Radioactivity & Radionuclide Production

RADIOACTIVITY & RADIONUCLIDE PRODUCTION

Dr. Mohammed Alnafea [email protected] 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”

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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

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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

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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

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

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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.

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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

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Interactions of Emissions  Alpha (α or 4He)

 High energy over short

linear range  Charged 2+  Beta (β

-

or e-)

 Various energy, random

motion  negative

 Gamma (γ )

 No mass, hv

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 Positron (β +)  Energy >1022 MeV, random

motion  Anihilation (2 511 KeV ~180°)  Neutrons (n)  No charge, light elements

Physical Half Life and Activity Radioactive decay is a

statistical phenomenon t1/2 λ = decay constant 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

Half-life is time needed to decrease nuclides by 50%

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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

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NB: Physical half-life and decay constant are inversely related and unique for each 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

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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

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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

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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

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Detection Energy Requirements  Best images between 100-

300 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 → 19

Gamma Isotopes Radionuclide T1/2 Tc-99m Tl-201 In-111 Ga-67 I-123 13.2 I-131 8d Xe-133

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γ (%)

6.02 hr 140 KeV (89) 73 hr 167 KeV (9.4) 2.21 d 171(90), 245(94) 78 hr 93 (40), 184 (20), 300(17) hr 159(83) 284(6), 364(81), 637(7) 5.3 d 81(37)

Radioactive Decay Kinetics

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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;

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• The traditional unit of radioactivity is the curie (Ci); 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

Number of neutrons (A-Z)

Stable nuclei Unstable – radioactive : halflife < 1ms Unstable – radioactive : halflife > 1000 years

No stable nuclei when Z > 83 or N > 126

Number of protons (Z)

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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.

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RADIONUCLIDE DECAY MODES

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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

A Z 28

nuclides (A > 150) and is often followed by gamma and characteristic x-ray emission A−4 4 +2

X → Z− 2Y + 2 He + transition energy

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 A Z

X→ Z+1Y + β + ν + energy

Any excess energy in the nucleus after

beta decay is emitted as gamma rays, internal conversion electrons or other associated radiations

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RADIONUCLIDE DECAY MODES β - decay

 Occurs in nuclei with

high neutron:proton ratio

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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

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RADIONUCLIDE DECAY MODES β + decay

 Occurs in nuclei with a

low neutron:proton ratio

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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- →

Y + ν + energy

A Z -1

Electron capture radionuclides used in

medical imaging decay to atoms in excited states that subsequently emit detectable gamma rays

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RADIONUCLIDE DECAY MODES Electron capture

 Occurs in nuclei with a

low neutron:proton ratio

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RADIONUCLIDE DECAY MODES γ emission

 Generally accompanies other radioactive decay  associated with energy loss from changes in nuclear

energy states

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RADIONUCLIDE DECAY MODES Spontaneous fission

 Used by high Z nuclei  2 nuclei of approximately

equal mass produced

 Accompanied by release

of energy and neutrons

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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;

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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 gammaray; 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.

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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?

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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?

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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 halflives ranging up to more than 600 years Am Z 45

X → X + energy A Z

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.

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Generalized Decay Scheme

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49

50

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Radionuclide Production All radionuclides commonly administered to

patients in nuclear medicine are artificially produced. Most are produced by cyclotrons, nuclear

reactors, or radionuclide generators

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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

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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

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NUCLEAR REACTOR Schematic Representation

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RADIONUCLIDE PRODUCTION Thermal neutron induced fission

U is most commonly used fissionable material

•

235

•

235

E

U + n → unstable nucleus → fission fragments + n +

•

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

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RADIONUCLIDE PRODUCTION Thermal neutron induced fission

•

U fission → > 370 nuclides

235

• observed mass range : 72 - 161 • distribution as indicated

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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

• 63

relatively cheap - not major function of reactor

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)

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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)

• • • 65

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

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

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U recovered for reuse

RADIONUCLIDE PRODUCTION Preparation of I-131 (carrier free)

•

target : 2.5g 99+% 130Te

•

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

•

130

•

≈ 65 GBq 131I obtained by distillation, as before

•

130

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Te (n,γ ) 131Te 

I

131

Te recovered for reuse

RADIONUCLIDE PRODUCTION

Preparation of Mo-99 (non-fission + fission) •

target : natural MoO3 - 23.78%

•

flux: 2 x 1014 n/cm2/sec, 7d

•

98

•

≈ 37 GBq 99 Mo from 1g MoO3

•

natural MoO3  98 Mo used

•

Starting material : 2.5g 93+% 235 U

•

99

•

produced in 1000 GBq quantities

•

high specific activity for generators

68 •

98

Mo

Mo (n,γ ) 99 Mo 185

W (T½ = 74d) - absent when enriched

Mo extracted from acidified solution of fission products

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

51

Cr

EC, γ

50

Cr(n,γ)51 Cr

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Fe

β-, γ

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Fe(n,γ)59 Fe

125

I

EC, γ

124

Xe(n,γ)125 Xe

131

I

β-, γ

130

Te(n,γ)131 Te

P(n,γ)32 P

I

EC 125 β- 131

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I

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

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RADIONUCLIDE GENERATORS

Cross-section of a typical radionuclide generator

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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

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6.02h

RADIONUCLIDE GENERATORS Radioactive Decay Laws

•

common simplifications

•

T½ parent >> T½ daughter (λ p >> λ d)

•

•

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secular equilibrium

Ad ( t ) = Ap (1 − e

− λdt

e.g. 68 Ge / 68 Ga generator 270d 68m

)

RADIONUCLIDE GENERATORS Desirable Properties

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•

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

Technetium Generator Elution

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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

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Commonly Used Radionuclides Nuclide IMAGING 18 F 67 Ga 81 Krm 99 Tcm 111 In 123 I 131 I 201 Tl THERAPY 90 Y 186 Re In Vitro 14 C 51 Cr 77 125 I

Characteristics

Production Method

Decay Mode

γ Emissions Half-life (keV)

Cyclotron Cyclotron Generator Generator Cyclotron Cyclotron Reactor Cyclotron

Positron EC IT IT EC EC Beta EC

511 92, 182, 300, 390

68-80

108 min 78 hr 13 s 6 hr 67 hr 13 hr 8d 73.5 hr

Reactor Reactor

Beta Beta

137

64 hr 90 hr

Reactor Reactor Reactor

Beta EC EC

323 27-35

5760 yr 27.8 d 60d

191 140 173, 247 160 280, 360, 640

Assignment The way of FDG interaction in the body. literature review about hypoxia & tumour

hypoxia. PET and radiopharmaceutical

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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

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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 Mo99, 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

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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.

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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

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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

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

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

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

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