Radiopharmaceuticals

• Nuclear pharmacy is a unique branch of

pharmacy services that focuses on the proper,
safe management and use of
radiopharmaceuticals.
• Radiopharmacy is the science which deals
with the preparation and dispensing of
radiopharmaceuticals
Introduction to Radio Pharmaceuticals
- Every atom of an element is compound of a nucleus
containing protons and neutrons surrounded by
electrons.
- In an electrically neutral atom, the number of
electron is equal to number of proton in the
nucleus and further the number of protons in the
nucleus is equal to the atomic number of the atom.
- This atomic number (Z) is always constant and is
characteristic of a particular element, e.g. carbon-6,
sodium-11 and is indicated in the following manner.
6C,11Na
- The mass number (A) is the total number of
protons and neutrons in the nucleus. Due to
the variation in the number of neutrons, the
atoms of a particular element can have
different mass numbers.
- Isotopes- those nuclides having same atomic
number but different mass numbers are called
isotopes and they vary in the number of
neutrons in the nucleus.
1
1H, 2
1H, 3
1H
- These are the three isotopes of hydrogen. Generally
isotopes can be categorized into following
1. Stable isotopes: Stable isotopes maintain their elemental
integrity and do not decompose to other isotopic and
elemental forms.
2. Unstable isotopes/radio active isotopes: Unstable or
radioactive isotopes decompose or decay by emission of
nuclear particles into other isotopes of the same or
different elements.
- Radio-active Decay whenever a radioactive isotopes
decays, it emits certain particles or quantities of energies
which is described as follows: Alpha particles, beta
particles and gamma radiation.
1. Alpha Particles:
- these particles are composed of two protons
and two neutrons and are identical to the
nucleus of a helium atom.
- They are heavy and positively charged.
- They are least penetrating, their range is
fraction of mm in body tissues.
- They are not used in pharmaceutical
preparations.
Beta particles:
• these particles are simply the electrons
emitted by the nucleus.
• They are negatively charged particles called
negatron.
• They have negligible mass but their energy
and velocity is very high.
• Beta particles have more penetrating power
than alpha particles.
Gamma radiation:
• this resembles X-rays as it is a photon of
electromagnetic radiation.
• It demonstrates both wave and particle properties.
• The rays are of short wavelength similar to X-rays
and travel at the speed of visible light.
• They have no mass and no charge but have high
energy giving them excellent penetrating power.
• In other words penetration power of gamma rays
is about 10,000 times more than the alpha
particles and 100 times more than the beta
particles.
Radio- active half life
- radio-active nuclei involves release of alpha, beta and gamma rays
depending upon the degree of instability of their nuclei.
- This process of disintegration of radio active nuclei is a continuous
process, and due to spontaneous decay, the activity of radio-active sample
diminishes with time.
- The rate of isotopic decay is dependent on the concentration of the radio-
active atoms present following first order kinetic which can be expressed
as.
-dA/dt=λA
Where
dA/dt= rate of change in the number of radio-active Nuclei.
λ = Probability of disintegration in unit time (decay constant).
A= Number of radio-active nuclei present at a particular time
The equation is integrated for a period of time
between t=0 and t=t, hours, it becomes
ln At-ln A0 = λt
At/A0= e-λt
At=A0 e-λt
Where
A0=Initial number of radio-active nuclei
At=Number of radio-active nuclei at time t
Half Life
When At=1/2 A0 and t=t1/2
Substituting these values in the above equation
At=A0 e-λt
1/2A0=A0e- λt1/2
Hence
ln ½=- λ t1/2
Multiplying by -1 on both sides
-ln ½= λ t1/2
-(ln1-ln2)= λ t1/2
Ln 2- ln 1 = λ t1/2
Ln 2/1= λ t1/2
Decay constant λ is given by
λ= ln 2/ t1/2
λ= 0.693/ t1/2
t1/2 =0.693/ λ
- Half life is defined as the time required for any
radio-active isotope to decay to one half of
the original value at any given point of time.
- It is denoted by t1/2.
- Half life of radio pharmaceutical must be
taken into consideration while calculating the
dose and rate of decay of radio
pharmaceutical.
 Radioactivity Units
• International Unit
– becquerel (Bq)
• U.S. Unit
– curie (Ci)

– 1 Ci = 37 GBq
– 1 mCi = 37 MBq
– 1 µCi = 37 kBq
 Radiation Exposure Units
• International Unit
– coulomb per kilogram (C/kg)
• U.S. Unit
– roentgen (R)
• defined only for measurement in air
• applies only to X and gamma rays up to energies of about
3 MeV

– 1 R = 2.58 x 10-4 C/kg

– 1 mR = 0.258 C/kg
– 1 µR = 258 C/kg
 Radiation Exposure Units
• Roentgen
– Historically used to measure the amount of
energy in a photon beam just prior to
entering the skin of a patient
– Often still used when discussing the
entrance skin exposure for medical x-ray
exams
 Radiation Absorbed Dose Units
• International Unit
– gray (Gy)
• U.S. Unit
– rad

– 1 rad = 0.01 Gy
– 1 mrad = 0.01 mGy
– 1 µrad = 0.01 µGy
 Radiation Absorbed Dose Units
• Radiation absorbed dose is the amount
of energy deposited per unit of tissue.

• It is usually measured in ergs per gram or

joules per kilogram.
- The fundamental unit of radio-activity is
curie(ci).
- It is defined as the amount of radio-active
substance which undergoes disintegration at the
rate of 3.7 x 1010 per second and this amounts to
1gm of radium which undergoes 3.7x10 10
disintegrations per second.
- Consequently sub units of curie like milli curie
and micro curie.
- They are the amounts of radio-active material in
which the number of disintegrations per second
are 3.7 x 10 7 and 3.7 x 10 4 respectively.
1. Roentgen: it is the unit of exposed dose and can
be measured directly. It is the quantity of X-rays
or gamma radiation that produces in 1 cm3 in air
1 roentgen(r)= 84x 10-7 joules/gramme (in air)
2. RAD. It is the unit of absorbed dose and RAD is
that quantity of radiation form any source that
delivers 100 x 10-7 joules of energy per gramme
of tissue or other specified medium.
1 RAD = 10-2 J/kg
The grey (GY), (1 joule per kg. equivalent to 100
RADS) had been assigned as the SI unit for
absorbed dose.
3. REM (Roentgen Equivalent Man)
Generally particular absorbed dose does not
produce same biological response, and energy
release patterns depends upon nature and energy
of incident radiation.
Hence for calculation of dose in REM, it is essential
to consider various factors like quality factor and
distribution factor.
Dose in REM= Dose in RADS x quality factor x
distribution factor
4. Becquerel (Bq): One disintegration per second
equivalent to 2.7x 10-11 Ci. Is the SI unit of activity.
Production of Radio- Pharmaceuticals
Artificial radio-nuclides are produced by following
methods:
1. Pile produced isotopes:
- Most of the radioactive materials today in
industry/research/medicine are prepared in a nuclear
pile (nuclear reactor).
- In this uranium fission reaction produces large supply
of neutrons. The neutrons in reactors are a mixture of
fast neutrons (high energy) and thermal neutrons.
- The thermal neutrons are obtained by passing the fast
neutrons through a moderator (either heavy water or
graphite).
 n γ Reaction: Target nuclei captures these
thermal neutron to yield a radioactive nucleus
in an excited state. The surplus energy is
emitted as γ-radiation as shown in example:

In a critical reactor, one neutron for each uranium atom undergoes

fission and other neutrons are used to produce plutonium by
interaction with 238 U nucleus. These neutrons are either lost or are
used to interact with specific target which have been inserted into
the pile and is called Neutron Activation.
Hence there are two main sources of radio-active substances from the
pile:
1. Radio-active material through Fission process
2. Radio-active material by Neutron activation
Neutron Activation:
- When simple neutron is captured or during
transmutation process, neutron activation
occurs as radio-active phosphorous 32 P can be
prepared form stable 31P by neutron capture.
2. Cyclotron Produced Isotopes:
- Certain radio-active isotopes are cyclotron
produced as they are deficient in neutrons
and normally can not be produced in nuclear
reactors. In this, they are obtained by
bombarding target nuclei with protons,
deuterons, alpha particles.
- Cyclotron consists of two flat semi-cylinders
called as “dees” placed in a very high vacuum
chamber, supplied with a high frequency
voltage.
- This vacuum chamber contains two magnets.
When charged particles are injected into the
centre of the dees, they are induced to follow
a spiral path towards circumference.
- Dees get accelerated to very high energies
10-20 Mev approx., which is used for
radioactive isotope production.
- The beam is deflected from the outermost
orbit to strike the target nuclei.
3. Radio-isotope Generators
- During diagnostic investigations, hazards to
patient can be reduced by using as isotopes with
short half life but it is difficult to supply such
isotopes.
- Such isotopes can be supplied in the form of long
lived parent that decays to the isotopes required.
- The parent nuclide is prepared in the form of a
suitable ion which is adsorbed on to an ion
exchange column resin or alumina.
- The whole assembly is known as “ radioisotope
generator ”.
Example: Technetium 99m (99mTc)
- 99mTc generator consist of column containing

alumina on which Molybdenum 99 is adsorbed

in the form of ammonium molybdate.
- Radioactive decay of 99Mo produces 99mTc
which is eluted from the column.
- This isotopes is used for brain, liver, and in
thyroid scanning as it is safer to use in the
body.
- It has a short half life and does not emit beta
radiation.
Measurement of radioactivity
- A Geiger counter (Geiger-Muller tube) is a device used
for the detection and measurement of all types of
radiation: alpha, beta and gamma radiation.
- Basically it consists of a pair of electrodes surrounded by
a gas.
- The electrodes have a high voltage across them.
- The gas used is usually Helium or Argon. When radiation
enters the tube it can ionize the gas.
- The ions (and electrons) are attracted to the electrodes
and an electric current is produced.
- A scaler counts the current pulses, and one obtains a
"count" whenever radiation ionizes the gas.
Liquid Scintillation Detector
• The liquid scintillation detector is the detector often
used by biologists.
• The detector is a liquid and the sample is placed in the
liquid.
• The liquid contains a substance that fluoresces when a
charged particle is slowed down (or absorbed) by it.
• The fluorescence that it emitted is in the visible light
region.
• Photo-multiplier tubes are placed around the liquid to
detect this emitted light.
• The detector is designed to detect mainly (or only) beta
particles.
Permissible radiation dose level
- Permissible radiation dose is the dose of
radiation which should not cause appreciable
body harm to an individual at any time during
his life.
- Their main aim is to prevent harmful effects
on gonads and the blood forming organs.
- Permissible dose for any age above 18 years is:
Maximum permissible dose= 5 (N-18)
N= Age of person in years.
This ensures that the dose to the gonads is not
more than 60 REMs by the age of 30.
To ensure the exposure below the maximum
permissible levels it is very important to
consider the following:
i dose rate (from the isotopes being used).
ii dose received (by the operator).
2. Dose received: there are various methods
which are used to measure the dose received
by the personnel handling these radio-
isotopes.
i Film badges: these badges contains small strip
of photographic paper which is clipped on to
the pocket.
The darkening of the film depends upon on the
amount of energy absorbed. The film is then
developed after a week/month and results are
compared with standard dose of radiation.
Pocket ionization chambers (dosimeters):
• These dosimeters are quartz fibre electroscopes
and they are always charged before use.
• Ionization caused by the radiation cause the
charge to leak away and the fibre gradually
moves back.
• Its image is then viewed by lenses.
• Whenever it exceeds the preset dose rate, there
is an audiable alarm which sounds immediately.
• Hence these instruments give immediate
indication of dose received particularly in case
of hazardous operations.
Radiation hazards and their prevention
- Then excitation plays little role as in case of U.V. rays
(excitation without ionisation) damage caused is less.
Although it is assured that the damage due to irradiation
is mixture of direct and indirect effect.
1.Direct radiation effects: it results from ionisation or
excitation with in a biological functional molecule and
probably will abolish its biological functions. In this
protein molecules get aggregated which leads loss of
solubility and some degree of fragmentation. DNA, RNA
and polysaccharide exhibit fragmentation and some
crosslinking occurs. This cross linking abolishes the
biological activity since it prevents the uncoiling of
closely coiled structure(DNA) and forms immobile
configuration.
2. Indirect radiation effects:
Damage caused by indirect radiation effects is
due to radiolysis of intracellular water which
comprises of about 80% of most cells and of
any extracellular water which may be present.
Action on water molecules leads to the
production of free radicals. This hydrogen
peroxide H2O2 is a powerful oxidizing agent
and the free radicals OH and HO2 are
responsible for radiation damage.
3. Effect on rate of cell division: all cells are prone to
radiation damage but the extent of damage varies
considerably. This can be observed as any defect will
be multiplied at each cell division. More the rate of
cell divisions, greater will be the observed damage.
4. Effect on human body: effect of radiation and
absorbed radio-active material on the entire body
depends on the proportion irradiated. It becomes
most severe if whole get exposed and least if only
small mass of a tissue such as hands or feet is
exposed. Further it depends upon the dose rate
because fractionation of a dose permit recovery to
occur.
Short term effect: when human body get exposed
to a dose of 25 REM, it may cause transient
change in WBC count, nausea etc, where as the
dose of about 100 REMs may lead to diarrhoea,
vomitng and 400REM is a median lethal dose.
This may lead to death within 30 days.
Long term effects: these effects are observed after
an exposure over long periods. They may
appear with in few months or even after 50
years. These effects include permanent skin
damage, bone necrosis, leukaemia, cataract,
anemia, etc.
5. Effects on skin: Persons receiving X-rays for a
prolong period showed damaging effects on skin
like loss of hair, dryness, brittleness. Even a short
time exposure of intense radiation is responsible
for erythema.
6. Genetic effects: Radiations can damage the
chromosomes and increase the frequency of gene
mutation. Damage to genetic makeup is
cumulative and irrepairable. These mutations are
always inherited from one generation to next and
are believed to be very harmful. Hence it is very
essential to avoid to minimize radiation during the
first years of life.
What does a Radiopharmacist do?
• The main responsibility of
the Radiopharmacist or Radiopharmaceutical
Scientist in nuclear medicine is the preparation
of radiopharmaceuticals to ensure their safety
and efficacy.
• Many radiopharmaceuticals are administered by
intravenous injection, so that preparation needs
to be performed under aseptic conditions.
• All radiopharmaceuticals are, by definition,
radioactive, so that radiation protection forms
an integral part of the job.
• Quality of the product is essential to the correct
interpretation of the results of the investigation, or the
delivery of the correct therapeutic dose, so that quality
assurance and quality control testing form an
important part of the responsibility.
• There is considerable scope for research and
development in the field of radiopharmaceutical
science.
• A major challenge is the development of new
radiopharmaceuticals, but there is still much work to
be done in examining the mechanisms of action of
established products, ways in which they interact with
patient medication, and methods of improving
performa.
What skills are required?
• A working knowledge of pharmaceutical
sciences including microbiology, chemistry,
physiology/pharmacology together with some
radiation physics provides the essential
academic background required of a
radiopharmacist or radio-pharmaceutical
scientist.
• In addition, practical skills in aseptic
manipulation, and in the safe handling of
radioactive products are required.
• A knowledge of analytical techniques
including chromatography, gel filtration and
electrophoresis is useful in relation to quality
control, and in research and development
activities.
• From the professional viewpoint, the practice
of radiopharmacy is highly regulated, and it is
necessary to be aware of proper procedures,
bearing in mind the dual nature of
radiopharmaceuticals as both medicines and
radioactive products.
• Isotopic labeling (or isotopic labelling) is a technique
used to track the passage of an isotope (an atom with a
detectable variation) through a reaction, metabolic
pathway, or cell.
• The reactant is 'labeled' by replacing specific atoms by
their isotope.
• The reactant is then allowed to undergo the reaction.
• The position of the isotopes in the products is measured
to determine the sequence the isotopic atom followed in
the reaction or the cell's metabolic pathway.
• The nuclides used in isotopic labeling may be stable
nuclides or radionuclides.
• In the latter case, the labeling is called radiolabeling.
• In isotopic labeling, there are multiple ways to
detect the presence of labeling isotopes; through
their mass, vibrational mode, or radioactive
decay. 
• Mass spectrometry detects the difference in an
isotope's mass, while infrared
spectroscopy detects the difference in the
isotope's vibrational modes. 
• Nuclear magnetic resonance detects atoms with
different gyromagnetic ratios.
• The radioactive decay can be detected through
an ionization chamber or autoradiographs of gels.
• An example of the use of isotopic labeling is the
study of phenol (C6H5OH) in water by replacing
common hydrogen (protium)
with deuterium (deuterium labeling).
• Upon adding phenol to deuterated water (water
containing D2O in addition to the usual H2O), the
substitution of deuterium for the hydrogen is
observed in phenol'shydroxyl group (resulting in
C6H5OD), indicating that phenol readily undergoes
hydrogen-exchange reactions with water.
• Only the hydroxyl group was affected, indicating
that the other 5 hydrogen atoms did not
participate in these exchange reactions.
Isotope labeling measuring techniques
• Any technique in measuring the difference
between isotopomers can be used.
• The two primary methods, nuclear magnetic
resonance (NMR) and mass
spectrometry(MS), have been developed for
measuring mass isotopomers in stable isotope
labeling.
• Proton NMR was the first technique used
for C-labeling experiments. .
• Using this method, each single protonated carbon
position inside a particular metabolite pool can be
observed separately from the other positions.
• This allows the percentage of isotopomers labeled at
that specific position to be known.
• The limit to proton NMR is that if there are n carbon
atoms in a metabolite, there can only be at
most n different positional enrichment values, which is
only a small fraction of the total isotopomer
information.
• Although the use of proton NMR labeling is limiting,
pure proton NMR experiments are much easier to
evaluate than experiments with more isotopomer
information
• Stable isotope labeling involves the use of non-
radioactive isotopes that can act as a tracers used to model
several chemical and biochemical systems.
• The chosen isotope can act as a label on that compound that can
be identified through nuclear magnetic resonance(NMR)
and mass spectrometry(MS).
• Some of the most common stable isotopes are 2H, 13C, and 15N,
which can further be produced into NMR solvents, amino
acids, nucleic acids, lipids, common metabolites and cell
growth media. 
• The compounds produced using stable isotopes are either
specified by the percentage of labeled isotopes (i.e. 30%
uniformly labeled 13C glucose contains a mixture that is 30%
labeled with 13 carbon isotope and 70% naturally labeled carbon)
or by the specifically labeled carbon positions on the compound
(i.e. 1-13C glucose which is labeled at the first carbon position of
glucose).
• Radioisotopic labeling
• Radioisotopic labeling is a technique for tracking the
passage of a sample of substance through a system.
The substance is "labeled" by
including radionuclides in its chemical composition.
• When these decay, their presence can be determined
by detecting the radiation emitted by them.
• Radioisotopic labeling is a special case of isotopic
labeling.
• For these purposes, a particularly useful type of
radioactive decay is positron emission. When a
positron collides with an electron, it releases two
high-energy photons traveling in diametrically
opposite directions.
• If the positron is produced within a solid
object, it is likely to do this before traveling
more than a millimeter. If both of these
photons can be detected, the location of the
decay event can be determined very precisely.
• Radioisotopic labeling includes only cases
where radioactivity is artificially introduced by
experimenters, but some natural phenomena
allow similar analysis to be performed.