Radiotracers in pharmacy

RADIOTRACERS IN
PHARMACY
Submitted by:
Viraj Sukthankar
Dept. of Pharmaceutics
KLE college of Pharmacy
Belagavi-Karnataka.
KLEU'S College of Pharmacy
1

CONTENTS:
 Introduction
 Preparation and Characterization of radiotracers
 Applications of radiotracers
 Nuclear Imaging Techniques
 Marketed Products
 Patents
 Future scope
 Conclusion and References.
2

Introduction:
 A radioactive tracer, or radioactive label, is a chemical compound in
which one or more atoms have been replaced by a radioisotope so
by virtue of its radioactive decay it can be used to explore the
mechanism of chemical reactions by tracing the path that the
radioisotope follows from reactants to products. Radiolabeling is
thus the radioactive form of isotopic labeling
3

 Radioisotopes of hydrogen, carbon, phosphorus, Sulphur, and iodine have been
used extensively to trace the path of biochemical reactions.
 A radioactive tracer can also be used to track the distribution of a substance
within a natural system such as a cell or tissue or as a flow tracer to track fluid
flow.
 Radioactive tracers are also used to determine the location of fractures created by
hydraulic fracturing in natural gas production. Radioactive tracers form the basis
of a variety of imaging systems, such as, PET scans, SPECT scans and
technetium scans
4

Principle:
The basic principle of the radiotracer is that the radioactive tracer will have the same
chemical and biochemical properties as that of its non-radioactive counterpart, as the
chemical and biochemical properties are governed in both tracer as well as in the
non-radioactive entity by their reactivity which are depending only on the number of
extra nuclear electrons and their organization in the electronic orbits.
5

Classification:
 Uniformly Labelled (U): Uniformly labeled compounds are labeled in all positions
in a uniform or nearly uniform pattern.
E.g. L-Valine-14C (U) implies that all carbon atoms in L-valine are labeled with equal
amounts of 14C.
 Specifically Labelled (S): Chemicals are designated as specifically labeled when all
labeled positions are included in the name of the compound and 95% or more of the
radioactivity of the compound is at these positions.
E.g. Aldosterone1,2-3H implies that <95% of tritium label is in position 1 and 2.
 Randomly Labelled or Generally Labelled (G): This designation is for compounds
in which there is random distribution of labelled atoms in the molecule. Not all
positions in a molecule are necessarily labeled.
 Nominally Labelled (N): This designation means that some part of the label is at a
specific position in the material but no further information is available as to the extent
of labelling at other positions.
E.g. Cholestrol-7-3H (N), some tritium is at position 7, but may also be at other positions.
6

Advantages:
 The chemical behavior of radiotracers is not altered.
 Radiotracers can be quantified in minute quantities with high sensitivity.
 The detection instruments are inexpensive and easily available.
 Detection is fast and reliable.
 Sample preparation is easier and in many cases the radiotracers need not be
isolated.
Disadvantages:
 Nuclear/Radiation safety.
 Requirement of further chemical processing to determine the mass of material
isolated and the specific activity.
7

There are two ways in which radiotracers are used
 When a radiotracer undergoes chemical reactions one or more of chemical
products will be generated containing the radioactive label. The analysis of the
radioactivity will be able to provide detailed information on the mechanism of
such chemical reactions and thus enable in vitro biological investigations in
biological systems.
 A radioactive compound (radiotracer) is administered into a living organism and
the administered radioisotope provides a means to construct an image showing
the way in which that compound and its reaction products are distributed around
the organism. This image is generally known as scintigraphy.
8

 Criteria for selection of tracers:
In order to have meaningful results from a set of radiotracer experiments, it is very
important that an appropriate radiotracer methodology is chosen based on certain
parameters such as:
 Nature of the radiotracer.
 Nature of radiation.
 Specific activity of the radiotracer.
 Half-life of the radioisotope.
 Radio purity.
9

 Preparation and characterization of radiotracers:
There are four basic methods available for the preparation of radiotracers
1. Isotope exchange reactions
2. Chemical synthesis
3. Biochemical reactions
4. Recoil labelling
 Isotope Exchange reactions:
A chemical reaction in which interchange of the atoms of a given element between
two or more chemical forms of the element occurs, the atoms in one form being
isotopically labeled so as to distinguish them from atoms in the other form.
10

 Chemical synthesis
 A 14C label may be introduced into a variety of compounds by the standard
synthetic procedures of organic chemistry.
 In addition, some new methods have been devised to conserve the radionuclides
being used. When chemical synthesis is at all possible it is usually the method of
choice.
 Synthetic method gives the greatest control over yield, position of label and
purity of the product.
 Chemical synthesis of labelled compounds suffers from some limitations and
problems such as the amount and cost of radioactive starting material.
 Another disadvantage of chemical synthesis is that when it is used to produce
certain biologically important compounds such as amino acids, a racemic mixture
results which may lead to undesirable confusion during investigation.
E.g. Radiotracer synthesis from [11C] iodomethane.
11

 Biosynthesis/Biochemical reactions:
Living organisms or active enzyme preparations, offers a biochemical means of
synthesizing certain labeled compounds that are not available by chemical synthesis.
This includes both the macromolecules (proteins, Polysaccharides, nucleic acids,
etc.) and many simpler molecules (vitamins, hormones, amino acids and sugars).
Few factors should be considered while production of labeled compound by
biosynthesis
 First, an organism must be selected that will synthesize and accumulate practical
quantities of desired compound.
 Culture conditions must be established so as to provide optimal yields of desired
radiolabeled compounds.
 Isolation and purification as well as determination of distribution pattern of the
label must planned accordingly.
E.g. Biochemical synthesis of 11C and 13N.
12

Recoil labeling:
In recoil labeling a recoil atom enters a given molecule. It causes a chemical change by
breaking the existing chemical bonds but also give rise to new bonds for production of
marked compounds. The method used recoil labelling is tritium labeling.
E.g. Recoil labelling of flourine-18 labelled chlorofluoromethanes and
tetrafluoromethane.
 Tritium Labeling:
Compounds may be labeled with tritium by several methods.
 By reduction of unsaturated precursors
The method of choice for labeling with tritium is the reduction of a suitable unsaturated
precursor containing a double bond carbonyl group etc. with carrier free tritium gas or
tritiated metal hydrides.
13

 By exchange reactions:
Random tritium labeling may be secured by simple exchange methods, with or
without catalytic action.
 By gas exposure:
In this method, the compound to be labelled is exposed to curie amounts of carrier free
tritium gas in a sealed reaction vessel for a period of a few days to several weeks. Hence
giving rise to tritium labelled compounds.
14

Application of radiotracers:
Radiotracers in metabolic studies:
Metabolic studies can be divided into two categories viz. primary and secondary
metabolism. Primary metabolism are vital to living organism and secondary
metabolites play valuable role in pharmaceuticals, food, flavors etc.
E.g. The biochemical pathways of carbon in photosynthesis:
 Photosynthesis is a multistep process and very complex. When chlorella cells
were grown in a medium containing 14CO2, it was found that radioactive carbon
from the carbon dioxide turned up in glucose molecules within 30 seconds after
the starting of photosynthesis.
 For identification of steps or pathway, compounds containing 14C were separated
by chromatography and detected by autoradiography. In this way the pathway of
CO2 fixation of phosphoglyceric acid and its transformation products ending
with glucose were identified.
15

 ADME studies:
 Radiolabeled compounds are excellent investigative tools and are widely used
to carry out ADME studies during drug development stages. The most
commonly used radioisotopes for ADME studies are 14C and 3H (tritium).
 For in vitro studies, radiolabeled probes are utilized to test affinity with various
transporters, to perform metabolism comparison among species and to assess
possible formation of reactive metabolites.
 For in vivo studies, radiolabeled compounds are employed to identify and
elucidate metabolites formed, to investigate the extent of absorption, pre
systemic metabolism, bioavailability, tissue distribution and routes of excretion.
 Thus radioisotopes have proven to be an indispensable tool in biomedical
research and have played an important role in investigation of ADME properties
of new chemical entities over past few decades.
16

 Tritiated Thymidine:
Tritiated Thymidine was first employed in the investigation of chromosomes. Today,
it is used in many different immunological tests and has become a standard for
studies in cell proliferation. Tritiated Thymidine also proved useful in studies of cell
migration and growth throughout the body. The few of the radiotracers which are
being used for research are tritaited thymidine, 32P nucleotides, 14C labelled amino
acids, 14C labelled glucose, steroids, plant growth regulators and phytochemicals.
 Radioiodine (131I )
Bioavailability of iodine in iodized salt is investigated using radioiodine (Iodine-
131). Bio-distribution using radioiodine helped to determine the bioavailability of
iodine in the human body.
17

Drug Delivery:
Polymers such as thermosensitive polymers are now finding applications in drug
delivery system development. Radiotracers have been used for the evaluation and
determination of efficiency and target evaluation of these novel drug delivery
systems. These polymers based drug delivery systems can be used for radiotherapy.
Radioimmunoassay:
Radioimmunoassay is yet another application of the radiotracer. Since development
of Radioimmunoassay (RIA), variety of immunoassays and their variants have been
developed in clinical, analytical and research laboratories for the detection and
quantification of molecules in very minute quantities. Apart from the precise
measurement they have provided an insight into basic mechanism and revolutionized
our understanding of many physiological and pathological phenomenon.
18

Functional Imaging:
Radiotracers with nuclear imaging modalities are being used in drug research and
development to measure drug pharmacokinetics and drug pharmacodynamics.
Radiolabeled drugs as radiotracer can serve as research tool for early identification
of problems such as poor bioavailability and non-target interactions which may lead
to failure later on.
A unique scientific tool called Positron Emission Tomography(PET) plays a major
role in drug discovery programme. PET imaging, can be used to demonstrate the
effect of a drug through a biochemical marker of processes such as glucose
metabolism or blood flow.
21

Role of Radiotracers in drug development:
 Radiolabeled compounds have been playing an active role as radiotracers based
research tools in the better understanding of the molecular behavior of lead
molecules and support every stage of drug development process. This includes all
the stages basic research, identifying lead molecules, ADME studies, Tissue
distribution, Optimization of formulation, Pre-clinical development. Radiotracers
can also be used for functional studies of organs which can be used as therapeutic
index in determination of therapeutic efficacy of the drug molecules
Radiotracers techniques applied in-vivo
ADME studies: The most popular in vivo application of radiolabeled compounds is
for ADME (absorption, distribution, metabolism, excretion) studies,
pharmacokinetics (PK), pharmacodynamics (PD) and mass balance studies. ADME
studies in human have two purposes: (a) to evaluate the mass balance of the drug
and (b) to learn about its metabolism.
22

Quantitative Whole-Body Autoradiography (QWBA):
 QWBA in animals and dissected human tissues has emerged as an effective
radiotracers technique for the assessment of drug safety. Whole body
autoradiography produces images of distribution of a radiolabeled drug over the
entire animal body section.
 The distribution of radioactivity is imaged by exposing x-ray film on to the cut
tissue sections. Radioactivity levels in individual structures are quantified by
determination of level of radiation effect on the film and results are expressed as
quantity of drug equivalent per unit weight of tissue. QWBA is preferred method
for tissue distribution studies for regulatory filing of a new drug entity.
23

Whole Body Auto Radioluminography (WBAL)
This technique is different from QWBA, as it uses phosphor imaging plate, instead of
x-ray film, for the detection of radioactivity which considerably enhanced the
sensitivity and reduced the exposure time in autoradiography technique. The use of
imaging plate (IP) has led to WBAL as a new detection method for radiation and is
attractive because it possesses high sensitivity and wide dynamic range. By
radioluminography, it is now possible to observe not only the two-dimensional
distribution, but also possible to quantify the radioisotope uptake in various sections
of specimen.
24

Micro-dosing:
 Micro-dosing is relatively a new concept introduced to investigate one of the
major causes for failure of drug-leads during development due to the
unsatisfactory pharmacokinetic (PK) or ADME parameters. This problem can be
addressed great extent by studying the behavior, PK and ADME characteristics of
chemical entity at an early phase of development by micro dosing with labelled
chemical entity.
 Micro-dosing involves the administration of drug candidate in human enough to
respond in cellular levels but unlikely to produce toxic effects. The basic
approach is to label a candidate drug using 14C or 3H and then administering the
radiolabeled compound to human volunteers at levels typically about 100 times
lower than the proposed therapeutic dosage based on animal studies.
 Thus micro-dosing allows not only evaluation of PK/ADME features, but also
enables standard mass balance study in humans. When drug is present in very
small amount in tissue or blood after micro dosing, its detection requires other
very sensitive analytical techniques such as Positron Emission Tomography
(PET) or Accelerator Mass spectrometry (AMS). 11C is most commonly used for
PET and 14C for AMS. AMS is preferred for accurate estimation of very minute
amounts of 14C in biological samples.
25

Nuclear Imaging:
One of the most important new applications of radiotracers is expected to be in the
area of drug efficiency assessment by nuclear imaging. Nuclear imaging procedures
such as PET (Positron Emission Tomography), SPECT (Single Photon Emission
Computed Tomography) and AMS (Accelerator Mass Spectrometry) are options
based on the use of specially designed radiotracers called radiopharmaceuticals that
can provide criteria based status of the disease progression and functionality of the
disease organ. Furthermore, PET study reveals the metabolic and physiological
changes and activity in target organ which is effective quantitatively to the
therapeutic effect of drug action.
26

Positron Emission Tomography (PET)
Positron Emission Tomography (PET) is a nuclear medicine, functional imaging
technique that produces a three-dimensional image of functional processes in the
body. The system detects pairs of gamma rays emitted indirectly by a positron-
emitting radionuclide (tracer), which is introduced into the body on a biologically
active molecule.
Positron emission tomography (PET) is a powerful imaging technique which enables
in vivo examination of brain functions. It allows non-invasive quantification of
cerebral blood flow, metabolism, and receptor binding. Positron emission
Operation
To conduct the scan, a short-lived radioactive tracer isotope is injected into the living
subject (usually into blood circulation). There is a waiting period while the active
molecule becomes concentrated in tissues of interest; then the subject is placed in the
imaging scanner. The molecule most commonly used for this purpose is F-18 labeled
fluorodeoxyglucose (FDG), a sugar, for which the waiting period is typically an hour.
During the scan, a record of tissue concentration is made as the tracer decays.
27

Radiotracers used in PET:
Radionuclides used in PET scanning are typically isotopes with short half-lives such
as carbon-11 (~20 min), nitrogen-13 (~10 min), oxygen-15 (~2 min), fluorine-18
(~110 min), zirconium-89 (~78.41 hours), or rubidium-82(~1.27 min). These
radionuclides are incorporated either into compounds normally used by the body
such as glucose (or glucose analogues), water, or ammonia, or into molecules that
bind to receptors or other sites of drug action.
28

Single-photon emission computed tomography (SPECT)
 Single-photon emission computed tomography (SPECT) is a nuclear medicine
tomographic imaging technique using gamma rays. It is very similar to
conventional nuclear medicine planar imaging using a gamma camera.
 However, it is able to provide true 3D information. This information is typically
presented as cross-sectional slices through the patient, but can be freely
reformatted or manipulated as required.
 The technique requires delivery of a gamma-emitting radioisotope (a
radionuclide) into the patient, normally through injection into the bloodstream.
On occasion, the radioisotope is a simple soluble dissolved ion, such as a
radioisotope of gallium (III) whose properties bind it to certain types of tissues.
Difference between PET and SPECT:
 SPECT is similar to PET in its use of radioactive tracer material and detection of
gamma rays. In contrast with PET, however, the tracers used in SPECT emit
gamma radiation that is measured directly, whereas PET tracers emit positrons
that annihilate with electrons up to a few millimeters away, causing two gamma
photons to be emitted in opposite directions.
31

 A PET scanner detects these emissions "coincident" in time, which provides more
radiation event localization information and, thus, higher spatial resolution
images than SPECT (which has about 1 cm resolution). SPECT scans, however,
are significantly less expensive than PET scans, in part because they are able to
use longer-lived more easily obtained radioisotopes than PET
32

Study Radioisotope
Half-
life
Radiopharma
ceutical
Activity
(MBq)
Rotation
(degrees)
Projections
Image
resolution
Time
per
project
ion (s)
Bone scan
technetium-
99m
6
hours
Phosphonates /
Bisphosphonat
es
800 360 120 128 x 128 30
Myocardial
perfusion
scan
technetium-
99m
6
hours
tetrofosmin; Se
stamibi
700 180 60 64 x 64 25
Sestamibi
parathyroid
scan
technetium-
99m
6
hours
Sestamibi
Brain scan
technetium-
99m
6
hours
HMPAO; ECD
555-
1110
360 64 128 x 128 30
Neuroendo
crine or
neurologic
al tumor
scan
iodine-
123 oriodine-
131
13
hours
or 8
days
MIBG 400 360 60 64 x 64 30
White cell
scan
indium-111 &
technetium-
99m
67
hours
in vitro labelled
leucocytes
18 360 60 64 x 64 30
35

Radiotracer techniques applied in-vitro:
 Radiolabeled compounds are also excellent in vitro research tools for target
evaluation, receptor-drug binding studies, biomarker identification, formulation
evolution, drug analysis, drug delivery system evaluation etc.
 For in-vitro studies, radiolabeled probes are utilized to test the affinity and
binding of the drugs with various transporters and receptors and to compare
metabolism among species and to assess possible formation of reactive
metabolites.
Radio-receptor assay:
Radio-receptor binding has been extensively used for identifying and characterizing
a large number of enzymes and receptors for targeting in every therapeutic area. The
pharmaceutical researchers routinely use this technique for identifying novel
molecules which can inhibit or mimic the endogenous biochemical receptors avid
molecules to cell bound receptors.
36

Patents regarding Radiotracers:
1. OPTICAL REACTION CELL AND LIGHT OTHER PUBLICATIONS
SOURCE FOR [18F] FLUORIDE RADIOTRACER SYNTHESIS. (United
States Patent)
2. NOVEL COMPOSITIONS FOR RADIOTRACER LOCALIZATION OF
DEEP VEIN THROMBI. (United States Patent)
3. A PROCESS AND DEVICE FOR PRODUCING PET RADIOTRACERS.
(European Patent)
4. DISPOSABLE KIT FOR PREPARATION. (United States Patent)
5. METHOD AND DEVICE FOR QUANTIFYING THE UPTAKE OF AT
LEAST ONE RADIOTRACER IN A BODY REGION OF A PATIENT OF
INTEREST TO A POSITRON EMISSION TOMOGRAPHY
MEASUREMENT. (United States Patent)
37

Marketed Products or Marketed Imaging agents:
FLORBETABEN (18F)/ NeuraCeqTM :
Florbetaben, a fluorine-18 (18F)-labeled stilbene derivative trade
name NeuraCeqTM (florbetaben F18 injection), is a diagnostic
radiopharmaceutical developed for routine clinical application to visualize ß-amyloid
plaques in the brain. It is indicated for Positron Emission Tomography (PET)
imaging of ß-amyloid neurotic plaque density in the brains of adult patients with
cognitive impairment who are being evaluated for Alzheimer’s disease (AD) and
other causes of cognitive impairment
Dosage: Adult: Follow injection with an IV flush of 10 mL of 0.9% NaCl.
Developer/Manufacturer: Piramal Enterprises.
38

MIBITEC (600 MBq/ml solution injectable):
Most widely used SPECT cardiac imaging agent, Tetrakis (2-methoxyisobutyl iso
nitrile) copper (I) tetra fluoroborate. They are approved for myocardial exploration,
localization of parathyroid issue and breast cancer diagnosis.
Developer/Manufacturer: Advanced Accelerator Applications (AAA)
39

IASOflu®:
Is the brand name for Sodium Fluoride 18. This PET tracer is indicated as a bone
imaging agent to define areas of altered osteogenic activity. It accumulates in the
vicinity of primary and metastatic malignancy in bone.
40

IASOcholine®:
This drug is purely for diagnostic use. 18F-choline (FCH) is intended for Positron
Emission Tomography (PET). 18F-choline is indicated for imaging in patients
undergoing oncologic diagnostic procedures describing function or diseases where
enhanced choline influx of specific organs or tissues is the diagnostic target.
41

Future aspect of Radiotracers:
1. The expenditure on the development of new drug molecules has been
phenomenal and has been increasing day by day. Focused efforts are necessary
to tackle the problems of the cost evaluation without compromising on
efficiency and safety aspects.
2. The use of radiolabeled compounds and radiotracer techniques has shown great
promise to drug developers and researchers and the technique is in-dispensable
in drug research. The unique detection sensitivity and possibility of requirement
of the radiotracers in small quantity that does not disturb the biochemical
equilibrium of the system under study has attracted researchers.
3. Applying radiolabeled compound based techniques such as nuclear imaging and
micro-dosing in the early stages of drug development will enable the radiotracer
to further establish as a research tool in the evaluation of drug directly in human
and use of radiotracer will become an integral part of drug discovery and
development.
42

Conclusion:
One can understand the present status and enormous potential of
radiopharmaceuticals both for therapy and palliative treatment. In current scenario of
evidence based medicine practice, nuclear medicine i.e. radiotracers and other
radiopharmaceuticals are treated as an important modality both for diagnosis and
therapy and the future of nuclear medicine as “Therapeutic era”.
43

Reference:
1. Padmanabhan D. Applications of radiolabeled compounds. Pharma Times.
2014;46(5):13-5.
2. Sivaprasad N. Role of Radiotracers in Drug Development. Pharma Times.
2014;46(5):16-7.
3. Rajan MGR. Applications of Nuclear Imaging in Pharmacy. Pharma Times.
2014;46(5):18-26.
4. Isin EM, Elmore CS, Nilsson GN, Thompson RA, Weidolf L. Use of
radiolabeled compounds in drug metabolism and pharmacokinetic studies.
Chem. Res. Toxicol. 2011;25(3):532-42.
5. Penner N, Xu L, Prakash C. Radiolabeled absorption, distribution, metabolism,
and excretion studies in drug development: why, when and how? Chem. Res.
Toxicol. 2012;25(3):513-31.
6. Chaudhari P. Small Animal Imaging facility for Preclinical Research. Pharma
Times. 2014;46(5):27-8.
7. Dr. Banerjee S. Radiopharmaceutical Chemistry Research in the Development
of Radiopharmaceuticals. Pharm Times. 2015;47(5):25-7
44

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