Biomed Imaging Interv J 2006; 2(4):e57
© 2006 Biomedical Imaging and
Review of 18F-FDG synthesis and quality control
S Yu PhD
Departments of Nuclear Medicine & PET and Experimental
Surgery, Singapore General Hospital, Singapore
This review article covers a concise account on
fludeoxyglucose (18F‑FDG) synthesis and quality control
procedures with emphasis on practical synthesis Currently, 18F‑FDG
is the most successful PET radiopharmaceutical so far. The advancement in
synthesis and quality control of 18F‑FDG, together with its
approval by the US FDA and the availability of reimbursement, are probably the
main reasons for the flourish of clinical PET over the last 20 years. 18F‑FDG
can be synthesised by either electrophilic fluorination or nucleophilic
fluorination reaction. Nucleophilic fluorination using mannose triflate as
precursor and Kryptofix or tetrabutylammonium salts (TBA) is widely used
because of higher yield and shorter reaction time. The quality control
requirements of 18F‑FDG can be found in United States
Pharmacopeia (USP), British Pharmacopeia (BP), European Pharmacopeia (EP) and
the Chemistry, Manufacturing, and Controls (CMC) section from United States
Food and Drug Administration (US FDA) PET draft guidance documents. Basic
requirements include radionuclidic identity, radiochemical purity, chemical
purity, pH, residual solvent, sterility, and bacterial endotoxin level. Some of
these tests (sterility, endotoxins and radionuclidic purity) can be finished
after the 18F‑FDG has been released. Although USP, BP and EP
do not require filter membrane integrity test, many laboratories perform this
test as an indirect evident of the product sterility. It is also interesting to
note that there are major differences in 18F‑FDG quality
requirements among USP, BP, and CMC. � 2006 Biomedical Imaging and Intervention
Journal. All rights reserved.
Keywords: Fludeoxyglucouse (18F-FDG), positron emission tomography (PET), quality control (QC)
18F‑FDG is a glucose analogue in which the
hydroxyl group on the 2‑carbon of a glucose molecule is replaced by a
fluoride atom. Like glucose, 18F‑FDG is taken up into living
cells by facilitated transport and then phosphorylated by hexokinase. Unlike glucose,
18F‑FDG cannot undergo further metabolism because the hydroxyl
group at the 2‑carbon is a requirement for the process [1‑2].
Nevertheless, 18F‑FDG is a good indicator of glucose uptake
and cell viability.
The uptake of glucose analogues into living cells also
depends on modifications of various carbons at different positions. It has been
shown that the specificity of 3‑deoxyglucose (3‑DG) and 4
deoxyglucose (4‑DG) towards hexokinase reduced by 100‑fold ,
hence 3‑DG and 4‑DG were not retained inside the cells. Similarly, 3‑fluoro‑deoxyglucose
and 4‑fluoro-deoxyglucose do not accumulate in living cells as much as 18F‑FDG.
Although the nucleophilic substitution reaction is more widely used nowadays,
the electrophilic fluorination reaction has an important place in the synthesis
Synthesis of 18F-FDG by Electrophilic
The first synthesis of 18F‑FDG was carried
out in Brookhaven National Laboratory by Wolf et al in 1976 by electrophilic
fluroination . As shown in Figure 1, electrophilic fluorination refers to
the addition of fluorine atoms across a double bond, producing a difluoro
derivative of the parent compound. The electrophilic fluorination by Wolf et al
involved the use of 3, 4,6‑tri‑O‑acetyl‑D‑glucal
as precursor. The glucal was treated with 18F‑F2 to
produce a 3:1 mixture of 18F labelled difluoro‑glucose and
difluoro‑mannose derivatives. The difluoro‑glucose derivative was
separated and hydrolysed with hydrochloric acid to form 2‑fluoro‑2‑deoxyglucose
(Figure 2). The yield was 8% and the synthesis time was 2 hours .
Figure 1 Electrophilic fluorination
Figure 2 Synthesis of
18F-FDG by electrophilic fluorination.
Despite the low yield and long synthesis time, the
Brookhaven team was able to collaborate with The Hospital of the University of Pennsylvania
to map glucose metabolism in human brain . This was the first 18F‑FDG
trial in human.
Several improvements to the electrophilic fluorination
described above were made thereafter. One of the most useful modifications was
the use of acetylhypofluorite 18F‑CH3CO2F.
The acetylhypofluorite can be produced in situ from 18F‑F2.
The yield was higher and the synthesis reaction was easier to control [4‑6
The major limitation of electrophilic fluorination was that
only 50% of the radioactive fluorine atoms were incorporated into the
precursors. In addition, the 18F‑F2 was produced
from a Neon gas target with 0.1% to 1% of fluorine gas via a 20Ne(d,α)18F
reaction. The specific activity is lower due to the presence of the non‑radioactive
fluorine gas. The maintenance and operation of a Neon target is troublesome and
the yield of 18F‑ was much lower than with the 20Ne(d,α)18F
reaction than with the 18O(p,n)18F‑
reaction. [4, 7‑8]
Synthesis of 18F-FDG by Nucleophilic fluorination
Many attempts have been made to develop a nucleophilic
substitution for the synthesis of 18F‑FDG. This included the
use of 18F‑CsF, 18F‑Et4NF, and 18F‑KHF
[4, 9‑14]. But the major breakthrough was reported in 1986 by Hamacher et
al who had used Kryptofix 222TM as a catalyst . The reaction had
a consistent yield of over 50% and the reaction time was shortened to 50 min.
Nucleophilic substitution is a chemical reaction involving
the addition of a nucleophilic molecule (highly negatively charged molecule)
into a molecule with a leaving group (electron drawing group attached to the
parent molecule through an unstable chemical bond). Figure 3 is a general
scheme for an SN2 nucleophilic substitution reaction. The nucleophilic molecule
has a high affinity towards the relatively electron deficient centre in the
parent molecule created by the electron pulling leaving group. As a result, the
nucleophilic molecule forms a covalent bond with the parent molecule and
displaces the leaving group. The stereo‑configuration of the parent
molecule is also changed.
Figure 3 Nucleophilic substitution:
Nu = nucleophilic molecule, X = leaving group.
In the synthesis of 18F‑FDG, 18F
ion is the nucleophile. The precursor is mannose triflate in which the 1,3,4,6
position carbons of a mannose moleucle are protected with an acetyl group and
triflate is the leaving group at the 2‑carbon. In the presence of
Kryptofix 222TM as catalyst and acetonitrile as solvent, 18F
ion approaches the mannose triflate at the 2‑carbon, while the triflate
group leaves the protected mannose molecule to form 18F‑FDG
Figure 4 Synthesis of 18F-FDG by nucleophilic
Although synthesis of 18F‑FDG can be
carried out in different computer controlled automatic synthesizers, the
nucleophilic process proceeds in roughly same stages:
Removal of 18F from the 18O-
water coming out from the cyclotron target.
Fluorine has a high hydration energy, so water is not a
suitable solvent in this synthesis. Polar aprotic solvent such as acetonitile
should be used in an SN2 nucleophilic substitution reaction. Since 18F‑
is produced by a 18O(p,n)18F‑ reaction,
it is necessary to isolate the 18F ion from its aqueous environment.
The most convenient way to isolate is to use a light QMA (Quaternary ammonium
anion exchange) Sep‑Pak column (Accell Plus QMA Sep‑PakTM).
The 18F‑ is retained by or via an ion‑exchange
reaction and allowed the 18O‑water to flow through. The
retained 18F‑ is then eluted with an acetonitrile
solution of Kryptofix and potassium carbonate (Figure 5).
Figure 5 (a) Retention of 18F-FDG in
light QMA ion exchange column; (b) elution of 18F from light
QMA ion exchange column.
In an aqueous environment, any negatively charged ions must
be accompanied by positively charged counterparts. Usually, the 18F�
washed out from the cyclotron target is accompanied by traces of metal ions
from the surface of the target body. When passing through the light QMA anion
exchange ion, the 18F � is retained and the metal ions
will be lost in the 18O‑ water. Hence, it is
necessary to introduce a positively charged counter ion to restore the 18F�
reactivity before evaporation of residual 18O‑ enriched
Several types of positively charged counter ions have been
used, including large metal ions such as rubidium or caesium; potassium ion
complexed by a large ring structure such as Kryptofix 222TM and
tetrabutylammonium salts [16‑17]. Kryptofix 222TM is a cyclic
crown ether (Figure 6), which binds the potassium ion, preventing the formation
of 18F‑KF. Thus, potassium acts as the counter ion of 18F‑
to enhance its reactivity but does not interfere with the synthesis.
Figure 6 Kryptofix 222 ™ and K+.
Since Kryptofix 222TM causes apnoea and
convulsion, all automatic synthesis modules have multiple removal steps so that
there is only negligible amount of Kryptofix in the final 18F‑FDG
products. Tetrabutylammonium salts (TBA) are also widely used as catalyst in
place of Kryptofix 222TM .
Logically, the addition of a counter cation also includes
the addition of another anion. The carbonate anion is most widely used because
it is less likely to interfere with the synthesis .
Evaporation of residual 18O- water
from the 18F with acetonitrile
After the 18F‑ is eluted into reaction
vessel, it is necessary to evaporate any residual water from the solution. The
advantage of using acetonitrile as the eluting solvent is that it forms an
azeotropic mixture with water. Evaporation of the acetonitrile in a nitrogen
atmosphere will at the same time remove any residual 18O‑
water escaped into the reaction vessel together with the 18F.
Most of the 18F‑FDG automatic synthesizers perform the
acetonitrile evaporation step several times to ensure all the residual 18O‑
water is removed. All components of the synthesis system are also rinsed
with acetonitrile to remove moisture. Dry nitrogen (moisture content less than
3 ppm) should be used in the synthesis
Addition of mannose triflate into the 18F-
The nucleophilic substitution takes place in this stage.
After the evaporation of any residual water, the precursor is added to the 18F‑.
The choice of precursor depends on the ease of preparation, ease of producing
the final product, consistency, yields, and so on. The most commonly used
precursor molecule in synthesis of 18F‑FDG is 1,3,4,6‑O‑Acetyl‑2‑O‑trifluoro-methanesulfonyl‑beta‑D‑mannopyranose
(mannose triflate). Its structure (Figure 7) is similar to that of FDG, except
with a triflate group at the 2 carbon position and acetyl groups at 1,3,4,6
position carbons via ester bonds, which can be readily broken at a higher or
lower pH. The use of acetyl groups is to protect the hydroxy groups so that
fluorination would not occur at these positions. The 18F ion
approaches the mannose triflate at the 2 position carbon, while the triflate
group leaves the protected mannose molecule to form 18F‑FDG
(Figure 4). After the nucleophilic replacement of the triflate group by 18F‑,
the acetyl groups can be easily removed by hydrolysis to give rise to 18F‑FDG
Figure 7 Structures of mannose triflate
The choice of leaving a group is an important consideration.
A good leaving group should have the properties of leaving the parent molecule
readily. Once it departs from the parent molecule, its negative charge is
stabilised by delocalisation and it will not re‑enter the parent
Commonly available leaving groups include triflates,
tosylates, and mesylates, among others. The choice of leaving a group depends on the
nature of the reaction, the solvent, the stability of the precursor, and so on.
All of the leaving groups listed in Table 1 except chlorides have been used in
radio‑fluorination reactions. In the synthesis of 18F‑FDG,
triflates produces a higher and more consistent yield at about 50 to 60% .
Table 1 A comparison of various leaving
Hydrolysis to remove the protective acetyl groups to form
The final step of the synthesis is to remove the protective
acetyl groups on the 1,3,4,6 position carbons. This can be accomplished by
either using hydrochloric acid (acid hydrolysis) or sodium hydroxide (base
hydrolysis). Acid hydrolysis requires a longer time and higher temperature.
Base hydrolysis, which is more commonly used currently, is faster and takes
place at room temperature. One of the improved base hydrolysis is to adsorb the
1,3,4,6 acetyl protected 18F labelled 2 deoxyglucose on to a C‑18
reverse phase column. All other impurities can be removed by rinsing heavily
with water. Sodium hydroxide is added to the column so that the base hydrolysis
occurs on the column surface. The final 18F‑FDG product can be
eluted with water while the unhydrolysed or partially hydrolysed 1,3,4,6 acetyl
protected 18F labelled 2 deoxyglucose remains on the column .
Purification of the final 18F-FDG product.
Purification of the final 18F‑FDG can be
performed with a series of anion exchange column, C‑18 reverse phase
column and alumina column. Most automatic synthesizers can produce 18F‑FDG
of over 95% routinely.
Quality Control of 18F-FDG
The quality requirements of 18F‑FDG are set
out in various pharmacopoeia including the USP , BP , EP , etc. The
US FDA has also published a draft Chemistry, Manufacturing and Controls (CMC)
document concerning 18F‑FDG . It should be noted that the
quality control requirements of 18F‑FDG differ among these
references. An excellent comparison between them can be found elsewhere .
In Asia, Taiwan has established an official guideline for the compounding of
PET drug products, as well as for the quality control of 18F‑FDG.
Different countries my adopt a different set of standards.
The BP is described in this article solely because this is the standard adopted
by the author�s country. Table 2 lists the quality control tests required by BP
. Due to short half‑life of 18F‑FDG, not all the
listed tests can be completed before release of the 18F‑FDG
product. The BP allows the 18F‑FDG to be released before the
radionuclidic purity test, bacterial endotoxin test, and sterility test are
Table 2 Quality control tests of 18F-FDG
listed in BP
There are other tests not listed in the BP, but may be of
significance. The BP does not list a test for ethanol, which is widely used in
the synthesis of 18F‑FDG. Both USP and BP do not list the
membrane filter integrity test. However, the test is essential as an indirect
evidence of the 18F‑FDG product sterility because the
sterility test result will not be available until much later.
Although the BP does not specify the test method, it is
obvious that a visual inspection of the 18F‑FDG is implied.
The product should be observed behind adequate shielding. While BP allows a
slightly yellow colour, this may indicate the presence of impurities. An 18F‑FDG
product should only be clear and colourless.
Identity (radionuclidic and radiochemical)
In BP, the tests for radionuclidic identity and
radiochemical identity are the same tests for radionuclidic purity and
radiochemical purity. The radionuclidic identity can be confirmed either by
obtaining a gamma spectrum or measuring the half life of the product. However,
the photon energy of 0.511 MeV and the sum peak at 1.022 MeV are common
features to positron emitters. Hence, obtaining a gamma spectrum may not be
adequate in confirming the presence of 18F‑ .
Measurement of the half‑life can be carried out by
measuring the same test solution in the same dose calibrator at 2 or more time
points. The half‑life is then calculated by plugging the results into the
radioactivity decay equation. The BP does not specify the time interval between
each measurement, but it should be long enough to allow a significant decay.
The author suggests a minimum decay period of of 20 to 30 min. Other experts
have established that a minimum of 10 min is necessary . The measurement of
half‑life is a more reliable method in confirming the presence of 18F‑.
In BP, the radiochemical identity can be confirmed either by
HPLC or TLC. The TLC is easier, but as accurate and reliable as the HPLC.
However, TLC may take longer time. For the test of 18F‑FDG,
the TLC stationary phase is TLC‑SG and the mobile phase is acetonitrile :
water (95%:5% v/v). The Rf of the 18F‑FDG, free 18F‑,
and acetylated 18F‑FDG are abut 0.45, 0.0 and 0.8 to 0.95
respectively. It should be noted that TLC results can vary according to
different brands of TLC plates and operation conditions. It is therefore
important to use the same brand of TLC‑SG plate and freshly prepared
mobile phase if possible. When plates with a new batch number (from the same
brand) are used, the Rf values should be confirmed as per the validation
process. The spotting technique also has significant effects on the TLC
results. The spot size should be about 2 to 5 �L. It should be dried and placed
above the mobile phase level.
The pH value of an injectable should be as close to the
physiological pH as possible. The BP does not specify a method for testing the
pH of the 18F‑FDG. Some laboratories would use pH papers while
others would use pH meters. It should be noted that the pH paper used should be
verified with standard pH buffers, display a colour change for each 0.5 pH
unit, and the pH value measured using pH paper is only an approximate 
The BP specifies the chemical purity FDG and 2‑chloro‑deoxyglucose
(for acid hydrolysis synthesis only) to be determined by HPLC with a strong
basic anion exchange column. The author has used a Carbopac� column with good
results, however, other commercially available strong basic anion exchange
columns can perform equally well. The mobile phase is 0.1M NaOH and the flow
rate is 1ml/min. Since NaOH absorbs carbon dioxide from air readily, it should
be protected from air, stored in plastic containers and freshly prepared if
possible. The Carbopac� column is also very sensitive to carbonate ions. This
adds to the importance of protecting the NaOH from air.
The test protocol includes injecting and run the HPLC of a
reference standard solution and then run the HPLC of the test solution. The
acceptance criteria is the area under the FDG peak of the test solution should
be less than that of the reference solution. In theory, the reference material
used should be of pharmacopoeia grade. The USP has listed three USP grade FDG
reference standards, but so far it has not been available commercially. One can
only obtain non pharmacopoeia grade FDG or 2‑chloro‑deoxyglucose
from commercial vendors for preparation of reference solutions.
It is interesting to note that the BP states the preparation
of glucose reference solution in addition to FDG and 2‑chloro‑deoxyglucose
but does not require the reporting of glucose quantity presence in an 18F‑FDG
The test of Kryptofix involves spotting the test solution
and the reference standard on a TLC‑SG plate and then develop the plate
in a mixture of methanol and ammonia (9:1 v/v). The developed plate is then
exposed to iodine vapour. The test solution spot should have a colour lighter
than the reference solution spot. However, this TLC method is unreliable. The
spots can be indistinct . Alternatively, Kryptofix can be determined by
placing the TLC plate in an iodine chamber directly or by GC .
The BP lists only the determination of residual acetonitrile
in the 18F‑FDG product. But the BP does not specify the test
method, although the description implies that a GC should be used.. The GC
column should be used for aqueous solvent and the oven temperature should be
constant. A flame ionisation detector is adequate. The actual temperature,
carrier gas flow rate, and run time vary among different laboratories.
The BP does not mention any test of residual absolute
ethanol. Since absolute ethanol is widely used in deferent 18F‑FDG
synthesis modules and GC test takes only a few minutes, it is better to measure
the residual absolute ethanol concentration in the 18F‑FDG
product. Many laboratories adopt the USP limits of 0.05% or 5mg/mL
The BP lists recording gamma spectrum and measuring half‑life
as two methods to determine the radionuclidic purity of a 18F‑FDG
product. Measurement of half‑life can only confirm the presence of 18F.
It does not reveal the percentage purity of the 18F‑
present. The more accurate method is to obtain a gamma spectrum with a multi‑channel
analyzer after confirmation of 18F‑ by measuring
its half‑life The BP allows the 18F‑FDG to be released
before the completion of this test.
Some experts doubt the necessity of carrying out a
radionuclidic purity determination since its outcome is not crucial to patient
welfare and imagine quality. In fact, many laboratories measure the half‑life
of their 18F‑FDG, but they do not obtain gamma spectra of
their 18F‑FDG products routinely.
The BP lists both HPLC method and TLC method for the
determination of radiochemical purity. The method has been described in
radiochemical identity under section �(2) Identity (radionuclidic and
Sterility is to be tested by incubating the test sample with
both Soybean Casein Digest Medium(SCDM) and Fluid Thioglycollate (FTM) Medium
for 14 days at 37�C. Soybean Casein Digest Medium is a culture media for
aerobic bacteria and fungi while FTM is a media for anaerobic bacteria. Growth
Promotion Tests should be performed simultaneously. This test is performed by
incubating �reference bacteria� in SCDM and FTM. Bacterial growth should be
visible within a specified period of incubation (Table 3). Results of the growth
promotion would indicate that the SCDM and FTM are capable of supporting
bacterial growth, hence results of the sterility test are reliable. However,
the US FDA has recommended a 30‑hr window for 18F‑FDG
within which the sterility test must be started.
Table 3 Test microorganisms listed in
BP suitable for Growth Promotion test
Most PET facility would forward their samples to other
microbiology laboratories for sterility test. A period of decay is necessary to
ensure that the radioactivity level is not excessive. In many cases, a 24‑hr
window may not be long enough. Individual laboratories should establish their
own protocols in this matter.
Bacterial endotoxins (LAL test)
The bacterial endotoxins level is commonly tested using the
gel‑clot technique. The technique uses a lysate of amoebocytes from
horseshoe crab, Limulus polyphemus. The addition of bacterial endotoxins
to a lysate solution produces turbidity, precipitation or gelation of the
mixture. Most commercially available endotoxin testing kits require an
incubation period of 20 to 60 min. Hence, it is unlikely that the test can be
completed before release of the product. The BP allows the release of the 18F‑FDG
before completion of the bacterial endotoxins test. Some PET facility would
forward their samples to other microbiology laboratories for endotoxins test.
As described earlier, a period of decay is necessary to ensure that the
radioactivity level is not excessive.
Bacterial endotoxins level can also be determined by
spectrophotmetry. The chromogenic method makes use of the colour change of a
substrate produced by the formation of an enzyme which in turn results from the
addition of endotoxins to Limulus polyphemus lysate. Gram‑negative
bacterial endotoxins have been found to activate a proenzyme in Limulus
polyphemus lysate. The rate of this activation reaction depends on the
concentration of the endotoxins present. The activated proenzyme then catalyses
the spitting of substrates added. The splitting of the substrates results in a colour
change which can be monitored by spectrophotometry. Then time required for the
appearance of the colour change is inversely proportional to the endotoxins
concentration present. Hence, the endotoxins concentration can be determined by
comparing the reaction time of a sample to a standard curve generated from a
series of standards containing known concentrations of endotoxins [26, 27].
The endotoxins concentration in a sample can also be
determined by measuring the turbidity change during the gel‑clot
formation using spectrophotometry. The time for onset of turbity is inversely
related to the endotoxin concentration present. Endotoxin level in unknown
sample can be determined by comparing the time required for turbidity onset to
a standard curve generated from a series of standards with known endotoxins concentrations
. However, such method is extremely sensitive to interference from
polysaccharide such as β‑Glucans. Improved methods have been
developed to reduce such interference .
Filter membrane integrity test
This test is not required by BP and USP, but is required in
the CMC section of US FDA . Many laboratories have also included this test
as one of their routine quality control tests of 18F‑FDG.
Since the 18F‑FDG is released and injected
into patients before the sterility results are available, there is virtually no
assurance of the product sterility. Filter membrane integrity test provide an
indirect evident that the product is sterile. The argument is that if the
integrity of the filter membrane is not compromised, the filter would have performed
its function of removing any bacteria present in the 18F‑FDG
A few filter membrane integrity testing devices are
available commercially. Some of them rather complicated and some of them are
simple hand‑held types. The mechanisms behind them are similar. A stream
of air is passed through the devices to the filter, then to a reservoir of
water. An indicator will show the pressure exerted on the filter membrane by
the air stream. The filter membrane should be able to stand the maximum
pressure indicated in the specification of the filter. If the membrane is
broken the air stream will pass through the membrane into the water. Air bubble
will then be seen (Figure 8).
Figure 8 (a) Filter membrane is intact,
no air passes through the membrane, no air bubble in water;
(b) Filter membrane is broken or at bubble point, air passes
through the membrane, air bubble in water. The bubble point
should be higher than or equal to maximum pressure listed
in the specification of the filter.
The biggest disadvantage of performing filter membrane
integrity test is that usually the filter membranes are highly radioactive
immediately after production of 18F‑FDG. But allowing a 24‑hr
decay would defeat the purpose of providing an evident of sterility before
injecting the 18F‑FDG. Individual laboratories would have to
develop their own protocols in this matter.
Much of the current success in clinical PET can be
attributed to the development of 18F‑FDG. Synthesis of 18F‑FDG
is probably the most repeatable and highest yield in all PET
radiopharmaceuticals synthesis. However, the future of PET would depend on the
upcoming of new radiopharmaceuticals and the regulatory framework for the usage
and approval of new PET drug products (e.g. NDA, IND etc). Synthesis, quality
control and regulation of 18F‑FDG become a model in the
development new PET radiopharmaceuticals. Nucleophilic and electrophilic
fluorinations are very common reactions to label compounds with 18F.
The concept of using automatic synthesis modules is now a platform in PET
radiopharmaceuticals synthesis. It is hope that this article will provide a
brief review of 18F‑FDG synthesis and quality control for
those who are interested in development of PET radiopharmaceuticals. However,
this article is only a concise review and not complete. Interested readers are encouraged
to seek more detailed information
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|Received 1 August 2006; received in revised form 20 December 2006; accepted 30 December 2006
Correspondence: Departments of Nuclear Medicine
& PET and Experimental Surgery, Singapore General Hospital,
Outram Road, Singapore. Tel.: +(65) 6326-5666; E-mail: firstname.lastname@example.org
Please cite as: Yu S,
Review of 18F-FDG synthesis and quality control, Biomed Imaging Interv J 2006; 2(4):e57
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