Radiopharmaceuticals

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Radiopharmaceuticals

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Definition of a Radiopharmaceutical

• A radiopharmaceutical is a radioactive compound
  used for the diagnosis and therapeutic treatment
  of human diseases.
• In nuclear medicine nearly 95 of the
  radiopharmaceuticals are used for diagnostic
  purposes, while the rest are used for therapeutic
  treatment.
• Radiopharmaceuticals usually have minimal
  pharmacologic effect, because in most cases they
  are used in tracer quantities.
• Therapeutic radiopharmaceuticals can cause tissue
  damage by radiation.

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Definition of a Radiopharmaceutical

• Because they are administered to humans, they
  should be sterile and pyrogen free, and should
  undergo all quality control measures required of
  a conventional drug.
• A radiopharmaceutical may be a radioactive
  element such as 133Xe, or a labeled compound such
  as 131I-iodinated proteins and 99mTc-labeled
  compounds.

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Definition of a Radiopharmaceutical

• Although the term radiopharmaceutical is most
  commonly used, other terms such as radiotracer,
  radiodiagnostic agent, and tracer have been used
  by various groups.
• We shall use the term radiopharmaceutical
  throughout, although the term tracer will be used
  occasionally.

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Definition of a Radiopharmaceutical

• Another point of interest is the deference
  between radiochemicals and radiopharmaceuticals.
• The former are not usable for administration to
  humans due to the possible lack of sterility and
  nonpyrogenicity.
• On the other hand, radiopharmaceuticals are
  sterile and nonpyrogenic and can be administered
  safely to humans.

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Definition of a Radiopharmaceutical

• A radiopharmaceutical has two components
• a radionuclide and a pharmaceutical.
• The usefulness of a radiopharmaceutical is
  dictated by the characteristics of these two
  components.
• In designing a radiopharmaceutical, a
  pharmaceutical is first chosen on the basis of
  its preferential localization in a given organ or
  its participation in the physiologic function of
  the organ.

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Definition of a Radiopharmaceutical

• Then a suitable radionuclide is tagged onto the
  chosen pharmaceutical such that after
  administration of the radiopharmaceutical,
  radiations emitted from it are detected by a
  radiation detector.
• Thus, the morphologic structure or the
  physiologic function of the organ can be
  assessed. The pharmaceutical of choice should be
  safe and nontoxic for human administration.

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Definition of a Radiopharmaceutical

• Radiations from the radionuclide of choice should
  be easily detected by nuclear instruments, and
  the radiation dose to the patient should be
  minimal.

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Ideal Radiopharmaceutical
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Ideal Radiopharmaceutical

• Since radiopharmaceuticals are administered to
  humans, and because there are several limitations
  on the detection of radiations by currently
  available instruments, radiopharmaceuticals
  should possess some important characteristics.
• The ideal characteristics for radiopharmaceuticals
  are

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Ideal radiopharmaceutical

• Easy availability
• Short effective Half-Life
• Minimal Particle Emission
• Decay by Electron Capture or Isomeric Transition
• High Target-to Non target Activity Ratio

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Ideal Radiopharmaceutical

• 1. Easy Availability
• The radiopharmaceutical should be easily
  produced, inexpensive, and readily available in
  any nuclear medicine facility
• Complicated methods of production of
  radionuclides or labeled compounds increase the
  cost of the radiopharmaceutical.
• The geographic distance between the user and the
  supplier also limits the availability of
  short-lived radiopharmaceuticals.

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Ideal Radiopharmaceutical

• 2. Short Effective Half-Life
• A radionuclide decays with a definite half-life,
  which is called the physical half-life, denoted
  Tp (or t1/2).
• The physical half-life is independent of any
  physicochemical condition and is characteristic
  for a given radionuclide

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Ideal Radiopharmaceutical

• 2. Short Effective Half-Life (cont,..)
• Radiopharmaceuticals administered to humans
  disappear from the biological system through
  fecal or urinary excretion, perspiration, or
  other mechanisms.
• This biologic disappearance of a
  radiopharmaceutical follows an exponential law
  similar to that of radionuclide decay.
• Thus, every radiopharmaceutical has a biologic
  half-life (Tb).
• It is the time needed for half of the
  radiopharmaceutical to disappear from the
  biologic system and therefore is related to a
  decay constant, 0.693/Tb.

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Ideal Radiopharmaceutical

• 2. Short Effective Half-Life (cont,..)
• Obviously, in any biologic system, the loss of a
  radiopharmaceutical is due to both the physical
  decay of the radionuclide and the biologic
  elimination of the radiopharmaceutical.

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Ideal Radiopharmaceutical

• 2. Short Effective Half-Life (cont,..)
• The net or eective rate (le) of the loss of
  radioactivity is then related to the physical
  decay constant lp and the biologic decay constant
  lb. Mathematically, this is expressed as
• ?e ?p ? ?b
• Since ? 0.693/t1/2, it follows that
• 1/Te 1/Tp ?1/Tb
• OR
• Te ( Tp X Tb) / ( Tp ? Tb )

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• Problem
• The physical half-life of 111In is 67 hr and the
  biologic half-life of 111In-DTPA
• used for measurement of the glomerular filtration
  rate is 1.5 hr. What is the effective half-life
  of 111In-DTPA?
• Answer
• Using Eq. Te ( Tp X Tb) / ( Tp ? Tb )
• Te 1.46 h

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Particle Emission
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High Target-to-Non target Activity Ratio
For any diagnostic study, it is desirable that
the radiopharmaceutical be localized
preferentially in the organ under study since the
activity from nontarget areas can obscure the
structural details of the picture of the target
organ. Therefore, the target-to-non target
activity ratio should be large. An ideal
radiopharmaceutical should have all the above
characteristics to provide maximum efficacy in
the diagnosis of diseases and a minimum radiation
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Radiopharmaceuticals

• Radioactive element - 133Xe
• Labeled compounds - 131I iodinated proteins
• 99mTc labeled compounds
• 18FFDG

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Production of Radionuclides

• Reactor-Produced Radionuclides
• Cyclotron-Produced Radionuclides

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Reactor-Produced Radionuclides

• Iodine-131
• Molybdenum-99

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Iodine-131

• I-131 decays with a half-life of 8.02 days with
  beta minus and gamma emissions. This nuclide of
  iodine has 78neutrons in its nucleus, while the
  only stable nuclide, 127I, has 74. On decaying,
  131I most often (89 of the time) expends its 971
  keV of decay energy by transforming into the
  stable 131Xe (Xenon) in two steps, with gamma
  decay following rapidly after beta decay
• 606 keV
• 364 keV

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Molybdenum-99

• 99Mo can be obtained by the neutron activation
  (n,? reaction) of 98Mo in a high neutron
  flux reactor. However, the most frequently used
  method is through fission of uranium-235 in
  a nuclear reactor. While most reactors currently
  engaged in 99Mo production use highly enriched
  Uranium-235 targets

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Molybdenum-99

• 99Mo has a half-life of 66 hours1 and can be
  easily transported over long distances to
  hospitals where its decay product technetium-99m
  (with a half-life of only 6 hours, inconvenient
  for transport) is extracted and used for a
  variety ofnuclear medicine diagnostic procedures,
  where its short half-life is very useful.

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Technetium-99m

• Technetium-99m is a metastable nuclear
  isomer of technetium-99, symbolized as 99mTc,
  that is used in tens of thosunds of medical
  diagnostic procedures annually, making it the
  most commonly used medical radioisotope.

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Technetium-99m

• Technetium-99m when used as a radioactive
  tracer can be detected in the body by medical
  equipment (gamma cameras). It is well suited to
  the role because it emits readily detectable
  140 keV gamma rays

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• The "short" physical half-life (6h)of the isotope
  and its biological half-life of 1 day (in terms
  of human activity and metabolism) allows for
  scanning procedures which collect data rapidly
  but keep total patient radiation exposure low.
  The same characteristics make the isotope
  suitable only for diagnostic but never
  therapeutic use.

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Cyclotron-Produced Radionuclides

• . Fluorine-18 is used primarily to label glucose
  to give 18F-labeled fluorodeoxyglucose (FDG) for
• myocardial and cerebral metabolic studies. It is
  also used to label many
• potential ligands for a variety of tumors and
  recently approved by the U.S.
• Food and Drug Administration (FDA) for bone
  imaging

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Fluorine-18

• Fluorine-18 (t12) 110 min is commonly produced
  by the 18O(p n)F18
• reaction on a pressurized 18O-water target

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Fluorine-18
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Iodine-123

• Iodine-123 is very useful in nuclear medicine
  because it has good radiation
• characteristics such as decay by electron
  capture, half-life of 13.2 hr and gamma ray
• emission of 159 keV. It is produced directly or
  indirectly in a cyclotron
• by several nuclear reactions.

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• Another important method of producing pure 123I
  is by the 124Xe(p 2n) 123Cs reaction, in which
  case 123Cs(t0.55.9 min) decays to 123Xe. The
• 124Xe gas is contained under pressure in a
  chamber and the chamber is irradiated with
  protons. Sufficient time is allowed for 123Cs to
  decay completely to 123Xe, which is then decays
  with a half-life of 2.1 hr to produce 123I.
• Iodine-123 decays by electron capture, half-life
  of 13.2 hr and gamma ray emission of 159 keV.

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Kinetics of radioactive decay
Radioactive decay equations
Decay rate - Is the time rate at which atoms
undergo radioactive disintegration. -
Radionuclides are unstable and decay by particle
emission, electron capture or gamma ray
emission. - The decay of radionuclides is a
random process. i.e. one cannot tell which atom
from a group of atoms will decay at a specific
time. - The average number of radionuclides
disintegrating during a period of time. The
number of disintegrations/unit time
disintegration rate.
-dN/dt -dN The change in the
number of atoms, N. dt The change in the
time, t.
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? Radioactive decay is a first order process-
dN/dt of radionuclide at any time is proportional
to the total number of radionuclides present at
thet time.- dN/dt (D) ?N where N is the
number of radionuclides and ? is a decay constant
that is defined as the probability of
disintegration per unit time for a single
radionuclide. - dN/dt (D) ?radioactivity or
simply the activity of a radionuclide.
Rearrange Where N0 and Nt are the number of
radionuclides present at t 0 and time t,
respectively.
"e" is the base of natural logarithm 2.71828
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? If we remember the basic equation relating
activity to number of nuclei in a sample, A?N,
then we can write
Plot of radioactivity versus time on a linear
graph. The time is plotted in units of half-life.
Plot of the data in the previous figure on a semi
logarithmic graph, showing a straight-line
relationship.
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From the knowledge of the decay constant and
radioactivity of a radionuclide, D?N we can
calculate the total number of atoms or the total
mass of radionuclide present using Avogadros
number, 1gram-atom 6.02 1023 atoms.
Units of radioactivity Radioactivity is
expressed in units called curies. 1 curie (Ci)
3.7 1010 disintegration per second (dps) 1
millicurie (mCi) 3.7 107 disintegration per
second (dps) 1 microcurie (µCi) 3.7 104
dps The other unit for radioactivity is becquerel
(Bq) which is defined as one disintegration per
second. Thus 1 becquerel (Bq) 1 dps 2.7
10-11 Ci 1 megabecquerel (MBq) 106 dps 2.7
10-5 Ci Similarly, 1mCi 3.7 107 Bq 37 MBq
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Half-life and mean lifeEvery radionuclide is
characterized by a half-life, which is defined as
the time required to reduce its initial
disintegration rate or activity to one-half.It
is usually donated by t1/2 and is unique for a
given radionuclide. The decay constant ? of a
radionuclide is related to half-life by
Another relevant quantity of a radionuclide is
its mean life, which is the average life of a
group of the radionuclides. It is donated by t
and related to decay constant ? and half-life
t1/2 as follows
In one mean life, the activity of radionuclide is
reduced to 37 of the initial value.
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The physical half-life of 131I is 8.0 days.A. A
sample of 131I has a mass of 100 µg. How many
131I atoms are present in the sample?Number of
atoms N 4.6 1017atomsB. How many 131 I
atoms remain after 20 days have elapsed?Nt
N0e-(?t) (4.6 1017 atoms)e-(0.693/8 d)(20
d) 8.1 1016 atomsC. What is the activity of
the sample after 20 days?A or D ?N
(0.693/8.0 d)(1/86400 s/d)(8.1 1016 atoms)
8.2 1010 atoms/sec 8.2 104 MBq
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D. What activity should be ordered at 8 AM Monday
to provide an activity of 8.2 104 MBq at 8 AM
on the following Friday?Elapsed time 4 daysAt
A0e-?t8.2 104 MBq A0e-(0.693/8d)(4d)8.2
104 MBq A0(0.7072)A0 11.6 104 MBq must be
ordered
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ProblemCalculate the total number of atoms and
total mass of 131I present in 5 mCi (185 MBq)
131I (t1/2 8 days).Answer? for 131I
D 5 3.7 107 1.85 108 dps Using the
equation
Since 1 g. atom 131I 131 g 131I 6.02 1023
atoms of 131I (Avogadros number), Mass of 131I
in 5 mCi (185 MBq)
40.3 10-9 g

40.3 ng Therefore, 5 mCi 131I contains 1.85
1014 atoms and 40.3 ng 131I.
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Important Factors in Labeling

• Shelf Life
• A labeled compound has a shelf life during which
  it can be used safely for its intended purpose.
• The loss of efficacy of a labeled compound over a
  period of time may result from radiolysis and
  depends on the physical half-life of the
  radionuclide, the solvent, any additive, the
  labeled molecule, the nature of emitted
  radiations, and the nature of the chemical bond
  between the radionuclide and the molecule.
• Usually a period of three physical half-lives or
  a maximum of 6 months is suggested as the limit
  for the shelf life of a labeled compound.
• The shelf-life of 99mTc-labeled compounds varies
  between 0.5 and 18 hr, the most common value
  being 6 hr.