 Radiopharmaceutical : A Chemical

compound tagged with a radionuclide

and prepared in a form suitable for
human use in known as
radiopharmaceutical.
 Design consideration for a
Radiopharmaceutical :
Radiopharmaceutical consist of a
radionuclide and a biochemical, two
consideration apply in designing or
developing a radiopharmaceutical, one
relating to the radionuclide and the
other relating to the biochemical.
 Selection of a Radionuclide : The choice of
radionuclide for imaging purpose is chiefly
dictated by the necessity of minimizing the
radiation dose to the patient and the
detection characteristic of present day
nuclear medicine instrumentation.
 Physical half life of the radionuclide should
be about 0.693x T obs.
 Where T obs is the time interval between the
time of administration of radionuclide and
the time at which measurement or imaging
is to be performed.
 Technetium 99m , with its 6 hour half life
and 140-KeV λ-ray emission.
 Selection of a Chemical : Beside being
nontoxic in the desired amounts , the
choice of the biochemical or
pharmaceutical substance in a
radiopharmaceutical is dictated by the
requirement that it be distributed or
localized in the desired organ or
compartment and that the uptake by that
organ in a normal condition differs
substantially from uptake in a pathologic
condition.
 Three important determinants in this regard
are route of administration , blood flow to
the organ or tissues and extraction by the
tissues.
 Development of Radiopharmaceutical :
When appropriate radionuclides and
chemical have been selected ,the
following steps are involved in the eventual
development of radiopharmaceutical.
 Chemical studies
 Animal distribution and toxicity studies
 Human or clinical studies
 Chemical Studies : Are aimed to
establishing the best method of
radiolabeling the chemical defining
optimum condition of labeling and in Vitro
stability and determining the nature and
the extent of the radiochemical impurities.
 Animal distribution and toxicity studies : The
main purpose of these studies is to determine
biodistribution of labeled material and establish
safe amounts (Radioactivity mainly as the mass
of the chemical used is in trace amount ) of
the radiochemical that can be administered to
humans without subjecting them to under risk.
 Human Or Clinical studies : Human r clinical
studies are performed as an investigational
new drug under a notice of claimed
exemption to the FDA.
 Once these data are collected , a new drug
application is submitted to the FDA.
 Which must appropriate it before its chemical
use.
 Quality Control of a Radiopharmaceutical :
 Because all radiopharmaceutical are
intended eventually for human use , Strict
quality control is very important .
 To ensure optimum quality the following
properties of radiochemical must be
considered.
 Radionuclide purity
 Radiochemical purity
 Chemical purity
 Sterility
 Apyrogenicity
 Radionuclide Purity : Ideally the
radiopharmaceutical should contain
only the desired radionuclide.
 The most common method of
determining the nature and extent of
radionuclide impurity is with gamma
spectroscopy using a Nal (TI) or Ge (Li)
detector.
 Radiochemical Purity : A common
method for the detecting for
radiochemical impurities is thin layer or
paper chromatography.
 Chemical Purity : A radiopharmaceutical
should contain only the desired chemical.
 In the final preparation of the
radiopharmaceutical , there may be a
number of chemicals involved besides the
radiochemical of interest.
 These chemical should be compatible with
each other in Vitro and safe for the patient.
 In addition, these must not distort the in Vivo
function for the main chemical.
 Aluminum break through in a 99Mo – 99m
Tc generator is an example of potential
chemical impurity.
 Sterility :
 A radiopharmaceutical should be sterile
(i.e. free from any microbial contamination
) and therefore should be tested to this
effect before use in patients.
 In the case of radiopharmaceutical labeled
with short lived radionuclide (99m Tc and
113m In ) ,

 Where prior testing of the final product is

not feasible , the sterility of the labeling
technique should be tested adequately
and periodically.
 Apyrogenicity :
 Even if the preparation is sterile ,it may
still contain pyrogens that , when
intravenously administered to a patient ,
may cause reaction.
 LABELING of Radiopharmaceuticals with
Technetium – 99m :
 Because of very attractive physical
characteristic 99m Tc a variety of chemical
have been labeled with this radionuclide.
 Technetium 99m in the form of sodium
pertechnetate (Na 99m TcO4 ) is easily
obtained in the laboratory from a 99m Mo –
99m Tc generator.
 The labeling most chemicals by 99m Tc is
achieved by first reducing the
pertechnetate t ionic technetium (mostly
Tc4+ ) and then complexing it with the
desired chemical.
 The common agent used for reducing
purpose is stannous chloride (SnCl2).
 Because the half life of 99m Tc is short
(6hours) ,most labeling has to be
performed “in –house”.
 This is greatly simplified by the use sterile
and pyrogen –free kits ,in which all the
desired chemicals are premixed and
held together in a lyophilized state under
an inert atmosphere (nitrogen gas ),
except radionuclide(hence ,quite often
referred as “ cold kit ”) .
 To labeled a particular chemical
compound , it is necessary only to
introduce a known amount of sterile and
pyrogen free sodium 99m Tc
pertechnetate into the kit vital .
 The labeled compound is ready to use
with in a few minutes.
 Three parameters
 labeling efficiency
 In Vitro stability
 In Vivo stability are important
consideration in the selection of “Kit.
 Most “Kits currently use in nuclear medicine
, labeled efficiencies under optimum
conditions are in excess of 90%.
 The remainder of the radioactivity (which is
not tagged to the desired compound) is
present as radiochemical impurity .
 Vitro Stability : A labeled compound
determines the time it can be stored n the
shelf without significant deterioration.
 A high in vitro stability allows the
compound to be labeled once and then
used in a number of patients at different
times of the day.
 Vivo Stability : A labeled compound
determines how closely the distribution of
radiolabeled compound in the
biological system parallels that of the
unlabeled compound.
 In vivo stability made inside the body.
 The distribution of a labeled compound
should be similar to the unlabeled
compound at least for the duration of
the study.
 Technetium 99m labeled
Radiopharmaceutical :
 The distribution and use of the most
common technetium – labeled
compounds in nuclear medicine are
described below .
 Most of these compound can be easily
and rapidly prepared from the
commercially available kits.
 Technetium-99m Pertechnetate (99m TcO- 4)
 Technetium-99m-Labeled Sulfur Colloid
 Technetium-99m-Labeled Macroaggregated Albumin (
99m Tc MAA)
 Technetium-99m- Labeled Polyphosphate ,
Pyrophosphate , and Diphosphonate
 Technetium-99m-Labeled Human Serum Albumin
 Technetium-99m-labeled Red Cells
 Technetium-99m-labeled 2,3-Dimercaptosuccinic Acid
(DMSA)
 Technetium-99m-labeled Diethylenetriamine Pentaacetic
Acid( DTPA )
 Technetium-99m-labeled Glucoheptonate
 Technetium-99m-labeled Mertiatide ( MAG3 )
 Technetium-99m-labeled 2,6-Dimethyl Acetanilide
Iminodiacetic Acid ( HIDA) and related Compounds
(Diethyl-IDA,PIPIDA, and , DISIDA )
 Technetium-99m-labeled Sestamibi (
Cardiolite)
 Technetium-99m-labeled Teboroxime (Cardiolitec )
 Technetium-99m-labeled Tetrofosmin (
Myoview)
 Technetium-99m-labeled Brain imaging agents (
Exametazime [ Ceretec ] , Hexamethylproppyleneamine
Oxime [ HMPAO] , and Ethyl Cysteinate Dimer[
ECD])
 Technetium-99m-labeled Pertechnetate : This
radiopharmaceutical is obtained directly
from the 99Mo- 99m Tc generator using
saline as the eluting solution.
 In Biological system its behave similarly
to iodine.
 It is administrated oral , Intravenous .
 The stomach which is major organ of
uptake contains 20% to 25 % of the
injected dosage at 4 hours.
 Technetium 99m pertechnetate is
presently used for :
 Thyroid gland
 Salivary gland
 And stomach imaging
 Technetium-99m labeled Sulfur Colloid :
 This radiopharmaceutical is easily prepared
using commercially available kits.
 Colloids In generally removed from the
blood stream by the reticloendothelial RE
cells of the body.
 The relative distribution of the colloids
among the RE cells of the various organs
depends on factors such as the size , nature
and amount of colloidal particles : blood
supply to the organ and other
pathophysiological consideration.
 This agent is used for liver , spleen , and
bone marrow imaging.
 Technetium-99m labeled
Macroaggregated Albumin ( 99m Tc
MAA ) : This Radiopharmaceutical
primarily used in lung imaging.
 Within a few seconds after IV
administration of 99m Tc MAA ,90% to 95
% of the injected dosage is trapped in
the capillary bed of the lungs.
 The biological half life of 99m Tc in the
lungs is about 8 to 12 hours.
 Technetium-99m- Labeled
Polyphosphate , Pyrophosphate , and
Diphosphonate : This
radiopharmaceutical primary used for
bone imaging.
 After IV injection is about 50 % to 60% of
the injected dosage is localized in the
skeleton within 15 to 20 minutes.
 Use of 99m Tc pyrophosphate and 99m
Tc Diphosphonate for the detection of
myocardial infarction is now well
established.
 Technetium-99m-Labeled Human Serum
Albumin : This radiopharmaceutical is
used for blood pool imaging such as :
heart or placenta.
 After Intravenous administrated it is
retained in the plasma for long period of
time.
 99m Tc labeled albumin is not stable in
vivo as albumin labeled with radioiodine
or radiochromium.
 Therefore it is not preferred agent for
plasma volume determination.
 Technetium-99m-labeled Red Cells :
labeling of red cells with radionuclides ,in
general is a complex and time consuming
procedure.
 Simple and expeditious method has been
developed to label red cells in vivo
with99mTc.
 99m Tc labeled albumin for blood pool
scanning , particularly for the heart.
 Damaged red cells are used to imaging
the spleen ,without interference from the
liver ,which is the case when sulfur or other
colloids are used to image the spleen.
 Technetium-99m-labeled 2,3-
Dimercaptosuccinic Acid (DMSA) : This
radiopharmaceutical is the agent of choice
when morphology of the renal cortex is of
interest.
 After IV administration this
radiopharmaceutical is quickly mixed with
plasma volume from where it is cleared with
a half life time of about 1 hour.
 By 2 hour between 40% and 50 % of the
injected dosage is taken up by the renal
cortex and about 15% is excreted in urine.
 Because of rapid in vitro decomposition
of 99m Tc- labeled DMSA.
 It should be stored in a refrigerator and
used within half an hour of labeling.
 Technetium-99m-labeled
Diethylenetriamine Pentaacetic Acid(
DTPA ) : This radiopharmaceutical is used
for Kidney imaging.
 After IV administration 99m Tc DTPA is
rapidly cleared by the kidneys.
 The biological half life in plasma of DTPA
chelates in humans is about 15minutes.
 Technetium-99m-labeled Glucoheptonate :
 This pharmaceutical used for renal
imaging.
 Another use of radiopharmaceutical is in
detection of myocardial infarction at an
early stage (with in 2 to 3 days post
infarction ) .
 Biological behavior of this
radiopharmaceutical is somewhere
between that of 99m Tc DTPA and 99m Tc
DMSA.
 It is clearance from plasma is slower than
99m Tc DTPA but faster than 99m Tc DMSA.
 Technetium-99m-labeled Mertiatide
(MAG3):
 This compound is recently introduced to
study renal function and serves as a
substitute for iodohippuran.
 After Iv injection dosage is rapidly
cleared by kidneys through both active
tubular secretion and glomerular
filtration.
 90 % injected dosage discovered in
urine.
 Technetium-99m-labeled 2,6-Dimethyl
Acetanilide Iminodiacetic Acid ( HIDA) and
related Compounds (Diethyl-IDA,PIPIDA,
and , DISIDA ) : This pharmaceuticals are
used for imaging hepatobiliary system.
 In Normal subjects 99m Tc HIDA is rapidly
cleared from blood by hepatocytes.
 The half time for blood clearance is
approximately several minutes.
 The transit of the radioactivity from the liver
through gallbladder to the intestine is also
fast.
 Within an hour after administration , over
70% of the injected dosage is in intestine.
 About 15% of the injected dosage is
excreted in urine during the first hour.
 The remainder of the activity is
eventually excreted in feces.
 Urinary excretion of diethyl-IDA is smaller
than that of PIPIDA or DISIDA.
 The transit and excretion of these
compounds through the hepatobiliary
system is strongly dependent on the
patency of his system.
 Technetium-99m-labeled Sestamibi
( Cardiolite) : This compound is used
imaging of the heart.
 Its use in tumor imaging ( e.g. in the breast )
is also being explored.
 Being a technetium- labeled compound , it
has an advantage over thallium for heart
imaging.
 After IV injected dosage is excreted by the
myocardium in proportion to the blood
flow.
 The 20 % and 14 % injected dosage
excreted by Liver , kidney and hepatobiliary
system .
 Technetium-99m-labeled Teboroxime
(Cardiolitec ) : This is another
technetium-labeled compound for
imaging the myocardium .
 After Iv injected dosage is rapidly
cleared from the blood.
 The primary route of excretion is the
hepatobiliary system, with some
excretion through the kidneys.
 Technetium-99m-labeled Tetrofosmin
( Myoview) : This is the most recent
radiopharmaceutical approved for heart
imaging.
 After Iv injection it is rapidly cleared by
skeleton muscle , heart 1% , liver 7.5 % and
kidney 6.2 % less than 5 % of the injected
dosage remains in blood.
 Salivary and thyroid glands show elevated
concentrations .with in 48 hours of
administration , 75 % of the dose is excreted
from the body (40% urine and 35 % fecal
excretion. )
 Excretion , particularly from the skeletal
muscle is increased significantly during
exercise.
 Technetium-99m-labeled Brain imaging
agents ( Exametazime [ Ceretec ] ,
Hexamethylproppyleneamine Oxime [
HMPAO] , and Ethyl Cysteinate Dimer[
ECD]):
 These radiopharmaceutical cross the
blood brain barrier and therefore actively
localize in the brain.
 Because their uptake is generally a function
of regional blood flow, these agents in
conjunction with SPECT (single photon
emission computed tomography) are now
being used to measure brain function.
 After IV injection of Ceretec, the peak
uptake 7% in the brain is reached at 1
minute.
 The remainder of the dosage is
distributed in the whole body ,
particularly in muscle and soft tissues. It is
excreted from the body by way f the
gastrointestinal tract and the kidneys in
similar amounts.