RADIOACTIVITY & RADIONUCLIDE PRODUCTION

Dr. Mohammed Alnafea alnafea@hotmail.com www.dralnafea.com

History of Radiopharmacy

Medicinal applications since the

discovery of Radioactivity Early 1900s Limited understanding of Radioactivity and dose2

1912 George de HevesyFather 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 medicine1926: 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. generator

1960: Powell Richards developed the Mo-99/Tc-99m

1963: Paul Harper, MD injected Tc-99m pertechnetate for

human brain tumor imaging

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Part 1: Characteristics of a RadiopharmaceuticalWhat is a radiopharmaceutical?A radioactive compound used for the diagnosis and

therapeutic treatment of human diseases.

Radionuclide + Pharmaceutical6

Radioactive MaterialsChart of the Nuclides Z

N

Unstable nuclides Combination of neutron and protons Emits particles and energy to

become a more stable isotope7

Radiation decay emissions

Alpha ( or

He2+ ) Beta ( or e-) Positron ( +) Gamma ( ) Neutrons (n)48

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. (decay) of atoms.

Radioactivity (radioactive decay) is the spontaneous break up

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 radiationWhen 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 ( or 4He) High energy over short

Positron ( +) Energy >1022 MeV, random

linear range Charged 2+ Beta (-

Various energy, random

or e-)

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

motion negative

Gamma ( )

No mass, hv

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Physical Half Life and ActivityRadioactive decay is a

statistical phenomenon t1/2 = decay constantdecay 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= 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

Half Life and decay constant Half-life is time needed to decrease nuclides by 50% Relationship between t1/2 and N/No=1/2=e- 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 radionuclidet

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Why use radioactive materials ?RadiotracersHigh 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 MedicineImagingGamma or positron emitting isotopes 99m Tc, 111 In, 18 F, 11 C, 64 Cu Visualization of a biological process Cancer, myocardial perfusion agents

TherapyParticle 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 RadiopharmaceuticalNuclear 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 AgentsReasonable energy emissions.Radiation must be able to penetrate several

layers of tissue.No particle emission (Gamma only)Isomeric transition, positron ( +), electron

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

(%)

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)

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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= t Probability of not decaying: 1-p=1- t22

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

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ATOMIC STRUCTUREAtomic number (Z):

number of protons in nucleusMass number (A):

Number of protons + neutronsNeutron number (N):

Nuclear forces:

"Strong" attractive force electrostatic repulsive force Radioactive decay caused by nuclear instability Due to p-p electrostatic repulsion24

RADIONUCLIDE DECAY MODESStable nuclei Unstable radioactive : halflife < 1ms Unstable radioactive : halflife > 1000 years

Number of neutrons (A-Z)

No stable nuclei when Z > 83 or N > 126

Number of protons (Z)

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Nuclear TransformationWhen the atomic nucleus undergoes

spontaneous transformation, called radioactive decay, radiation is emittedIf the daughter nucleus is stable, this

spontaneous transformation ends If the daughter is unstable, the process continues until a stable nuclide is reachedMost 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 DecayAlpha ( ) decay is the spontaneous

emission of an alpha particle (identical to a helium nucleus) from the nucleus.

Typically occurs with heavy

A Z28

X Z 2Y + 2 He + transition energy

nuclides (A > 150) and is often followed by gamma and characteristic x-ray emission A4 4 +2

RADIONUCLIDE DECAY MODES decay

Nuclei with Z > 8329

Beta-Minus (Negatron) DecayBeta-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) A A Z

X Z+1Y + + + 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 - decay

Occurs in nuclei with

high neutron:proton ratio

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Beta-Plus Decay (Positron Emission)Beta-plus ( +) decay characteristically

occurs with radionuclides that are neutron poor (i.e., low N/Z ratio)A Z

X Y + + + energyA Z-1 +

Eventual fate of positron is to annihilate

with its antiparticle (an electron), yielding two 511-keV photons emitted in opposite directions33

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RADIONUCLIDE DECAY MODES + decay

Occurs in nuclei with a

low neutron:proton ratio

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Electron Capture DecayAlternative to positron decay for neutron-

deficient radionuclides. L-shell) electronA Z

Nucleus captures an orbital (usually K- or

X + e-

A Z -1

Y + + energy

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 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 DecayFission: 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 DecayBeta 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 DecayElectron 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 calculationUsing Nt=Noe- 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 calculationA= 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 TransitionDuring 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 yearsAm Z45

X X + energyA Z

Decay SchemesEach radionuclides decay process is a

unique characteristic of that radionuclide. decay process and its associated radiation can be summarized in a line diagram called a decay scheme. daughter, mode of decay, intermediate excited states, energy levels, radiation emissions, and sometimes physical half-life.

Majority of pertinent information about the

Decay schemes identify the parent,

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Generalized Decay Scheme

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Radionuclide ProductionAll 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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CyclotronsCyclotrons produce radionuclides by

bombarding stable nuclei with high-energy charged particles. neutron poor and therefore decay by positron emission or electron capture. developed to produce positron-emitting radionuclides for positron emission tomography (PET)Usually located near the PET imager because of short

Most cyclotron-produced radionuclides are

Specialized hospital-based cyclotrons have been

half-lives of the radionuclides produced

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Nuclear ReactorsSpecialized nuclear reactors used to produce

clinically useful radionuclides from fission products or neutron activation of stable target material. separated from other fission products with essentially no stable isotopes (carrier) of the radionuclide present. produced radionuclides is very high

Uranium-235 fission products can be chemically

Concentration of these carrier-free fission-

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NUCLEAR REACTORSchematic Representation

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RADIONUCLIDE PRODUCTIONThermal neutron induced fission 235

U is most commonly used fissionable material U + n unstable nucleus fission fragments + n +

235

E

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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

RADIONUCLIDE PRODUCTIONThermal neutron induced fission

235

U fission > 370 nuclides

observed mass range : 72 - 161 distribution as indicated

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RADIONUCLIDE PRODUCTIONThermal 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

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relatively cheap - not major function of reactor

RADIONUCLIDE PRODUCTIONReactor Targetryirradiation 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 100C, sample temperature > 1000C ( 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 PRODUCTIONNeutron bombardment

Activity of a radionuclide produced by particle bombardment is given byA = 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)

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when t > 4 x T , (1 - e- t) approaches 1 saturation activity : A = N no gain from irradiating beyond 3 - 4 x T

RADIONUCLIDE PRODUCTIONPreparation 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 + heating13 3

Xe released - trapped (charcoal, liquid N2)

Al2O3.2H2O + NaI + H2SO4 + H2O2 - distilled

7500 GBq 131 I (+ 127 I + 124 I) i.e. carrier iodine25 3

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U recovered for reuse

RADIONUCLIDE PRODUCTIONPreparation of I-131 (carrier free) 67

target : 2.5g 99+% 130Te Neutron flux: 2 x 1014n/cm2/sec, 21d130

Te (n, ) 131Te

131

I

65 GBq 131I obtained by distillation, as before130

Te recovered for reuse

Preparation of Mo-99 (non-fission + fission) target : natural MoO3 - 23.78% flux: 2 x 1014 n/cm2/sec, 7d9 8 9 8

RADIONUCLIDE PRODUCTIONMo

Mo (n, ) 99 Mo15 8

37 GBq 99 Mo from 1g MoO3 natural MoO3 9 8 Mo used W (T = 74d) - absent when enriched

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Starting material : 2.5g 93+% 235 U9 9

Mo extracted from acidified solution of fission products

produced in 1000 GBq quantities high specific activity for generators may contain some 131 I and 103 Ru

REACTOR PRODUCED RADIONUCLIDESPRODUCT1 4 3 2 5 1 5 9

DECAY MODE PRODUCTION REACTION EC, -, EC, -, 14 2 10 3 1 4

C P

N(n,p)14 C P(n,)32 P

3 1 5 0 5 8

Cr Fe I I

Cr(n,)51 Cr Fe(n,)59 FeE 15 C 2 - 1 1 3

15 2 11 3

Xe(n,)125 Xe Te(n,)131 Te

I I

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RADIONUCLIDE PRODUCTIONRadionuclide 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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Cross-section of a typical radionuclide generator

RADIONUCLIDE GENERATORS

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RADIONUCLIDE GENERATORSRadioactive Decay Lawscommon simplificationsT parent 10 x T daughter

d Ad ( t ) = Ap p d66h 6.02h

transient equilibrium

e.g. 99Mo / 99Tcm generator

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RADIONUCLIDE GENERATORSRadioactive Decay Laws

common simplifications T parent >> T daughter ( p >> d)

Ad ( t ) = Ap (1 e

secular equilibrium

dt

)

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

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RADIONUCLIDE GENERATORSDesirable 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

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Technetium Generator Elution

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RADIONUCLIDE GENERATORSYield 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 column

improper initial packing of terminal sterilisation

procedures

pseudochannelling - dry vs.

wet generators

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Commonly Used RadionuclidesNuclide IMAGING 1 8 F 6 7 Ga 8 1 Krm 9 9 Tcm 11 1 In 13 2 I 11 3 I 21 0 Tl THERAPY 9 0 Y 16 8 Re In Vitro 1 4 C 5 1 Cr 775 1 2 I Production Method Cyclotron Cyclotron Generator Generator Cyclotron Cyclotron Reactor Cyclotron Reactor Reactor Reactor Reactor Reactor

CharacteristicsDecay Mode Positron EC IT IT EC EC Beta EC Beta Beta Beta EC EC

Emissions Half-life (keV) 108 min 78 hr 13 s 6 hr 67 hr 13 hr 8d 73.5 hr 64 hr 90 hr 5760 yr 27.8 d 60d

511 92, 182, 300, 390 191 140 173, 247 160 280, 360, 640 68-80 137 323 27-35

AssignmentThe way of FDG interaction in the body. literature review about hypoxia & tumour

hypoxia.PET and radiopharmaceutical

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Neutron ActivationNeutrons 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 GeneratorsTechnetium-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 EquilibriumBetween elutions, the daughter (Tc-

99m) builds up as the parent (Mo-99) continues to decay. 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.

After approximately 23 hours the Tc-

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Transient EquilibriumOnce transient equilibrium has been

reached, the daughter activity decreases, with an apparent half-life equal to the half-life of the parent. half-life of the parent is greater than that of the daughter by a factor of ~10

Transient equilibrium occurs when the

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Secular EquilibriumIf 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. the daughter are the same if all of the parent atoms decay directly to the daughter. will have an apparent half-life equal to that of the parent

In secular equilibrium, the activity of the parent and

Once secular equilibrium is reached, the daughter

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Ideal RadiopharmaceuticalsLow radiation dose High target/nontarget activity Safety Convenience Cost-effectiveness

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Mechanisms of LocalizationCompartmental 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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