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8/22/2019 Radiopharmaceuticals for Radioisotope Imaging
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8/22/2019 Radiopharmaceuticals for Radioisotope Imaging
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Nuclear imaging produces images of theNuclear imaging produces images of the
distribution of radionuclide in patients.distribution of radionuclide in patients.
Method of administration:Method of administration:
Injection (appropriate for organ)Injection (appropriate for organ)
How to determine distributionHow to determine distribution
Blood volume/flow/organ uptakeBlood volume/flow/organ uptakeWhat type of radionuclides?What type of radionuclides?
X-rays emittersX-rays emitters
-ray emitters-ray emitters
(charged particles are absorbed by body tissue)(charged particles are absorbed by body tissue)How to detect?How to detect?
Photon detectionPhoton detection
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There are several techniques for nuclear imaging:There are several techniques for nuclear imaging:
Static planar scintigraphy which providesStatic planar scintigraphy which provides two-dimensionaltwo-dimensional
representations of a three dimensional objectrepresentations of a three dimensional object by measuring theby measuring the
spatial distribution of the radioisotope in the body, (comparablespatial distribution of the radioisotope in the body, (comparable
to a plain X-ray projection).to a plain X-ray projection).
Dynamic planar scintigraphy which measures temporalDynamic planar scintigraphy which measures temporal
changes in the spatial distribution of the radioisotopes in thechanges in the spatial distribution of the radioisotopes in thebody, by takingbody, by taking multiple images over periods of time whichmultiple images over periods of time which
may vary from milliseconds to hours depending on themay vary from milliseconds to hours depending on the
timescale for the basic function of the organ to be examined.timescale for the basic function of the organ to be examined.
Single photon emission tomography (SPECT) or positronSingle photon emission tomography (SPECT) or positronemission tomography (PET)emission tomography (PET) which allows to form threewhich allows to form three
dimensional static or dynamic representations of the organ anddimensional static or dynamic representations of the organ and
organ functions by taking multiple images from differentorgan functions by taking multiple images from different
directions.directions.
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The great advantage of nuclear medicine is itsThe great advantage of nuclear medicine is its
ability to image qualitatively and quantitativelyability to image qualitatively and quantitatively
dynamic physiological processes of different bodydynamic physiological processes of different body
organs.organs.To highlight a particular organ the radioisotope must beTo highlight a particular organ the radioisotope must be
administered in the form of a chemical agentadministered in the form of a chemical agent
(radiopharmaceutical) which addresses preferably a particular(radiopharmaceutical) which addresses preferably a particular
organ (e.g. iodine in thyroid) or the physiological function of aorgan (e.g. iodine in thyroid) or the physiological function of a
particular organ (e.g. blood flow).particular organ (e.g. blood flow).
Therefore a radiopharmaceutical is typically made of twoTherefore a radiopharmaceutical is typically made of two
components, thecomponents, the radionuclide and the chemical compoundradionuclide and the chemical compound toto
which it is bound.which it is bound.
Since radiopharmaceuticals are used to study body functions,Since radiopharmaceuticals are used to study body functions,
it is important that they have no pharmacological orit is important that they have no pharmacological or
toxicological effects which may interfere with the organtoxicological effects which may interfere with the organ
function under study. Therefore the pharmaceutical isfunction under study. Therefore the pharmaceutical is
administered inadministered in extremely small amounts (10extremely small amounts (10-9-9 g).g).
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A number of factors is responsible for theA number of factors is responsible for the
ultimate distribution of the radioisotope:ultimate distribution of the radioisotope:
blood flowblood flow
(percent cardiac input/output of a specific organ)(percent cardiac input/output of a specific organ)
availability of compound to tissue, or the proportionavailability of compound to tissue, or the proportionof the tracer that is bound to proteins in the bloodof the tracer that is bound to proteins in the blood
basic shape, size, and solubility of molecule whichbasic shape, size, and solubility of molecule which
controls its diffusion capabilities through bodycontrols its diffusion capabilities through body
membranesmembranes
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The final fate of the radiotracer depends on how theThe final fate of the radiotracer depends on how the
addressed organ deals with the molecule, whether itaddressed organ deals with the molecule, whether it
is absorbed, broken down byis absorbed, broken down by intracellular chemicalintracellular chemical
processes or whether it exits from the cells and isprocesses or whether it exits from the cells and is
removed by kidney or liver processes. Theseremoved by kidney or liver processes. These
processes determine theprocesses determine the biological half-lifebiological half-life TTBBof theof the
radiopharmaceutical (half-liferadiopharmaceutical (half-life time to reducetime to reducematerial to 50% of its initial amount).material to 50% of its initial amount).
To design and administer a radiopharmaceutical withTo design and administer a radiopharmaceutical with
specific localizing properties all these functions as well asspecific localizing properties all these functions as well as
the choice of radionuclide has to be taken into account.the choice of radionuclide has to be taken into account.
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The choice of the appropriate radioisotope forThe choice of the appropriate radioisotope for
nuclear imaging is dictated by the physicalnuclear imaging is dictated by the physical
characteristics of the radioisotope:characteristics of the radioisotope:
a suitable physical half-life; long enough for monitoring thea suitable physical half-life; long enough for monitoring the
physiological organ functions to be studied, but not too long tophysiological organ functions to be studied, but not too long to
avoid long term radiation effectsavoid long term radiation effects
decay via photo emission (X-ray ordecay via photo emission (X-ray or-ray) to minimize absorption-ray) to minimize absorption
effects in body tissueeffects in body tissue
photon must have sufficient energy to penetrate body tissue withphoton must have sufficient energy to penetrate body tissue with
minimal attenuationminimal attenuation
but photon must have sufficiently low energy to be registeredbut photon must have sufficiently low energy to be registered
efficiently in detector and to allow the efficient use of leadefficiently in detector and to allow the efficient use of leadcollimator systems (must be absorbed in lead)collimator systems (must be absorbed in lead)
decay product (daughter) should have minimal short-lived activitydecay product (daughter) should have minimal short-lived activity
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The effective half-lifeThe effective half-life TTEEof a radiopharmaceutical is aof a radiopharmaceutical is a
combination of the physical half-lifecombination of the physical half-life TT1/21/2
and theand the
biological half-lifebiological half-life TTBB ::
The effective half-life of radiopharmaceuticalsThe effective half-life of radiopharmaceuticalscontaining a long lived radioisotope can be reducedcontaining a long lived radioisotope can be reduced
by choosing a chemical component with a shortby choosing a chemical component with a short
biological half-life.biological half-life.
A close matching of the effective half-life with theA close matching of the effective half-life with theduration of the study is important for dosimetricduration of the study is important for dosimetric
considerations. It also is important as far as theconsiderations. It also is important as far as the
availability and expense of the radiopharmaceutical isavailability and expense of the radiopharmaceutical is
concerned.concerned.
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Radioisotopes in common use are:Radioisotopes in common use are:9999TcTcmm (T(T1/21/2=6.02h, E=6.02h, E=140 keV) is used in more=140 keV) is used in more
than 70% of all medical applicationsthan 70% of all medical applications226226Ra (TRa (T1/21/2=1600 a, E=1600 a, E=186 keV) is an=186 keV) is an -emitter-emitter(('s are absorbed in body tissue), is used for's are absorbed in body tissue), is used for
highly localized studieshighly localized studies
6767Ga (TGa (T1/21/2
=78.3h, E=78.3h, E =93 keV, 185 keV, 300=93 keV, 185 keV, 300
keV) is often used as tumor localizing agentkeV) is often used as tumor localizing agent
(gallium citrate)(gallium citrate)123123I (TI (T1/21/2=13h, E=13h, E=159 keV) bonds good=159 keV) bonds good
with proteins and molecules that can bewith proteins and molecules that can be
iodinated. It has replacediodinated. It has replaced 131131I (TI (T1/21/2=6d, E=6d, E=364=364keV) because of the reduced radiationkeV) because of the reduced radiation
exposureexposure8181KrKrmm (T(T1/21/2=13s, E=13s, E=190 keV) is a very short-=190 keV) is a very short-
lived gas used to perform lung ventilationlived gas used to perform lung ventilation
studies, (short half-life limits its application)studies, (short half-life limits its application)
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Important forImportant for PETPET studies are neutron deficient isotopesstudies are neutron deficient isotopes
which decay by positron emission. Positrons annihilate withwhich decay by positron emission. Positrons annihilate with
electrons emitting two Eelectrons emitting two E=511 keV photons in opposite=511 keV photons in opposite
direction.direction.Currently used positron emitters are:Currently used positron emitters are:
6868Ga (TGa (T1/21/2=68 m, E=68 m, E= 511 keV)= 511 keV)
8282Rb (TRb (T1/21/2=1.3 m, E=1.3 m, E= 511 keV)= 511 keV)
1818F (TF (T1/21/2=110 m, E=110 m, E= 511 keV), (used in more than 80% of= 511 keV), (used in more than 80% ofall PET applications)all PET applications)
1313N (TN (T1/21/2=10 m, E=10 m, E= 511 keV)= 511 keV)
1111C (TC (T1/21/2=20.4 m, E=20.4 m, E= 511 keV)= 511 keV)
Most of the positron emitters are still being studied inMost of the positron emitters are still being studied in
terms of their applicability for diagnostic purposes.terms of their applicability for diagnostic purposes.
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The production of radioisotopes is expensive!The production of radioisotopes is expensive!
It is based on four different methods:It is based on four different methods:
nuclear fission (reactor breeding)nuclear fission (reactor breeding)
neutron activation processesneutron activation processes
charged particle induced reactionscharged particle induced reactions
radionuclide generator (chemical method)radionuclide generator (chemical method)
Each method provides useful isotopes withEach method provides useful isotopes with
differing characteristics for nuclear imaging.differing characteristics for nuclear imaging.
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Nuclear Fission: In nuclear fission, the nuclei of atoms are
split, causing energy to be released.
The atomic bomb and nuclear reactors work by fission. The
element uranium is the main fuel used to undergo nuclear
fission to produce energy since it has many favorable
properties. Uranium nuclei can be easily split by shooting
neutrons at them. Also, once a uranium nucleus is split,
multiple neutrons are released which are used to split otheruranium nuclei. This phenomenon is known as a chain
reaction.
http://library.thinkquest.org/3471/fission.htmlhttp://library.thinkquest.org/3471/abomb.htmlhttp://library.thinkquest.org/3471/abomb.htmlhttp://library.thinkquest.org/3471/fission.html8/22/2019 Radiopharmaceuticals for Radioisotope Imaging
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NUCLEAR FISSIONNUCLEAR FISSION takes place in the reactor coretakes place in the reactor core
and is induced by the slow neutron induced fissionand is induced by the slow neutron induced fission
(break-up) of(break-up) of235235U into medium mass nuclei.U into medium mass nuclei.
The most common radioisotopes produced by fission (withThe most common radioisotopes produced by fission (with
subsequent isotope separation based on different physicalsubsequent isotope separation based on different physical
and chemical methods) areand chemical methods) are 9999MoMo (which decays to(which decays to 9999TcTcmm),), 131131II,,
andand 133133XeXe!!
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NEUTRON ACTIVATIONNEUTRON ACTIVATION is based on captureis based on capture
reactions of thermal neutrons (produced in the reactorreactions of thermal neutrons (produced in the reactor
as consequence of the fission process) on stableas consequence of the fission process) on stable
isotopes which are positioned near the reactor core.isotopes which are positioned near the reactor core.
Examples for radioisotope production via neutron capture are:Examples for radioisotope production via neutron capture are:
9898Mo + nMo + n 9999Mo +Mo +
5050Cr + nCr + n 5151Cr +Cr +
3131P + nP + n 3232P +P +
3232S + nS + n 3232P + pP + pThe yieldThe yield NN
rr for the radioisotope production over thefor the radioisotope production over the
time periodtime period tt depends on the cross sectiondepends on the cross section [cm[cm22] of] of
the neutron capture process, the neutron-fluxthe neutron capture process, the neutron-flux [cm[cm-2-2ss--
11], the number of target nuclei], the number of target nuclei nnTT, and the decay, and the decay
constantconstant = ln2/T= ln2/T1/21/2
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The table shows several radioisotopes produced byThe table shows several radioisotopes produced by
neutron absorption.neutron absorption.
Disadvantage is that the produced radioisotope isDisadvantage is that the produced radioisotope is
typically an isotope of the target element, thereforetypically an isotope of the target element, therefore
chemical separation is not possible. This means that thechemical separation is not possible. This means that the
(n,(n,) produced radionuclide are not carrier-free.) produced radionuclide are not carrier-free.
1 barn = 10-24 cm2
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CHARGED PARTICLE INDUCED REACTIONSCHARGED PARTICLE INDUCED REACTIONS areare
based on the use of accelerators. Charged particlesbased on the use of accelerators. Charged particles
like protons, deuterons or alphas are accelerated tolike protons, deuterons or alphas are accelerated to
energies between 1 to 100 MeV and bombard a targetenergies between 1 to 100 MeV and bombard a targetmaterial.material.
The most used accelerator type is the cyclotron, whereThe most used accelerator type is the cyclotron, where
the charged particles are accelerated by oscillatingthe charged particles are accelerated by oscillating
accelerating potentials perpendicular to a deflectingaccelerating potentials perpendicular to a deflectingmagnetic field.magnetic field.
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Examples of typical reactions in the target are listed inExamples of typical reactions in the target are listed in
the tablethe table
The advantage of production via charge particleThe advantage of production via charge particle
interaction is the large difference in Z between theinteraction is the large difference in Z between the
target material and the radionuclide. That allows goodtarget material and the radionuclide. That allows good
physical and chemical separation procedures.physical and chemical separation procedures.
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RADIONUCLIDE GENERATORSRADIONUCLIDE GENERATORS allow to separate chemically short-allow to separate chemically short-
lived radioactive daughter nuclei with good characteristics for medicallived radioactive daughter nuclei with good characteristics for medical
imaging from long-lived radioactive parent nuclei. Typical techniquesimaging from long-lived radioactive parent nuclei. Typical techniques
used are chromatographic absorption, distillation or phase separation.used are chromatographic absorption, distillation or phase separation.
This method is in particular applied for the separation of the rather short-This method is in particular applied for the separation of the rather short-
livedlived 9999TcTcmm (T(T1/21/2=6 h) from the long lived=6 h) from the long lived9999Mo (TMo (T1/21/2=2.7 d).=2.7 d).
Applying the radioactive decay law the growth of activity of the daughterApplying the radioactive decay law the growth of activity of the daughter
nuclei Anuclei A22 with respect of the initial activity of the mother nucleuswith respect of the initial activity of the mother nucleus AA1100cancan
be expressed in terms of their respective decay constantsbe expressed in terms of their respective decay constants
22 andand
22 withwith
22 >>>> 11::
Milking cow analogy
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Radionuclide Generator system used to generate a radionuclide for routine
clinical practice. The most widely used generator system is the molybdenum99/technetium-99m generatoron which much of current routinenuclear imaging relies.
In this generator, the mother nuclide Mo-99 decays into the daughter nuclideTc-99m with a half life of2.7 days, which itself has a half life of6 hours(technetium (Tc) (I), Fig. 1).
Other generator systems have been built, among them a Sr-82/Rb82generator for PET imaging, with Rb82 having a half-life of2 minutes andbehaving like thallium Tl and a Rb-81/Kr81m generatorwhich yields a short-
lived (13 s) krypton Kr gas for ventilation studies. These generator systemsare so expensive that their clinical use is only feasible in centers with a verylarge patient throughput.
http://www.amershamhealth.com/medcyclopaedia/Volume%20I/radionuclide.htmlhttp://www.amershamhealth.com/medcyclopaedia/Volume%20I/nuclear%20imaging.htmlhttp://www.amershamhealth.com/medcyclopaedia/Volume%20I/half%20life.htmlhttp://www.amershamhealth.com/medcyclopaedia/Volume%20I/half%20life.htmlhttp://www.amershamhealth.com/medcyclopaedia/Volume%20I/nuclear%20imaging.htmlhttp://www.amershamhealth.com/medcyclopaedia/Volume%20I/radionuclide.html8/22/2019 Radiopharmaceuticals for Radioisotope Imaging
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In a generator such as the Mo-99/Tc-99m radionuclide generator in which the
half-life of the mother nuclide is much longer than that of the daughter nuclide,50% of equilibrium activity is reached within one daughter half-life,
75% within two daughter half-lives. Hence, removing the daughter nuclide from
the generator ("milking" the generator) is reasonably done every 6 hours or,
at most, twice daily in a Mo-99/Tc-99m generator.
Most commercial Mo-99/Tc-99m generators use column chromatography,
in which Mo-99 is adsorbed onto alumina. Pulling normal saline through the
column of immobilized Mo-99 elutes the soluble Tc-99m, resulting in a saline
solution containing the Tc-99m which is then added in an appropriate
concentration to the kits to be used. The useful life of a Mo-99/Tc-99m
generator is about 3 half lives or approximately one week. Hence, any clinicalnuclear medicine units purchase at least one such generator per week or order
several in a staggered fashion.
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The table lists typical generator produced radionuclide.The table lists typical generator produced radionuclide.