9. DIAGNOSTIC NUCLEAR MEDICINE 9.1. RADIOPHARMACEUTICALS FOR ...

Nuclear imaging produces images of the Nuclear 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 distributionBlood volume/flow/organ uptakeBlood volume/flow/organ uptake

What 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

There are several techniques for nuclear imaging:There are several techniques for nuclear imaging:

Static planar scintigraphy which provides Static planar scintigraphy which provides two-dimensional two-dimensional representations of a three dimensional objectrepresentations of a three dimensional object by measuring the by measuring the spatial distribution of the radioisotope in the body, (comparable spatial 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 temporal Dynamic planar scintigraphy which measures temporal changes in the spatial distribution of the radioisotopes in the changes in the spatial distribution of the radioisotopes in the body, by taking body, by taking multiple images over periods of time whichmultiple images over periods of time which may vary from milliseconds to hours depending on the may 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 positron Single photon emission tomography (SPECT) or positron emission tomography (PET)emission tomography (PET) which allows to form three which allows to form three dimensional static or dynamic representations of the organ and dimensional static or dynamic representations of the organ and organ functions by taking multiple images from different organ functions by taking multiple images from different directions.directions.

The great advantage of nuclear medicine is its The great advantage of nuclear medicine is its ability to image qualitatively and quantitatively ability to image qualitatively and quantitatively dynamic physiological processes of different body dynamic physiological processes of different body organs. organs.

To highlight a particular organ the radioisotope must be To highlight a particular organ the radioisotope must be administered in the form of a chemical agent administered 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 a organ (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 two Therefore a radiopharmaceutical is typically made of two components, the components, the radionuclide and the chemical compoundradionuclide and the chemical compound to to 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 or it is important that they have no pharmacological or toxicological effects which may interfere with the organ toxicological effects which may interfere with the organ function under study. Therefore the pharmaceutical is function under study. Therefore the pharmaceutical is administered in administered in extremely small amounts (10extremely small amounts (10-9-9 g). g).

A number of factors is responsible for the A 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 proportion availability of compound to tissue, or the proportion of the tracer that is bound to proteins in the blood of the tracer that is bound to proteins in the blood

basic shape, size, and solubility of molecule which basic shape, size, and solubility of molecule which controls its diffusion capabilities through bodycontrols its diffusion capabilities through bodymembranesmembranes

The final fate of the radiotracer depends on how the The final fate of the radiotracer depends on how the addressed organ deals with the molecule, whether it addressed organ deals with the molecule, whether it is absorbed, broken down by is absorbed, broken down by intracellular chemicalintracellular chemical processes or whether it exits from the cells and is processes or whether it exits from the cells and is removed by kidney or liver processes. These removed by kidney or liver processes. These processes determine the processes determine the biological half-life biological half-life TTBB of the of the

radiopharmaceutical (half-life radiopharmaceutical (half-life time to reduce time to reduce material to 50% of its initial amount).material to 50% of its initial amount).

To design and administer a radiopharmaceutical with To design and administer a radiopharmaceutical with specific localizing properties all these functions as well as specific 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.

The choice of the appropriate radioisotope for The choice of the appropriate radioisotope for nuclear imaging is dictated by the physical nuclear imaging is dictated by the physical characteristics of the radioisotope:characteristics of the radioisotope:

a suitable physical half-life; long enough for monitoring the a suitable physical half-life; long enough for monitoring the physiological organ functions to be studied, but not too long to physiological organ functions to be studied, but not too long to avoid long term radiation effects avoid long term radiation effects

decay via photo emission (X-ray or decay via photo emission (X-ray or -ray) to minimize absorption-ray) to minimize absorptioneffects in body tissue effects in body tissue

photon must have sufficient energy to penetrate body tissue withphoton must have sufficient energy to penetrate body tissue withminimal attenuationminimal attenuation

but photon must have sufficiently low energy to be registered but photon must have sufficiently low energy to be registered efficiently in detector and to allow the efficient use of lead efficiently in detector and to allow the efficient use of lead collimator 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

The effective half-life The effective half-life TTEE of a radiopharmaceutical is a of a radiopharmaceutical is a

combination of the physical half-life combination of the physical half-life TT1/21/2 and the and the

biological half-life biological half-life TTB B ::

The effective half-life of radiopharmaceuticals The effective half-life of radiopharmaceuticals containing a long lived radioisotope can be reduced containing a long lived radioisotope can be reduced by choosing a chemical component with a short by choosing a chemical component with a short biological half-life.biological half-life.

A close matching of the effective half-life with the A close matching of the effective half-life with the duration of the study is important for dosimetric duration of the study is important for dosimetric considerations. It also is important as far as the considerations. It also is important as far as the availability and expense of the radiopharmaceutical is availability and expense of the radiopharmaceutical is concerned.concerned.

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 applications than 70% of all medical applications 226226Ra (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 studies highly 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 agent keV) 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 be with proteins and molecules that can be iodinated. It has replaced iodinated. It has replaced 131131I (TI (T1/21/2=6d, =6d,

EE=364 keV) because of the reduced radiation =364 keV) because of the reduced radiation exposure exposure 8181KrKrmm (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 ventilation lived gas used to perform lung ventilation studies, (short half-life limits its application)studies, (short half-life limits its application)

Important for Important for PET PET studies are neutron deficient isotopes studies are neutron deficient isotopes which decay by positron emission. Positrons annihilate with which 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% of

all 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 in Most of the positron emitters are still being studied in terms of their applicability for diagnostic purposes.terms of their applicability for diagnostic purposes.

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 reactions charged particle induced reactions

radionuclide generator (chemical method) radionuclide generator (chemical method)

Each method provides useful isotopes with Each method provides useful isotopes with differing characteristics for nuclear imaging.differing characteristics for nuclear imaging.

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 other uranium nuclei. This phenomenon is known as a chain reaction.

NUCLEAR FISSIONNUCLEAR FISSION takes place in the reactor core takes place in the reactor core and is induced by the slow neutron induced fission and is induced by the slow neutron induced fission (break-up) of (break-up) of 235235U into medium mass nuclei. U into medium mass nuclei.

The most common radioisotopes produced by fission (with The most common radioisotopes produced by fission (with subsequent isotope separation based on different physical subsequent isotope separation based on different physical and chemical methods) are and chemical methods) are 9999MoMo (which decays to (which decays to 9999TcTcmm), ), 131131II, , and and 133133XeXe!!

NEUTRON ACTIVATIONNEUTRON ACTIVATION is based on capture is based on capture reactions of thermal neutrons (produced in the reactor reactions of thermal neutrons (produced in the reactor as consequence of the fission process) on stable as 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 + n Mo + n 9999Mo + Mo +

• 5050Cr + n Cr + n 5151Cr + Cr +

• 3131P + n P + n 3232P + P +

• 3232S + n S + n 3232P + pP + pThe yield The yield NNrr for the radioisotope production over the for the radioisotope production over the

time period time period tt depends on the cross section depends on the cross section [cm[cm22] of ] of the neutron capture process, the neutron-flux the 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

constant constant = ln2/T = ln2/T1/21/2

The table shows several radioisotopes produced by The table shows several radioisotopes produced by neutron absorption.neutron absorption.

Disadvantage is that the produced radioisotope is Disadvantage is that the produced radioisotope is typically an isotope of the target element, therefore typically an isotope of the target element, therefore chemical separation is not possible. This means that the chemical 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

CHARGED PARTICLE INDUCED REACTIONSCHARGED PARTICLE INDUCED REACTIONS are are based on the use of accelerators. Charged particles based on the use of accelerators. Charged particles like protons, deuterons or alphas are accelerated to like protons, deuterons or alphas are accelerated to energies between 1 to 100 MeV and bombard a target energies between 1 to 100 MeV and bombard a target material.material.

The most used accelerator type is the cyclotron, where The most used accelerator type is the cyclotron, where the charged particles are accelerated by oscillating the charged particles are accelerated by oscillating accelerating potentials perpendicular to a deflecting accelerating potentials perpendicular to a deflecting magnetic field.magnetic field.

Examples of typical reactions in the target are listed in Examples of typical reactions in the target are listed in the tablethe table

The advantage of production via charge particle The advantage of production via charge particle interaction is the large difference in Z between the interaction is the large difference in Z between the target material and the radionuclide. That allows good target material and the radionuclide. That allows good physical and chemical separation procedures.physical and chemical separation procedures.

RADIONUCLIDE GENERATORSRADIONUCLIDE GENERATORS allow to separate chemically short-allow to separate chemically short-lived radioactive daughter nuclei with good characteristics for medical lived radioactive daughter nuclei with good characteristics for medical imaging from long-lived radioactive parent nuclei. Typical techniques imaging 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-lived lived 9999TcTcmm (T (T1/21/2=6 h) from the long lived =6 h) from the long lived 9999Mo (TMo (T1/21/2=2.7 d).=2.7 d).

Applying the radioactive decay law the growth of activity of the daughter Applying the radioactive decay law the growth of activity of the daughter nuclei Anuclei A22 with respect of the initial activity of the mother nucleus with respect of the initial activity of the mother nucleus AA11

00 can can

be expressed in terms of their respective decay constants be expressed in terms of their respective decay constants 22 and and 22 with with

22 >> >> 11::

Milking cow analogy

Radionuclide Generator system used to generate a radionuclide for routine clinical practice. The most widely used generator system is the molybdenum-99/technetium-99m generator on which much of current routine nuclear imaging relies.

In this generator, the mother nuclide Mo-99 decays into the daughter nuclide Tc-99m with a half life of 2.7 days, which itself has a half life of 6 hours (technetium (Tc) (I), Fig. 1).

Other generator systems have been built, among them a Sr-82/Rb82 generator for PET imaging, with Rb82 having a half-life of 2 minutes and behaving like thallium Tl and a Rb-81/Kr81m generator which yields a short-lived (13 s) krypton Kr gas for ventilation studies. These generator systems are so expensive that their clinical use is only feasible in centers with a very large patient throughput.

In a generator such as the Mo-99/Tc-99m radionuclide generator in which thehalf-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 fromthe 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 clinical nuclear medicine units purchase at least one such generator per week or order several in a staggered fashion.

The table lists typical generator produced radionuclide.The table lists typical generator produced radionuclide.