Nuclear pharmacyNuclear pharmacyLecture 4Lecture 4

Production of radionuclidesProduction of radionuclides

IntroductionIntroduction ● ●In 1896 Becquerel discovered the natural radioactive in In 1896 Becquerel discovered the natural radioactive in

potassium uranyl sulfatepotassium uranyl sulfate..

● ●Since then, Pierre and Marie Curie, Rutherford, and Soddy have Since then, Pierre and Marie Curie, Rutherford, and Soddy have all made tremendous progress in the discovery of many other all made tremendous progress in the discovery of many other radioactive elementsradioactive elements..

● ●The work of all these scientists has shown that all elements The work of all these scientists has shown that all elements found in nature with an atomic number greater than 83 found in nature with an atomic number greater than 83 (bismuth) are radioactive(bismuth) are radioactive..

● ●Artificial radioactivity was first reported by I. Curie and F. Artificial radioactivity was first reported by I. Curie and F. Joliot in 1934. These scientists irradiated boron and aluminum Joliot in 1934. These scientists irradiated boron and aluminum targets with targets with αα particles from polonium and observed positrons particles from polonium and observed positrons emitted from the target even after the removal of the emitted from the target even after the removal of the αα particle particle source. This discovery of induced or artificial radioactivity source. This discovery of induced or artificial radioactivity opened up a brand new field of tremendous importanceopened up a brand new field of tremendous importance..

● ●Around the same time, the discovery of the cyclotron neutron Around the same time, the discovery of the cyclotron neutron and deuteron by various scientists added to the production of and deuteron by various scientists added to the production of many more artificial radioactivitiesmany more artificial radioactivities..

● ●At present, more than 1500 radionuclides have been produced At present, more than 1500 radionuclides have been produced artificially in the cyclotron, the reactor, the neutron generator, artificially in the cyclotron, the reactor, the neutron generator, and the linear acceleratorand the linear accelerator..

● ●Radionuclides used in nuclear medicine are mostly artificial Radionuclides used in nuclear medicine are mostly artificial ones. They are primarily produced in a cyclotron or a reactor. ones. They are primarily produced in a cyclotron or a reactor. The type of radionuclide produced in a cyclotron or a reactor The type of radionuclide produced in a cyclotron or a reactor depends on the irradiating particles, its energy and the target depends on the irradiating particles, its energy and the target nucleinuclei..

Radionuclides productionRadionuclides production

All radionuclides commonly administered to patients in nuclear medicine are artificially produced.

Most are produced by cyclotrons, nuclear reactors, or radionuclide generators

Types of radioactivity: How to produce a radioactive Types of radioactivity: How to produce a radioactive nuclidenuclide? ?

11 . .Natural radioactivityNatural radioactivity::Nuclear reactions occur spontaneouslyNuclear reactions occur spontaneously..

22 . .Artificial radioactivityArtificial radioactivity::The property of radioactivity produced by particle bombardment or The property of radioactivity produced by particle bombardment or electromagnetic irradiationelectromagnetic irradiation..

A- Charged-particle reactionsA- Charged-particle reactionsReactions of these types may be produced withReactions of these types may be produced withe.g. protons (e.g. protons (1 1

11H or P)H or P)

e.g. deuterons (e.g. deuterons (2 2 11H or d)H or d)

e.g. alpha particles (e.g. alpha particles (44He or He or αα))

B- Photon-induced reactionsB- Photon-induced reactions

Electromagnetic radiations or photons may induce nuclear Electromagnetic radiations or photons may induce nuclear reactions. reactions. The source of electromagnetic energy may be The source of electromagnetic energy may be gamma-emitting radionuclide or high-voltage x-ray generatorgamma-emitting radionuclide or high-voltage x-ray generator..

C- Neutron-induced reactionsC- Neutron-induced reactions-It is the most widely used methodIt is the most widely used method

-It is the bombardment of a non radioactive target nucleus with It is the bombardment of a non radioactive target nucleus with a source of thermal neutronsa source of thermal neutrons..

Production of radionuclidesProduction of radionuclides::

11 . .Charged particle bombardmentCharged particle bombardment

Radionuclides may be produced by bombarding target materials with charged particles in particle accelarators such as cyclotrons.

-A cyclotron consists ofA cyclotron consists of: : Two flat hollow objects called deesTwo flat hollow objects called dees..The dees are part of an electrical circuitThe dees are part of an electrical circuit..

On the other side of the dees are large magnets that (drive) steer the injected On the other side of the dees are large magnets that (drive) steer the injected charged particles charged particles (protons, deutrons, alpha and helium)(protons, deutrons, alpha and helium) in a circular path in a circular path

The charged particle follows a circular path until the particle has sufficient The charged particle follows a circular path until the particle has sufficient energy that it passes out of the field and interact with the target nucleusenergy that it passes out of the field and interact with the target nucleus..

CyclotronCyclotron

Cyclotron-produced isotopes (accelerator):Cyclotron-produced isotopes (accelerator):

- It can be used only with charged particles such as: electrons, - It can be used only with charged particles such as: electrons, protons, deuterons because the operation of such machine depends protons, deuterons because the operation of such machine depends upon the interaction of magnetic and/or electrostatic fields with the upon the interaction of magnetic and/or electrostatic fields with the charge of the particle undergoing acceleration.charge of the particle undergoing acceleration.

- When the particles have been accelerated to a high velocity, they are - When the particles have been accelerated to a high velocity, they are caused to strike a target, containing the atoms to be bombarded.caused to strike a target, containing the atoms to be bombarded.

- Sodium 22 is prepared in this way by the interaction of high velocity - Sodium 22 is prepared in this way by the interaction of high velocity deuterons with magnesium 24.deuterons with magnesium 24.2424Mg (d, Mg (d, αα) ) 2222NaNa where where 2424Mg is the target, the deuteron (d) is the irradiating Mg is the target, the deuteron (d) is the irradiating

particle, the particle, the αα is the emitted particle, and is the emitted particle, and 2222Na is the product radionuclideNa is the product radionuclide . .

-Other medically important ultra-short-lived radionuclides which have Other medically important ultra-short-lived radionuclides which have been produced in a cyclotron by use of high-energy deuterons include been produced in a cyclotron by use of high-energy deuterons include 1111C, C, 1313N, N, 1515O. O. Example:Example:Carbon-11 has a half-life of 20.4 min and can be produced byCarbon-11 has a half-life of 20.4 min and can be produced by 1010B (d, n) B (d, n) 1111CC

Short-Lived Radionuclides most of which are used to positron emission tomography (PET) Carbon-11 ( t1/2 = 20.4 min ) Nitrogen-13 ( t1/2 = 10 min ) Oxygen-15 ( t1/2 = 2 min )Fluorine-18 (t1/2 = 110 min)

- Those which have been produced using high-energy alpha particles - Those which have been produced using high-energy alpha particles include include 1818F, F, 123123I, I, 124124I.I.

- High energy protons have been used to produce - High energy protons have been used to produce 127127Xe, Xe, 201201Pb, Pb, 111111In, In, 6767GaGa.. For example: 68Zn (p,2n) 67Ga, 111Cd (p, n)111In

-Most cyclotron-produced radionuclides are neutron poor and therefore, decay by positron emission or electron capture. These positron emitters are very useful in imagining by positron emission tomography (PET).

- Since various isotopes of different elements may be produced in a particular irradiating system, it is necessary to isolate isotopes of a single element, this can be accomplished by appropriate chemical methods such as solvent extraction, precipitation, and distillation.

-Iodine-123 has gained considerable importance in nuclear medicine because it has good radiation characteristics. It is produced directly or indirectly in a cyclotron by several nuclear reactions.

● Direct nuclear reactions, whereby 123I is produced directly and likely to be contaminated with other iodine radioisotopes such as 124I and 125I, depending on the type of target and irradiating particle. 121Sb (α, 2n)123I 123Te (p, n)123I

● In direct nuclear reaction is so chosen that 123Xe is produced initially, which then decays with a half-life of 2.1hr to produce 123I with a half-life of 13hr. These reactions allow the production of 123I free of other radioisotopes of iodine.123Te (α, 2n) 123Xe127I (p, 5n) 123Xe

22 - -Neutron bombardmentNeutron bombardment

● ● Radionuclides may be produced by bombarding target materials with Radionuclides may be produced by bombarding target materials with neutrons in neutrons in nuclear reactors.nuclear reactors.●● The majority of radiopharmaceuticals are produced by this process.The majority of radiopharmaceuticals are produced by this process.●● The nuclear reactors are devices for producing high fluxes of neutrons. The nuclear reactors are devices for producing high fluxes of neutrons.●● Specialized nuclear reactors used to produce clinically useful Specialized nuclear reactors used to produce clinically useful radionuclides from fission products or neutron activation of stable radionuclides from fission products or neutron activation of stable target material target material

● ● A nuclear reactorA nuclear reactor is constructed with fuel rods made of fissile is constructed with fuel rods made of fissile materials such as enriched materials such as enriched 238238U and U and 239239Pu. These fuel nuclei undergo Pu. These fuel nuclei undergo spontaneous fission with extremely low probability.spontaneous fission with extremely low probability.

● Fission is defined as the break up of a heavy nucleus into two fragments of ● Fission is defined as the break up of a heavy nucleus into two fragments of approximately equal mass, accompanied by the emission of 2-3 neutrons with mean approximately equal mass, accompanied by the emission of 2-3 neutrons with mean energies of about 1.5 MeV (low probability of interaction with other nuclei)energies of about 1.5 MeV (low probability of interaction with other nuclei). Neutrons Neutrons with thermal energy (0.025 eV) interact with many other nuclei, efficiently producing with thermal energy (0.025 eV) interact with many other nuclei, efficiently producing various radionuclidesvarious radionuclides..

Neutrons are usually created by nuclear fission where the nuclei are split which; a process that releases energy.

The nuclear reactors work by fission. The element uranium is the main fuel and is easily split by thermal neutrons diffusing into the nucleus. In the process several new high energy neutrons arecreated, moderated in energy and are used to do new reactions – chain reaction. This chain reaction , ultimately leading to an explosive situation in the reactor.

● ●This chain reaction must be controlled, excess neutrons (more This chain reaction must be controlled, excess neutrons (more than one) are removed by positioning cadmium (cd) rods in than one) are removed by positioning cadmium (cd) rods in the fuel core (cadmium has a high probability of absorbing a the fuel core (cadmium has a high probability of absorbing a thermal neutron)thermal neutron)..

●●In order to make the high-energy or so-called fast neutrons In order to make the high-energy or so-called fast neutrons more useful, they are thermalized or slowed down by more useful, they are thermalized or slowed down by interaction with low molecular weight materials, such as interaction with low molecular weight materials, such as heavy water, beryllium and graphite, which are distributed in heavy water, beryllium and graphite, which are distributed in the spaces between the fuel rods (moderators)the spaces between the fuel rods (moderators)..

Schematic Diagram of a Nuclear Reactor

Nuclear ReactorsNuclear ReactorsThe reaction is kept in The reaction is kept in

check by the use of check by the use of control rodscontrol rods..

These block the paths of These block the paths of some neutrons, keeping some neutrons, keeping the system from reaching the system from reaching a dangerous supercritical a dangerous supercritical massmass..

The neutrons in reactor are mixture of fast neutrons (high energy) and The neutrons in reactor are mixture of fast neutrons (high energy) and thermal neutrons have higher probability of causing nuclear reactionthermal neutrons have higher probability of causing nuclear reaction . .

In the reactor the uranium fission reaction produces a large supply of In the reactor the uranium fission reaction produces a large supply of neutronsneutrons..

- -One neutron for each uranium atom undergoing fission is used to One neutron for each uranium atom undergoing fission is used to sustain the reactionsustain the reaction..

- -The remaining neutrons are used either to produce plutonium by The remaining neutrons are used either to produce plutonium by interaction with interaction with 238238U nuclei or are used to produce radioactive U nuclei or are used to produce radioactive products by causing the neutrons to interact with specific substances products by causing the neutrons to interact with specific substances which have been inserted into the pile (neutron activation)which have been inserted into the pile (neutron activation)

Neutron activationNeutron 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.

In the reactor, two types of interaction with thermal neutrons are of In the reactor, two types of interaction with thermal neutrons are of considerable importance in the production of various useful considerable importance in the production of various useful radionuclidesradionuclides::

● ●Fission of heavy elementsFission of heavy elements

1 .fissionable heavy elements : some nuclides having atomic number greater than 92. (235U, 239Pu, 237Np, 233U, 233Th ).

2 .The atomic number of nuclide produced by fission is about 28 to 65 .

3 .The methods used to product separation are : precipitation, solvent extraction, ion exchange, chromatography and distillation .

4 .The fission products are usually neutron rich and decay by β- emission .

5 .Many clinically useful radionuclides such as 131I, 99Mo, 133Xe and 137Cs are produced by fission of 235U .

6 .Two radionuclides, 131I AND 99Mo are of extreme importance in nuclear medicine.

7 .The fission radionuclides are normally carrier free or NCA, and therefore isotopes of high specific activity are available from fission.

● ●Neutron capture or (n,Neutron capture or (n,γγ) reaction) reaction

● ●This is one of the most important reactions induced by thermal neutron in the This is one of the most important reactions induced by thermal neutron in the reactorreactor..

● ●In this reaction, the target nucleus captures one thermal neutron and emits rays to In this reaction, the target nucleus captures one thermal neutron and emits rays to produce an isotope of the same elementproduce an isotope of the same element..

● ●Since the target and the product nuclei belong to the same element, chemical Since the target and the product nuclei belong to the same element, chemical separation is obviously unnecessaryseparation is obviously unnecessary..

● ●Various useful radionuclides produced by this reaction are Various useful radionuclides produced by this reaction are 131131Te (which produces Te (which produces 131131I by I by ββ- - decaydecay), ), 9999Mo, Mo, 197197Hg, Hg, 5959Fe. These radionuclides are often neutron rich Fe. These radionuclides are often neutron rich and therefore, decay by and therefore, decay by ββ-- emission emission..

● ●Some examples of neutron capture reactions areSome examples of neutron capture reactions are9898Mo (n, Mo (n, γγ) ) 9999Mo, Mo, 196196Hg (n, Hg (n, γγ))197197Hg. Hg. 9999Mo is not carrier free or NCA type and Mo is not carrier free or NCA type and therefore has a low specific activitytherefore has a low specific activity..

Carrier : A stable element that is added in detectable quantities to a radionuclide of the same element, usually to facilitate chemical processing of the radionuclide .

Carrier-free: (1) Radionuclides produced with atomic numbers different from those of the target isotopes, do not contain any stable ( “cold” or “carrier”) isotope detectable by ordinary analytical methods .

)2 (A term used to indicate the absence of any stable atoms in a radionuclide sample .

No Carrier Added (NCA): A term used to characterize the state of a radioactive material to which no stable isotope of the compound has been added purposely .

Radionuclide productionRadionuclide production

Specific activitySpecific activity

● ●Defined as the radioactivity per unit mass of radionuclide, or Defined as the radioactivity per unit mass of radionuclide, or labeled compound, (radioactivity/mass, mCi/mg)labeled compound, (radioactivity/mass, mCi/mg)..

● In carrier-free radionuclide, the shorter the half-life, the higher the specific activity.

ProblemProblemWhat is the specific activity of carrier-free 111In (t1/2=67 hr) ?

Answer: In 1 mg 111In, the number of atoms N of 111In is

1 X 10-3 N=------------ X 6.02 x 1023

111 The decay constant λ of 111In is

0.693 λ = ------------------- sec-1

67 x 60 x 60 D = Nλ

0.693 x 10-3 x 6.02 x 1023

--------------------------------- =dps 67 x 60 x60 x 111

=1.56 x 1023 dps =4.22 x 105 mCi

Therefore, the specific activity of 111In is 4.22 x 105 mCi/mg or 1.56x104 GBq / mg .

● ●The specific activity of a carrier-free or NCA radionuclide can be calculated by The specific activity of a carrier-free or NCA radionuclide can be calculated by the following formulathe following formula..

Where Where AA is the mass number of the radionuclide is the mass number of the radionuclide

tt1/21/2 is the half-life in hours of the radionuclide is the half-life in hours of the radionuclide

2/1

91013.3)/(

tAmgmcitivityspecificac

●The specific activity of a radiopharmaceutical is very important information for a particular nuclear medicine test. This information is often provided on the label posted on the vial.

●Low specific activity radionuclide is of little use in some specified labeling procedures because the cold atoms ( non-radiative) will compete for the binding

sites of the reacting molecules ..

●High specific activity radionuclide can cause radiolysis in the solution of a compound, resulting in the breakdown of the compound into undesirable impurities.

Radiation measurementRadiation measurement::

)R (the roentgen for exposure: Is the amount of x or γ radiation that produces ionization of one electrostatic unit

of either positive or negative charge per cubic centimeter of air at 0 ºC and 760 mmHg .

)rad) radiation absorbed dose is a more universal unit, it is a measure of the energy deposited in unit mass of any material by any type of radiation. 1 rad = 10-2 J/kgIn SI units, the Gray (Gy) is the unit of radiation absorbed dose and is given by 1 Gy = 100 rad

)rem) Roentgen equivalent for man has been developed to account for the differences in effectiveness of different radiations in causing biological damage.

The dose of radiation which produces in man the effects of one rad.Rem = rad RBE or QFRBE is the relative biological effectiveness of the radiation.

In SI units, the dose equivalent is expressed in Sieverts which are defined as 1 Sievert (Sv) = 100 rem.

Roentegn:Roentegn:Unit for measuring amount of x or Unit for measuring amount of x or γγ rays in air. rays in air.

Rad:Rad:Unit for measuring absorbed energy from radiation.Unit for measuring absorbed energy from radiation.When a person is exposed to radiation, energy is deposited in the tissues of the body. The amount of energy deposited per unit of weight of human tissue is called the absorbed dose. Absorbed dose ismeasured using the conventional rad or the SI Gy.The rad, which stands for radiation absorbed dose, was the conventional unit of measurement, but it has been replaced by the Gy. One Gy is equal to 100 rad.Rem:Rem:Unit for measuring biological damage from radiattionUnit for measuring biological damage from radiattionMeasuring Biological RiskA person's biological risk (that is, the risk that a person will suffer health effects from an exposure to radiation) is measured using the conventional unit rem or the SI unit Sv.