into 2 or 3 fragments plus some neutrons. These fragments form new nuclei which are usually radioactive;
Alpha Decay: Two protons and two neutrons leave the nucleus together in an assembly known as an alpha-particle;
An alpha-particle is a He-4 nucleus;
Beta Decay - Electron Emission: Certain nuclei with an excess of neutrons may reach stability by converting a neutron into a proton with the emission of a beta-minus particle;
A beta-minus particle is an electron;

41. Summary: Radioactive Decay
Beta Decay - Positron Emission: When the number of protons in a nucleus is in excess, the nucleus may reach stability by converting a proton into a neutron with the emission of a beta- plus particle;
A beta-plus particle is a positron;
Positrons annihilate with electrons to produce two back-to-back gamma-rays;
Beta Decay - Electron Capture: An inner orbital electron is attracted into the nucleus where it combines with a proton to form a neutron;

42. Summary: Radioactive Decay
Electron capture is also known as K-capture;
Following electron capture, the excited nucleus may give off some gamma-rays. In addition, as the vacant electron site is filled, an X-ray is emitted;
Gamma Decay - Isomeric Transition: A nucleus in an excited state may reach its ground state by the emission of a gamma-ray;
A gamma-ray is an electromagnetic photon of high energy;
Gamma Decay - Internal Conversion: the excitation energy of an excited nucleus is given to an atomic electron.

43. Q1:Half-life calculation
Using Nt=Noe-lt
For an isotope the initial count rate was 890 Bq. After 180 minutes the count rate was found to be 750 Bq.What is the half-life of the isotope?

44. Q2: Half-life calculation
A=lN
A g sample of 248Cm has a alpha activity of mCi.What is the half-life of 248Cm?

45. Isomeric Transition
During radioactive decay, a daughter may be formed in an excited state.
Gamma rays are emitted as the daughter nucleus transitions from the excited state to a lower-energy state.
Some excited states may have a half-lives ranging up to more than 600 years

46. Decay Schemes
Each radionuclide’s decay process is a unique characteristic of that radionuclide.
Majority of pertinent information about the decay process and its associated radiation can be summarized in a line diagram called a decay scheme.
Decay schemes identify the parent, daughter, mode of decay, intermediate excited states, energy levels, radiation emissions, and sometimes physical half-life.

47. Generalized Decay Scheme

53. Radionuclide Production
All radionuclides commonly administered to patients in nuclear medicine are artificially produced.
Most are produced by cyclotrons, nuclear reactors, or radionuclide generators

54. Cyclotrons
Cyclotrons produce radionuclides by bombarding stable nuclei with high-energy charged particles.
Most cyclotron-produced radionuclides are neutron poor and therefore decay by positron emission or electron capture.
Specialized hospital-based cyclotrons have been developed to produce positron-emitting radionuclides for positron emission tomography (PET)
Usually located near the PET imager because of short half-lives of the radionuclides produced

58. Nuclear Reactors
Specialized nuclear reactors used to produce clinically useful radionuclides from fission products or neutron activation of stable target material.
Uranium-235 fission products can be chemically separated from other fission products with essentially no stable isotopes (carrier) of the radionuclide present.
Concentration of these “carrier-free” fission-produced radionuclides is very high

60. NUCLEAR REACTOR Schematic Representation

61. RADIONUCLIDE PRODUCTION Thermal neutron induced fission
235U is most commonly used fissionable material
235U + n  unstable nucleus  fission fragments + n + E
average number of neutrons per fission = 2.4
self-irradiation of 235U - self sustaining chain reaction
moderators included to slow neutrons to thermal energies - deuterium oxide, graphite

62. RADIONUCLIDE PRODUCTION Thermal neutron induced fission
235U fission  > 370 nuclides
observed mass range :
distribution as indicated

63. RADIONUCLIDE PRODUCTION Thermal neutron induced fission
radionuclides extracted when fuel elements replaced
chemical separation techniques used
precipitation, solvent extraction, chromatography
products usually carrier free, high specific activity
fission produced radionuclides usually neutron rich
decay by - emission
relatively cheap - not major function of reactor

64. RADIONUCLIDE PRODUCTION Reactor Targetry
irradiation positions
mobile : short irradiation times (minutes - 1 week)
fixed : long irradiation times (one or more reactor fuel cycles : weeks)
accessible only during reactor shutdown
both positions water cooled
reactor temperature  100°C, sample temperature > 1000°C ( heating)
target design
pure element often best choice – high melting point and density
prevention of target rupture primary safety consideration
use of mercury and cadmium prohibited
reactivity of mercury with aluminium (fuel cans)
high neutron absorption of cadmium (reactor operation)

65. RADIONUCLIDE PRODUCTION Neutron bombardment
Activity of a radionuclide produced by particle bombardment is given by
A = N (1 - e-t)
where: A = activity
 = particle flux (number/cm2/s)
N = number of target atoms
 = absorption cross section in barns (10-24 cm2/atom)
 = decay constant of product radionuclide
t = duration of irradiation (in seconds)
when t > 4 x T½ , (1 - e-t) approaches 1
saturation activity : A = N
no gain from irradiating beyond x T½

66. RADIONUCLIDE PRODUCTION Preparation of I-131 (carrier)
Starting material : 2.5g 93+% 235U
flux: 2 x 1014n/cm2/sec, 28d
target stored for 7d following irradiation
dissolved in 4.5M NaOH + heating
133Xe released - trapped (charcoal, liquid N2)
Al2O3.2H2O + NaI
+ H2SO4 + H2O2 - distilled
 7500 GBq 131I (+ 127I + 124I) i.e. carrier iodine
235U recovered for reuse

67. RADIONUCLIDE PRODUCTION Preparation of I-131 (carrier free)
target : 2.5g 99+% 130Te
Neutron flux: 2 x 1014n/cm2/sec, 21d
130Te (n,) 131Te  131I
 65 GBq 131I obtained by distillation, as before
130Te recovered for reuse

68. RADIONUCLIDE PRODUCTION Preparation of Mo-99 (non-fission + fission)
target : natural MoO % 98Mo
flux: 2 x 1014n/cm2/sec, 7d
98Mo (n,) 99Mo
 37 GBq 99Mo from 1g MoO3
natural MoO3  185W (T½ = 74d) - absent when enriched 98Mo used
Starting material : 2.5g 93+% 235U
99Mo extracted from acidified solution of fission products
produced in 1000 GBq quantities
high specific activity for generators
may contain some 131I and 103Ru

69. REACTOR PRODUCED RADIONUCLIDES
PRODUCT
DECAY MODE
PRODUCTION REACTION
14C β-
14N(n,p)14C
32P
31P(n,γ)32P
51Cr
EC, γ
50Cr(n,γ)51Cr
59Fe
β-, γ
58Fe(n,γ)59Fe
125I
124Xe(n,γ)125Xe EC I
131I
130Te(n,γ)131Te β I

70. RADIONUCLIDE PRODUCTION Radionuclide Generators
allows distribution of short lived nuclides to centres remote from production site
long(er) lived parent nuclide decays to daughter nuclide
allows separation of daughter from parent
separation achieved by difference in chemical properties e.g. charge - ion exchange chromatography

71. RADIONUCLIDE GENERATORS Cross-section of a typical radionuclide generator

72. RADIONUCLIDE GENERATORS Radioactive Decay Laws
common simplifications
T½ parent  10 x T½ daughter
transient equilibrium
e.g. 99Mo / 99Tcm generator h h

73. RADIONUCLIDE GENERATORS Radioactive Decay Laws
common simplifications
T½ parent >> T½ daughter
(p >> d)
secular equilibrium
e.g. 68Ge / 68Ga generator d m

74. RADIONUCLIDE GENERATORS Desirable Properties
ease of operation
daughter should have high chemical and radionuclidic purity
daughter should be a different chemical element to parent
should remain sterile and pyrogen free
daughter should be in a form suitable for preparation of radiopharmaceuticals

75. Technetium Generator Elution
WARNING - PLEASE NOTE:
If using a laptop and projector to display this presentation, the movie MAY not project correctly. It will, however, run OK on the laptop. This problem may be overcome, somewhat inelegantly, by temporarily disabling the display on the laptop display. If this is done (using the keystroke combination applicable for your particular laptop) the movie will then project OK. Simply toggle through the keystroke to display the presentation on both the laptop display and the projector when moving onto the next slide.
The movie is not quite shown in real time. There is about a 1 minute segment removed from the middle of the movie, when the saline is filling the elution vial – rather boring to watch once you’ve grasped what is happening. The entire elution process takes about 3 or 4 minutes in reality. This would normally be done behind thick lead shielding, often in a sterile glove box. However, for the sake of clarity, this elution of an expired generator has been done on a laboratory bench.

76. RADIONUCLIDE GENERATORS Yield Problems
yield is always < 100%
caused by reduced access of eluant to support bed due to -
poor quality ion exchange material
channelling in column during transportation
improper initial packing of column
terminal sterilisation procedures
pseudochannelling - dry vs. wet generators

77. Commonly Used Radionuclides Characteristics
Production Method
Decay Mode
 Emissions (keV)
Half-life
IMAGING
18F
Cyclotron
Positron
511
108 min
67Ga EC
92, 182, 300, 390
78 hr
81Krm
Generator IT
191
13 s
99Tcm
140
6 hr
111In
173, 247
67 hr
123I
160
13 hr
131I
Reactor
Beta
280, 360, 640
8 d
201Tl
68-80
73.5 hr
THERAPY
90Y -
64 hr
186Re
137
90 hr
In Vitro
14C
5760 yr
51Cr
323
27.8 d
125I
27-35
60d

78. Assignment The way of FDG interaction in the body.
literature review about hypoxia & tumour hypoxia.
PET and radiopharmaceutical

79. Neutron Activation
Neutrons produced by the fission of uranium in a nuclear reactor can be used to create radionuclides by bombarding stable target material placed in the reactor.
Process involves capture of neutrons by stable nuclei.
Almost all radionuclides produced by neutron activation decay by beta-minus particle emission

81. Radionuclide Generators
Technetium-99m has been the most important radionuclide used in nuclear medicine
Short half-life (6 hours) makes it impractical to store even a weekly supply
Supply problem overcome by obtaining parent Mo-99, which has a longer half-life (67 hours) and continually produces Tc-99m
A system for holding the parent in such a way that the daughter can be easily separated for clinical use is called a radionuclide generator

84. Transient Equilibrium
Between elutions, the daughter (Tc-99m) builds up as the parent (Mo-99) continues to decay.
After approximately 23 hours the Tc-99m activity reaches a maximum, at which time the production rate and the decay rate are equal and the parent and daughter are said to be in transient equilibrium.

85. Transient Equilibrium
Once transient equilibrium has been reached, the daughter activity decreases, with an apparent half-life equal to the half-life of the parent.
Transient equilibrium occurs when the half-life of the parent is greater than that of the daughter by a factor of ~10

88. Secular Equilibrium
If the half-life of the parent is very much longer than that of the daughter (I.e., more than about 100 longer), secular equilibrium occurs after approximately five to six half-lives of the daughter.
In secular equilibrium, the activity of the parent and the daughter are the same if all of the parent atoms decay directly to the daughter.
Once secular equilibrium is reached, the daughter will have an apparent half-life equal to that of the parent

90. Ideal Radiopharmaceuticals
Low radiation dose
High target/nontarget activity
Safety
Convenience
Cost-effectiveness

91. Mechanisms of Localization
Compartmental localization and leakage
Cell sequestration
Phagocytosis
Passive diffusion
Metabolism
Active transport

92. Localization (cont.) Capillary blockade Perfusion Chemotaxis
Antibody-antigen complexation
Receptor binding
Physiochemical adsorption