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PET Radiochemistry and PET Radiopharmaceuticals302
Tracers of physiological or biochemical pathways, include 18F-FDG for glucose metabolism
and GLUT-1 receptor expression, 18F-FET for amino acid metabolism and 18F-FLT for TK1
expression, nucleic acid synthesis and cell proliferation. Ligands, which bind to specific molecular
sites, are 18F-6-Fluoro-DOPA for melanomas, 18F-fluoro-octreotide for somatostatin receptor
imaging, 18F-choline analogues for prostrate carcinoma, 18F-fluoro-estradiol for estrogen receptors
in breast cancer and 18F-fluoromisonidazole as a hypoxia marker for tumours.
The large difference in the requirements of the facilities and equipment for a
99m
TcRadiopharmacy and 18F-Radiopharmacy is due to the differences in the physical and chemical
properties of the radio-isotopes as shown in table 2. However, it is important to note that since
both 18F- and
99m
Tc-radiopharmaceuticals are to be injected into patients, the preparations should
be sterile and endotoxin free.
Table 2: Important differences between
99m
Tc Radiopharmacy PET-Radiopharmacy
T½ = 6 h T½ = 1h 50 min for 18F, 20 min for 11C, 10 min for 13N
99m
Sterile
99m
TcO4 produced on site from Generator Isotope produced on site from Cyclotron
Tc RPs are complexes of
99m
Tc and a chelating PET RPs are ‘true analogs’ of metabolites and have to
agent with required properties, and are hence easy to be synthesized with the PET isotope at a specific site
prepare – no chemical synthesis. in the molecule.
99m
Tc and PET radiopharmacy
and 2 min for 15O.
‘Cold’ sterile reagent available in a vial – just add Rapid chemical synthesis of the PET-RPs is necessary
sterile
99m
-
TcO
and mix well (no further processing using special precursors (to reduce synthesis time). Only
4
or minimal without opening the vial). simple molecules possible with 13N and 15O.
QC of radiopharmaceutical is minimal since ‘cold QC is more elaborate, since the PET- RP is synthesized
kit’ is already passed for sterility and is endotoxin everyday.
free.
The prepared radiopharmaceutical can be used
18
F-RPs should be used within a few hours – two
throughout the day. syntheses per day may be required. One production run
for 11C-RPs sufficient for 2-3 patients, hence high cost
per patient. Per patient cost higher for 13N and 15O RPs.
= 140 keV, 20 mm lead shielding is adequate. + emitter, = 2 x 511 keV, 70 mm lead shielding
required.
Multi-patient dose in a single vial possible Maximum 2-3 doses in a vial
It is important to note that the preparations of both 18F- and
99m
Tc-radiopharmaceuticals should be sterile
and endotoxin free for human use.
There are large number of published reports showing the utility of several PET-RPs labeled
with 18F, 11C, and some with 13N. Because of its short half life (2 min) 15O is used mostly as
15
H
O, C15O or C15O
2
.
Of the four isotopes (18F, 11C, 13N and 15O) produced in a medical
2
PET Radiochemistry and PET Radiopharmaceuticals 303
cyclotron, 18F is the most common, since it has a relatively longer half-life (t
= 110min) and
1/2
can be supplied to PET centers in the vicinity within couple of hours. In all cases, the synthesis
method should be suitable and give a stable product with good labeling yield, high specific
activity, high purity, and most importantly, high in vivo tissue selectivity. All PET RPs with
proven clinical use viz., 18FDG, 6-18F-L-dopa, etc., are in routine use because the radiochemistry
procedures for their production fulfill the above criteria. The PET radionuclides with very short
half-lives like 13N, 15O and 82Rb can be used only as simple compounds, like 13NH3, 11CO
82
Rb-RbCl etc. which do not require elaborate synthesis.
2, H2
15
PET isotope to PET-Radiopharmaceutical
Conversion of the short-lived radioisotope to radiopharmaceutical (RP) suitable for
injection into patients involves four major crucial steps:
1. Trapping of the desired isotope for synthesis of RP
2. Rapid and efficient chemical synthesis of the RP
3. Post synthesis purification of the RP to ensure radiochemical purity
4. Final RP product to fulfill stringent QC and pharmacopoeia requirements as it will be
injected to the patients intravenously.
For all these steps, the PET radiochemist has to pay extra attention to rapid and efficient
chemical synthesis of the PET-RP to minimize decay losses during synthesis and achieve better
yields with less impurities – cleaner RPs at low-cost.
O
Post synthesis purification of RP to ensure radiochemical purity is essential to keep the
background low and improve signal to noise ratio in PET scans. This depends upon the RP used.
For 18F-FDG, purification is simple and product is >95% pure and stable for hours. For 18F-FLT,
purification is by HPLC, since, several other products are formed. Radiolytic damage is seen
after some time. In case of 11C-compounds, purification by HPLC followed by concentration is
required. Autoradiolytic damage is severe i.e., the intense radiation destroys the neighbouring
molecules in the solution, and hence, a free radical scavenger like ethanol is added to the final
preparation.
Description of the syntheses and potential for future use of the common clinically used PET
radiopharmaceuticals is given below.
PET Radiopharmaceuticals
18
F-Sodium Fluoride
18
F-Sodium Fluoride (18F-NaF) is a natural bone seeker since it localizes in bone by exchanging
with PO
per se since the irradiation of 18O-water with protons directly produces 18F-fluoride in the
-
ion in the hydroxyapatite crystal matrix of bone. 18F-NaF, in fact, requires no synthesis
4
PET Radiochemistry and PET Radiopharmaceuticals304
cyclotron target and can be trapped by passing the irradiated 18O-water through a small bicarbonate
type anion-exchange resin column. The fluoride can be eluted as 18F-Sodium fluoride by eluting
with a small volume of sodium carbonate solution or even with normal saline directly. For use in
patients, it should be radioisotopically and radiochemically pure, with pH between 4.5 to 8.0.
While 18F-sodium fluoride is usually produced for the synthesis of 18F-fluorodeoxyglucose, the
residual 18F- in the cyclotron target can be rinsed out to provide sufficient quantity of 18F-NaF for
several bone scans. The US-FDA had approved it for bone scintigraphy and, in fact, is the first
PET-RP approved by the FDA.
18
F-Fluorodeoxyglucose (18F-FDG)
18
F-FDG is the principal PET-RP with molecular formula as C18H
18
FO5 and molecular
11
weight of 181.3 Daltons. The method of 18F-FDG production is by nucleophilic substitution of
the triflate moiety in 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethane-sulfonyl--D- mannopyranose
(mannose triflate) first reported by Hamacher et al. (1) and still in use with minor modifications.
The 18F- from the cyclotron target in 18O-water is trapped on a small bicarbonate column and the
unutilized 18O-water is collected for reuse after processing. The 18F- is eluted out with tert-butyl
ammonium bicarbonate (TBA-HCO3), and the water present is dried by adding twice its volume
of acetonitrile and azeotropic distillation of the mixture. The TBA-HCO3 also performs the role
of a phase transfer catalyst ensuring that the 18F- is available in an ionic form in acetonitrile for
the nucleophilic substitution reaction. The precursor, mannose triflate in dry acetonitrile is added
and at about 80º C, the displacement of the triflate by 18F- takes place. The acetonitrile present is
distilled off and the protecting acetyl groups are hydrolysed with 1M hydrochloric acid at a
temperature between 120 -125ºC. The 18F-FDG is purified from the reaction mixture by passing
it through a combination column consisting of anion exchange resin, cation exchange resin,
alumina and reverse phase resin. All the anionic and cationic components from the reagents
used, impurities from the reaction steps etc., are trapped on the purification column, while the
uncharged 18F-FDG passes through to the product vessel/vial and is dispensed aseptically into
vials/syringes for use. The schematic of the chemical reactions is given in figure 1.
The original Hamacher method uses K2CO3 for eluting 18F- from the separation column and
aminopolyether (Kryptofix 2.2.2) is used as the phase transfer catalyst. Although quite satisfactory
for the purpose, Kryptofix is reported to be a toxic chemical and QC tests are mandatory to
ensure that it is below permissible level in the final product. An additional purification step with
a C-18 Sep-Pak used earlier prior to acid-hydrolysis is not found to be necessary now. In lieu of
acid-hydrolysis, alkaline hydrolysis with 0.2M NaOH at 40 ºC can also be used. However, it
should be kept in mind that NaOH solutions can react with the glass of the reagent reservoir and
the reaction vessel.
A wide range of yields has been reported, but a 50% yield without decay correction is
routinely possible and acceptable. A good understanding of the kinetics of the chemistry processes
involved and pre-conditions required for efficient synthesis can help in tuning the equipment to
give >60% yield.
PET Radiochemistry and PET Radiopharmaceuticals 305
Figure 1: Steps in the synthesis of 18F-FDG
Synthesis times ranging from 30 min to 50 min have been reported for 18F-FDG with the
above procedure. The procedure can be completed within 30 minutes. Of this, the actual time for
fluorination and hydrolysis is only a few minutes and the remaining time is spent in bringing the
18F-
to a dry state prior to the fluorination and removing the solvent after the reaction. Hence,
there is scope for reducing the synthesis time and saving the 18F-FDG lost by decay with more
PET Radiochemistry and PET Radiopharmaceuticals306
efficient procedures employed in future. Electrophilic substitution with 18F-fluorine gas can also
be used but the yields are low, so the nucleophilic displacement reaction has become the method
of choice for 18F-FDG synthesis.
The 18F-2-FDG is used primarily for the study of metabolism in the brain and heart, and for
the detection of epilepsy and various tumors. In metabolism, 18F-2-FDG is phosphorylated by
hexokinase to 2-FDG-6-phosphate, which is not metabolized further. It should be noted that 3fluoro-deoxyglucose (3-FDG) is not phosphorylated and hence is not trapped and essentially
eliminated rapidly from the cell. That is why 3-FDG is not used for metabolic studies.
18
F-Fluorothymidine (FLT)
18
F-(FLT) is a promising PET-RP in oncology as it measures malignant-cell proliferation,
important in the diagnosis, characterization and prognosis of tumours. In the last couple of years,
there have been an increasing number of publications using this RP.
It is prepared by nucleophilic substitution of a leaving group in a suitably designed precursor
with 18F-. A suitable precursor is 2,3'-anhydro-5'-O-benzoyl-2’deoxythymidine, which is prepared
by standard organic synthesis (2). Nucleophilic fluorination of the precursor with dry 18F-fluoride
(prepared as in the first step of 18F-FDG synthesis) in the presence of a phase-transfer catalyst
(Kryptofix 2.2.2 and potassium carbonate, or TBA-HCO3) is carried out in dimethyl sulfoxide at
160°C for 5 - 10 minutes. Hydrolysis of the 5’-O-protecting group is performed with sodium
hydroxide. 18F-FLT is purified from the reaction mixture by passing through alumina Sep-Pak
and further purified by HPLC. The overall yield is about 15% and the radiochemical purity is
more than 95%. The synthesis time is about 60 minutes.
A few precursors are now available for FLT synthesis giving better yields at lower
temperatures. Important among them are (i) N-(2,4-Dimethoxybenzyl)-5’-O-dimethoxytrityl-Onosyl-thymidine and (ii) 3-N-Boc-1-[5-O-(4,4’-dimethoxytrityl)-3-O-nitrophenylsulfonyl-2-deoxy-D-lyxofuranosyl]thymidine, commonly referred to as Boc-FLT. The precursors giving a better
yield are costlier.
6-18F-L-FDOPA
The 6-18F-L-FDOPA (6-18F-fluoro-3,4-dihydroxyphenylalanine) is more conveniently
synthesized by the electrophilic route of fluorodemetallation as compared to the nucleophilic
reaction which is complicated for this PET-RP. Electrophilic reactions involve the reaction of
fluorine in the form of F2 with other molecules (unlike the use of F- in nucleophilic reactions). A
suitably protected organomercury precursor (N-[trifluoroacetyl]-3,4dimethoxy- 6trifluoroacetoxymercuriophenylalanine ethyl ester) of DOPA is the starting chemical that reacts
with [18F]-labeled acetylhypofluorite prepared in the gas phase in chloroform or acetonitrile at
room temperature (3). In lieu of mercury, the use of tin, silicon, selenium and germanium have
been reported. Acid hydrolysis with concentrated HBr gives the yield of ~10% of 18F-L-FDOPA.
PET Radiochemistry and PET Radiopharmaceuticals 307
The precursor is designed to provide substitution at position 6 since this does not alter the
behavior of DOPA, whereas substitutions at 2 and 5 can alter (4).
The 18F-L-FDOPA produced is sterilized by passing through a 0.2µm filter, and is supplied at
pH between 4.0 and 6.0. For stability of the RP, EDTA and ascorbic acid are added to the final
preparation. The molecular structure of 6-18F-L-fluorodopa is shown in figure 2. It is used for
imaging the presynaptic dopaminergic function in the brain. Being a derivative of the phenylalanine
amino acid, it can be used to study the amino acid metabolism of malignant tumours.
Figure 2: Electrophilic synthesis of [18F]fluoro-L-Dopa (3). (D. Le Bars, J Fluorine Chem 127
(2006) 1488–1493)
Importance of 18F-PET Radiopharmaceuticals
The relatively longer half life of 18F (110 min) and that it can be used to replace H or OH in
biomolecules to give effective PET-RPs makes it the isotope of choice. Much work is going on
worldwide to make 18F-equivalents of well-established 11C-PET RPs, since the latter is not
commercially viable. New chemistries for 18F-labeling are being tried out (3).
15
O- Water
The 15O-oxygen (t
= 2 minutes) is the ultra short-lived PET-isotope and is directly delivered
1/2
from the target to the site of use through stainless steel tubing – often over distances of 50 – 100
meters. It is produced by the nuclear reactions, 15N(p, n)15O, or 14N(d, n)15O. The former is the
only option in small (proton beam-only) medical cyclotrons, using enriched 15N2 gas. About 1%
O2 is mixed with the target gas for better recovery. The irradiated gas is transferred to [15O]water generator in which 15O is mixed with pure hydrogen gas and converted to water over a
palladium/charcoal catalyst at 170°C (5, 6). The H
15
O vapor is condensed in saline and filtered
2
through a 0.22µm membrane filter prior to use. The activity to be injected is quantified in a
radiation detector prior to injection into the patient. Due to the very short half-life, several
batches of H
15
O have to be continuously produced for a single patient study. It is used for
2
myocardial and cerebral perfusion studies.
13
N-Ammonia
Nitrogen-13-labeled ammonia is produced by reduction of 13N-labeled nitrates and nitrites
that are produced by proton irradiation of 16O-water in a cyclotron. The reduction can be carried
PET Radiochemistry and PET Radiopharmaceuticals308
out with alkali and Devarda’s alloy. The exothermic reaction and the hydrogen evolved flushes
out the 13N-NH3 which is dissolved in saline solution. It is aseptically filtered through a 0.22 µm
filter before use. Wieland et al. (7) have used a pressurized target of aqueous ethanol, in which
ethanol acts as a hydroxyl free radical scavenger to improve the yield of 13N-NH3. The mixture is
passed through an anion-exchange resin to remove all anion impurities. It is filtered through a
0.22µm membrane filter and its pH should be between 4.5 and 7.5. The US FDA has approved it
for measurement of myocardial and cerebral perfusion
11
C-Sodium Acetate
It is produced by the reaction of 11C-CO2 with methylmagnesium bromide (Grignard reagent)
in diethyl ether at ambient temperature. After reaction, the solvent is evaporated and the product
is hydrolyzed with water or aqueous acid, followed by further purification using the ion exchange
method or distillation at high temperatures (~175º C). Purification is simplified if the Grignard
reagent can be immobilized as a solid-phase (8). The product is sterilized by filtration and is
stable for 2 hours in solutions with a pH of 4.5 - 8.5. The overall yield is quite good (~ 70%). It
is used for the measurement of oxygen consumption (oxidative metabolism) in the heart, since
acetyl CoA synthetase converts 11C-acetate to acetyl-CoA after myocardial uptake, which is
metabolized to 11C-C02 in the tricarboxylic acid cycle.
11
C-L-Methionine
The importance of 11C-L-methionine is that it is a PET-tracer for studying amino acid
metabolism of malignancies. It has been found to be useful in imaging tumours in the brain
where 18F-FDG has limitations because of its very high uptake. 11C-methionine can be prepared
by incorporating 11C in the C-1 or in the methyl position to give L-[l-11C] methionine and L-[Smethyl-11C] methionine respectively. The former is obtained by the reaction between 11C-CO
precursor and carbonion produced by a strong base added to the respective isonitrile, followed
by hydrolysis with an acid. The latter is obtained by alkylation of the sulfide anion of Lhomocysteine with 11C-iodomethane. Unlike 18F-labeling by simple nucleophilic substitution, the
synthesis chemistry of 11C-labeling is quite involved as it uses gaseous 11CO2 and, hence, the
synthesis modules used are fairly complicated. Yields are poor since the synthesis and purification
time often exceeds two half lives of the isotope. Purification of the 11C-methionine is done by
HPLC and sterilization for patient use by filtering through a 0.22µm membrane filter. The final
product is buffered to have a pH between 6.0 and 8.0, where it is found to be stable for 2 hours
at room temperature. A new method without requiring HPLC purification has also been
reported (9).
11
C-Raclopride
The 11C-Raclopride is labeled by O-methylation with [11C] iodomethane and is a suitable
method for regular production. 11C-labeled iodomethane is prepared from 11C-C02. The product
is purified by HPLC giving a purity of more than 98%. The specific activity should be in the
2
PET Radiochemistry and PET Radiopharmaceuticals 309
range of 18.5 to 74 GBq/µmol (0.5 to 2Ci/µmol). The product at pH between 4.5 and 8.5 remains
stable for more than one hour at room temperature. 11C-raclopride is primarily used to detect
various neurological and psychiatric disorders, such as Parkinson’s disease, schizophrenia, etc.
82
Rb-Rubidium Chloride
82
Rb-rubidium chloride is conveniently obtained from the 82Sr-82Rb generator. It is eluted
with saline and must be checked for 82Sr and 85Sr breakthrough before using for patient studies.
The allowable limit for 82Sr is 0.02µCi/mCi or 0.02kBq/MBq of 82Rb and the limit for 85Sr is
0.2µCi/mCi or 0.2kBq/MBq of 82Rb. Since 82Rb has a short half-life of 75 seconds, it is
continuously infused into the patient for the period of study. The administered activity is the
integrated activity infused at a certain flow rate for a period of time set by the operator.
Commercially available generators usually have about 3.7 GBq (100 mCi) 82Sr loaded on the
column at calibration time. The 82Rb is approved by the FDA for myocardial perfusion imaging
to delineate ischemia from infarction.
Automated Synthesis Devices
Manual methods of synthesis of PET RPs are not recommended, as the chances of radiation
exposure are very high. Further, it requires considerable concentration on the part of the operator
to ensure that all chemical synthesis steps are meticulously carried out with remote-handlers,
standing behind a thick lead shield. Small errors could be very expensive if it entails loss of the
entire radioactivity produced in the cyclotron. This is particularly true with short-lived positron
emitters such as 11C, 13 N, 150, and 18F, which are used in large quantities for the synthesis of PET
RPs. Automated synthesis modules overcome the problem of radiation exposure and human
errors and are now available in various formats from a handful of manufacturers. All the PET-RP
production centres invariably use the automated synthesis devices.
The automated synthesis device, or synthesis module is a microprocessor controlled unit
operated by software programs, also called ‘time-lists’ containing the sequential physical and
chemical steps required to be carried out for the synthesis of the radiopharmaceuticals. Since
different PET-RPs require different synthesis steps, the equipment required viz., reagent containers,
reaction vessels, connecting tubing and valves would be different for different PET-RPs. This is
definitely so for 18F, 11C, 13N and 15O compounds, though several 18F-labeled compounds may be
prepared using a nucleophilic fluorination module. The unit consists of vials pre-filled with
required chemicals/reagents which can be made to pass through columns, into and out of the
reaction vial through inert Tefzel® or PEEK tubing having electromagnetic flipper-valves in its
path. These valves are operated by the software that controls the synthesis. Prior to synthesis,
these units are cleaned automatically with pharmaceutical grade, sterile acetone, ethanol and
water and dried thoroughly with He or N2 gas. These units are small, measuring about 60 cm x
60 cm, and housed in adequate lead shielding. Several units can be placed side by side with
interconnecting tubing.
PET Radiochemistry and PET Radiopharmaceuticals310
Timely addition of reagents, reaction time, pressure, heating, cooling and vacuum etc. are
controlled by the interfaced computer. This is by way of time lists which are a set of instructions
that control the addition of reagents, heating, drying, transferring the reaction mixture to the
purification column etc., that are executed sequentially with predetermined time intervals. The
unit has a graphic display showing the status of the on-going process. After the synthesis, a
report with the date, start and end time of the radiosynthesis, and the radioactivity present at
various zones in the module is printed out.
Newer units use disposable (expensive) cassettes for each synthesis run, saving the time
spent on cleaning between syntheses. Automated synthesis modules for 18F-FDG, 13N-NH3, 11Cmethionine, and a few other PET tracers are commercially available. A general purpose fluorination
module for the synthesis of a number 18F-PET-RPs is now also available from different
manufacturers.
Quality Control of PET Radiopharmaceuticals
PET-RPs must be tested for chemical purity, radionuclidic purity, radiochemical purity, pH,
isotonicity, sterility, apyrogenicity (free of bacterial endotoxin) and toxicity prior to administration
to humans, particularly as they are administered intravenously. However, since the radioisotopes
11
C and 18F are short lived, except for radiochemical purity, radionuclidic purity, radionuclidic
identity (by measuring T½), pH and isotonicity, the other tests, including sterility and apyrogenicity
tests, cannot be done on the final product before dispatch due to short T½, but assured by GMP
and process validation and ‘parametric’ release of product is the practice.
Quality assurance of the products is ensured by validating the standard operating procedure
(SOP) on at least 10 pre-production batches. However, batch control samples are maintained
from every production run and the QC tests viz., sterility, endotoxin tests, solvent residues etc.,
are performed on ‘radioactive decayed’ samples much after administration to patients. If a batch
is found to ‘not comply’ for sterility and BET, then the entire process has to be revalidated.
The QC tests can be divided into two categories: physicochemical tests and biological tests.
These tests are briefly outlined below.
Physicochemical Tests
As the name implies, these include physical and chemical parameters viz., physical appearance,
isotonicity, pH, radionuclidic identity, chemical purity, and radiochemical purity.
Physical Appearance: Physical appearance relates to the color, clarity or turbidity of a PET
radiopharmaceutical and should be checked by visual inspection of the sample. For example the
18
F-FDG should be a clear, colourless solution free of any suspended impurities.
pH: The pH of a PET radiopharmaceutical for human administration should be ideally 7.4,
but both slightly acidic and basic pH values are tolerated due to the buffer capacity of the blood.
The pH is usually adjusted between 4.5 to 8.0 by using an appropriate concentration of Na2HPO4.
PET Radiochemistry and PET Radiopharmaceuticals 311
Isotonicity: Isotonicity is the ionic strength of a solution, which is mainly adjusted by
adding appropriate electrolytes. Normally PET radiopharmaceuticals have appropriate isotonicity
for human administration.
Radionuclidic Purity: The radionuclidic purity of a radiopharmaceutical is the fraction of
total activity in the form of the desired radionuclide in the sample. These impurities primarily
arise from the radionuclides produced by various nuclear reactions in a target as well as the
impurities in the target material itself. Using a multichannel spectrometer, one can determine the
level of impurities in a sample of a positron-emitting radionuclide produced by a specific nuclear
reaction in a cyclotron. Using highly pure target material and appropriate chemical separation
techniques, the radionuclidic purity can be brought to an acceptable level. Short-lived radionuclides
can be allowed to decay to have a pure relatively long-lived radionuclide in question. Even
though the impurities in the routine preparations of PET radionuclides do not vary significantly
from batch to batch, periodic checkup is recommended to validate the integrity of the method of
production. The radionuclidic impurities must be established in 11C, 13N, 15O, and 18F radionuclides,
prior to their use in the synthesis of radiolabeled compounds.
Chemical Purity: Chemical purity is the fraction of a radiopharmaceutical in the form of
the desired chemical molecule whether all of it is radiolabeled or not. The presence of extraneous
stable atoms may cause adverse reactions and is not desirable in a PET radiopharmaceutical.
These impurities arise from the incomplete synthesis, in addition to extraneous ingredients
during the synthesis, and so on. Chemical methods such as the spectrophotometry, ion exchange,
solvent extractions, chromatography, etc. are applied to measure the level of these chemical
impurities. Again, these tests can be performed a priori in many dry runs and thus the level of
chemical impurities can be established, prior to human administration.
Radiochemical Purity: The radiochemical purity of a radiopharmaceutical is defined as the
fraction of the total activity in the desired chemical form in the sample. These impurities arise
from incomplete labeling, breakdown of the labeled products over time due to instability, and
introduction of extraneous labeled ingredients during synthesis. These impurities cause altered in
vivo biodistribution after administration, resulting in an unnecessary radiation dose to the patient.
For these reasons, the United States Pharmacopoeia (USP) and the United States Food and Drug
Administration have set limits on the impurities in various radiopharmaceuticals, and these
limits must not be exceeded in clinical applications.
Since most PET radiopharmaceuticals are produced on site daily, the radiochemical purity
must be checked for each batch. For very short-lived radionuclides, however, the methodology
must be validated beforehand by carrying out many dry runs so that the radiochemical purity of
the product remains within the limit set for human administration.
Various analytical methods are employed to establish the radiochemical purity of PET
radiopharmaceuticals. The most common method is high performance liquid chromatography
(HPLC), which gives separation of components with high resolution. The general principle of
HPLC involves forcing a sample at high pressure through a column of special packing material
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