RADIOACTIVITY & RADIONUCLIDE

PRODUCTION

Dr. Mohammed Alnafea

alnafea@hotmail.com
www.dralnafea.com
 History of Radiopharmacy

Medicinal applications since the

discovery of Radioactivity Early 1900’s
Limited understanding of Radioactivity
and dose

2
 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”

3
 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

4
 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
5
 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

6
 Radioactive Materials
Chart of the Nuclides
↑
Z

N→

Unstable nuclides
Combination of neutron and protons
Emits particles and energy to
become a more stable isotope
7
Radiation decay emissions

Alpha (α or
4
He2+ )
Beta (β − or e-)
Positron (β +)
Gamma (γ )
Neutrons (n)
8
 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.

9
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

10
 Interactions of Emissions
 Alpha (α or 4He)  Positron (β +)
 High energy over short
 Energy >1022 MeV, random
linear range
 Charged 2+ motion
 Beta (β  Anihilation (2 511 KeV
-
or e-)
 Various energy, random ~180°)
motion  Neutrons (n)
 negative
 No charge, light elements
 Gamma (γ )
 No mass, hv

11
 Physical Half Life and Activity
Radioactive decay is a
statistical phenomenon Half-life is
t1/2 time needed
to decrease
λ = decay constant nuclides by
50%
decay constant is the Number of
atoms decaying per unit time is
proportional to the number of
 Activity is the amount of
unstable
radioactive material
atoms

12
 Measured Activity
 In practicality, activity (A)
is used instead of the
number of atoms (N).
 A= cλ t, m
where c is the detection
coefficient
A=AOe-λ t
 Units
Curie (Ci),
3.7E10 decay/s
1 g Ra
Becquerel (Bq)
1 decay/s
 Half Life and decay
constant
 Half-life is time needed to
decrease nuclides by 50%
 Relationship between t1/2 and λ

N/No=1/2=e-λ t

ln(1/2)=-λ t1/2
ln 2= λ t1/2
t1/2 =(ln 2)/λ
NB: Physical half-life and
decay constant are inversely
related and unique for each
14 radionuclide
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

15
 Applications in Nuclear
Medicine
Imaging
Gamma or positron emitting isotopes
 99m Tc, 111 In, 18 F, 11 C, 64 Cu
Visualization of a biological process
 Cancer, myocardial perfusion agents

Therapy
Particle emitters
Alpha, beta, conversion/auger electrons
 188 Re, 166 Ho, 89 Sr, 90 Y, 212 Bi, 225 Ac, 131 I
Treatment of disease
 Cancer, restenosis, hyperthyroidism

16
 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

17
 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 (β +), electron
capture
High abundance or “Yield”
Effective half life
Cost

18
Detection Energy Requirements

 Best images between 100-

300 KeV
 Limitations
 Detectors (NaI)
 Personnel (shielding)
 Patient dose

 What else happens at Cs-137 decay (662 KeV)

higher energies?
Lower photoelectric peak
abundance, due to the
Compton effect Energy
→
19
 Gamma Isotopes

Radionuclide T1/2 γ (%)

Tc-99m 6.02 hr 140 KeV (89)
Tl-201 73 hr 167 KeV (9.4)
In-111 2.21 d 171(90), 245(94)
Ga-67 78 hr 93 (40), 184 (20), 300(17)
I-123 13.2 hr 159(83)
I-131 8d 284(6), 364(81), 637(7)
Xe-133 5.3 d 81(37)

20
Radioactive Decay Kinetics

21
 Basic decay equations
 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=λ ∆ t

Probability of not decaying: 1-p=1- λ ∆ t
22
 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);

23
1 Ci = 3.7 x 1010 radioactive decays per second
 ATOMIC STRUCTURE
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
24
RADIONUCLIDE DECAY MODES
Stable nuclei
Unstable – radioactive : half-
life < 1ms
Unstable – radioactive : half-
life > 1000 years
Number of neutrons (A-Z)

No stable nuclei when Z >

83 or N > 126

Number of protons (Z) 25

 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.
26
RADIONUCLIDE DECAY MODES

27 No stable nuclei when Z > 83 or N > 126

 Alpha Decay
Alpha (α ) 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
A−4 x-ray
+2 emission
A
Z X → Z− 2Y + 2 He + transition energy
4

28
RADIONUCLIDE DECAY MODES
α decay

Nuclei with  Z > 83

29
 Beta-Minus (Negatron)
Decay
Beta-minus (β -) decay characteristically
occurs with radionuclides that have an
excess number of neutrons compared
with the number of protons (i.e., high
N/Z ratio)
A
Z X→ Z+1Y + β + ν + energy
A -

Any excess energy in the nucleus after

beta decay is emitted as gamma rays,
internal conversion electrons or other
associated radiations
30
31
RADIONUCLIDE DECAY MODES
β - decay

 Occurs in nuclei with

high neutron:proton
ratio
32
 Beta-Plus Decay (Positron
Emission)

Beta-plus (β +) decay characteristically

occurs with radionuclides that are
“neutron poor” (i.e., low N/Z ratio)
A
Z X→ Y + β + ν + energy
A
Z-1
+

Eventual fate of positron is to annihilate

with its antiparticle (an electron),
yielding two 511-keV photons emitted in
opposite directions

33
34
RADIONUCLIDE DECAY MODES
β + decay

 Occurs in nuclei with a

low neutron:proton
ratio
35
 Electron Capture Decay
Alternative to positron decay for neutron-
deficient radionuclides.

Nucleus captures an orbital (usually K- or

L-shell) electron
A
Z X + e- → A
Y + ν + energy
Z -1

Electron capture radionuclides used in

medical imaging decay to atoms in
excited states that subsequently emit
detectable gamma rays
36
RADIONUCLIDE DECAY MODES
Electron capture

 Occurs in nuclei with a

low neutron:proton
ratio
37
RADIONUCLIDE DECAY MODES
γ emission

 Generally accompanies other radioactive decay

 associated with energy loss from changes in nuclear
energy states
38
RADIONUCLIDE DECAY MODES
Spontaneous fission

 Used by high Z nuclei

 2 nuclei of approximately
equal mass produced
 Accompanied by release
of energy and neutrons
39
 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;

40
 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;

41
 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.

42
 Q1:Half-life calculation

Using Nt=Noe-λ t
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?

43
 Q2: Half-life calculation

A=λ N
 A 0.150 g sample of 248Cm has a alpha activity of
0.636 mCi.What is the half-life of 248Cm?

44
 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
Am
Z X → X + energy
A
Z

45
 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.
46
 Generalized Decay
Scheme

47
48
49
50
51
52
 Radionuclide Production
All radionuclides commonly administered to
patients in nuclear medicine are artificially
produced.

Most are produced by cyclotrons, nuclear

reactors, or radionuclide generators

53
 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

54
55
56
57
 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

58
59
 NUCLEAR REACTOR
Schematic Representation

60
 RADIONUCLIDE PRODUCTION
Thermal neutron induced fission

• 235
U is most commonly used fissionable material

• 235
U + 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
61
 RADIONUCLIDE PRODUCTION
Thermal neutron induced fission

• 235
U fission → > 370 nuclides
• observed mass range : 72 - 161

• distribution as indicated

62
 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 β - emission

• relatively cheap - not major function of reactor

63
 RADIONUCLIDE PRODUCTION
Reactor Targetry
• irradiation positions
• mobile : short irradiation times (minutes - 1 week)
• fixed : long irradiation times (one or more reactor fuel
cycles : 2 - 4 weeks)
• accessible only during reactor shutdown
• both positions water cooled
• reactor temperature ≈ 100°C, sample temperature > 1000°C
(γ 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)
64
 RADIONUCLIDE PRODUCTION
Neutron bombardment
• Activity of a radionuclide produced by
particle bombardment is given by
A = φ Nσ (1 - e-λ t)
where: A = activity
φ = particle flux (number/cm2/s)
N = number of target atoms
σ = absorption cross section in barns (10-24
cm2/atom)
λ = decay constant of product radionuclide
t = duration of irradiation (in seconds)
• when t > 4 x T½ , (1 - e-λ t) approaches 1
• saturation activity : A = φ Nσ
• no gain from irradiating beyond 3 - 4 x T½
65
 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

133
Xe released - trapped (charcoal, liquid N2)

Al2O3.2H2O + NaI

+ H2SO4 + H2O2 - distilled

≈ 7500 GBq 131 I (+ 127 I + 124 I) i.e. carrier iodine

235
U recovered for reuse
66
 RADIONUCLIDE PRODUCTION
Preparation of I-131 (carrier free)

• target : 2.5g 99+% 130Te

• Neutron flux: 2 x 1014n/cm2/sec, 21d

• Te (n,γ ) 131Te 
130
I
131

• ≈ 65 GBq 131I obtained by distillation, as before

• Te recovered for reuse

130

67
 RADIONUCLIDE PRODUCTION
Preparation of Mo-99 (non-fission + fission)
• target : natural MoO3 - 23.78% 98
Mo
• flux: 2 x 1014 n/cm2/sec, 7d
• 98
Mo (n,γ ) 99 Mo
• ≈ 37 GBq 99 Mo from 1g MoO3
• natural MoO3  185
W (T½ = 74d) - absent when enriched
98
Mo used

• Starting material : 2.5g 93+% 235 U

• 99
Mo extracted from acidified solution of fission products
• produced in 1000 GBq quantities
• high specific activity for generators
•
68 may contain some 131 I and 103 Ru
REACTOR PRODUCED RADIONUCLIDES

PRODUCT DECAY MODE PRODUCTION REACTION

14
C β- 14
N(n,p)14 C
32
P β- 31
P(n,γ)32 P
51
Cr EC, γ 50
Cr(n,γ)51 Cr
59
Fe β-, γ 58
Fe(n,γ)59 Fe
125
I EC, γ 124
Xe(n,γ)125 Xe EC 125
I
131
I β-, γ 130
Te(n,γ)131 Te β- 131
I
69
 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

70
 RADIONUCLIDE GENERATORS
Cross-section of a typical radionuclide generator

71
 RADIONUCLIDE GENERATORS
Radioactive Decay Laws

• common
simplifications
• T½ parent ≈ 10 x T½ daughter

• transient equilibrium
λd
Ad ( t ) = Ap
λ p − λd
• e.g. 99Mo / 99Tcm generator
66h 6.02h

72
 RADIONUCLIDE GENERATORS
Radioactive Decay Laws

• common simplifications
• T½ parent >> T½ daughter
(λ p >> λ d)
• secular equilibrium

Ad ( t ) = Ap (1 − e − λdt
)
• e.g. 68 Ge / 68 Ga generator
270d 68m

73
 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

74 preparation of radiopharmaceuticals
Technetium Generator Elution

75
 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
76
Commonly Used Radionuclides
Characteristics
Nuclide Production Decay γ Emissions Half-life
Method Mode (keV)
IMAGING
18
F Cyclotron Positron 511 108 min
67
Ga Cyclotron EC 92, 182, 300, 390 78 hr
81
Krm Generator IT 191 13 s
99
Tcm Generator IT 140 6 hr
111
In Cyclotron EC 173, 247 67 hr
123
I Cyclotron EC 160 13 hr
131
I Reactor Beta 280, 360, 640 8d
201
Tl Cyclotron EC 68-80 73.5 hr
THERAPY
90
Y Reactor Beta - 64 hr
186
Re Reactor Beta 137 90 hr
In Vitro
14
C Reactor Beta - 5760 yr
51
Cr Reactor EC 323 27.8 d
77
125
I Reactor EC 27-35 60d
 Assignment
The way of FDG interaction in the body.

literature review about hypoxia & tumour

hypoxia.

PET and radiopharmaceutical

78
 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

79
80
 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

81
82
83
 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.

84
 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

85
86
87
 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

88
89
 Ideal
Radiopharmaceuticals
Low radiation dose
High target/nontarget activity
Safety
Convenience
Cost-effectiveness

90
 Mechanisms of
Localization
Compartmental localization and leakage
Cell sequestration
Phagocytosis
Passive diffusion
Metabolism
Active transport

91
 Localization (cont.)
Capillary blockade
Perfusion
Chemotaxis
Antibody-antigen complexation
Receptor binding
Physiochemical adsorption

92