radiopharmaceuticals for radioisotope imaging

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.html


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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.html


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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.

radiopharmaceuticals for radioisotope imaging

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