k-
>.
BNL-68513
Design and Synthesis of 2-Deoxy-2-[18F] fluoro-D-glucose
(18FDG)
JoannaS. Fowler and Tatsuo Ido
ChemistryDepartment,Brookhaven National Laboratory, Upton NY 11973
Tohoku University, Sendai,Japan
THE FIRST SYNTHESIS of 2-deoxy-2-[’ 8F]fluoro-D-glucose (18FDG)for human
studiestook place in 197ti the result of a collaboration between scientists at the National
Institutesof Health the Universityof Pennsylvaniaand Brookhaven National Laboratory which
had begun three years earlier. ‘8FDG was developed for the speci.iicpurpose ofmapping glucose
metabolism in the living humanbrain thereby serving as a tool in the basic human neuroscience
(Ido et al, 1978; Reivich et al, 1979). With ‘8FDG it was possible for the f~st time to translate
the [’4C]2-DG autoradiogiraphicmethod (Sokoloff, 1979) to the clinical arena. Around the same
time that ‘ 8FDG was developed, preclinical studies suggestedthe utilityof’8F13G for studies of
myocardial metabolism (Gallagher et al, 1977) and for tumor metabolism (Sore et al, 1980).
In the fust human studies and many that followed, ‘ 8FDG was synthesized at Brookhaven
National Laboratory on Long Island and sent by small plane to PhiladelphiaAirport and then
transportedto the Hospital of the University of Pennsylvaniawhere the fust images of a human
volunteer were made (ilgure 1). In spite of the 110 minutehalf-life of fluorine-18 and the
relatively low yields of’ 81’DG,this remote supply of’8FDG served to demonstrateits unique
properties and its utilityas a scientific tool for basic researchand clinical diagnosis. In the next
few years BNL supplied ‘ 8FDG to the Hospital of the Universityof Pennsylvania and also to the
National Institutesof Health. SOOI>however, most of the major institutionshaving a cyclotron
produced ‘8FDG for their own use, It is remarkablethat25 years later,the production of ‘8FDG
1
at regional cyclotron-synthesis centers and its distributionto remote hospitals and other
institutionsfor clinical use particularlyin cancer is the major mode for supplying ‘8FDG.
In this article we will highlightthe major milestones in chemistry from the conceptual
design throughthe evolution of its chemical syntheses. We note that there have been other
reviews of various aspects of’8FDG design and chemistry (Fowler and Wolf, 1986; Gatley et a~
1988) including a very recent article on *8FDGchemistry(Beuthien-Baumannet al, 2000).
DESIGN OF 18FDG: THE IMPORTANCE
OF C-2
‘8FDG was modeled after carbon-14 labeled 2-deoxy-glucose (14C-2DG). 2-Deoxy-Dglucose (2-DG) is a derivative of glucose in which the hydroxyl group (-OH) on C-2 is replaced
by a hydrogen atom (Figure 2). The biological behavior of 2-DG is remarkably similar to
glucose, with a few importantdi.fllerences.Like glucose, 2-DG undergoes facilitated transport
into the brain followed by phosphorylation by hexokinase because the hydroxyl group on C-2 is
not a critical element for eitherof these processes. In contrastto glucose, however, metabolism
does not proceed beyond phosphorylation because the hydroxyl group on C-2 is crucial in the
next step, phosphohexose isomerase. As a result,2-deoxy-D-gluco se-6-phosphate is trapped in
the cell providing a record of metabolism. In essence, removal of the hydroxyl on C-2 isolates
the hexokinase reaction. This property of 2-DG was noted in 1954 by Sols and Crane (Sols and
Crane, 1954) who remarked:
“2-deoxy-glucose possesses certain advantages over glucose as a substrate for
experimental stu~iies with crude preparations
of brain and other tissue hexokinases.
phosphate
is not inhibitory and it is not a substrate for either
ester fonnedfiorn
2-deoxyglucose
phosphohexose
isornerase or glucose-6-phosphate
dehydrogenase.
deoxyglucose
isolates the hexokinase reaction. ”
2
The
Thus, the use of 2-
..
,.
The translationof the “C-2-DG method to humansrequired that2-DG be labeled with an
isotope which decayed by body penetratingradiationand thatthe chemical properties of the
isotope and its position on the deoxyglucose skeleton would not significantly perturb its
biochemical and transportproperties. Of course, this could be achieved by isotopic substitution
of stable carbon in the 2-deoW-D-glucose structurewith carbon-11, and this synthesis was
accomplished shortly after the development of 18FDG(MacGregor et al, 1981). However,
fluorine-L18was chosen fclr initialstudies both because the C-F bond is a strong bond and
- because its 110 rninptehalflife was sufficiently long for transportfi-omLong Island to
Philadelphiawhere the first human studieswere carried out on the Mark IV scanner (Kuhl et al,
1977).
The design of an F-18 labeled version of 2-deoxyglucose hinged on substitutingthe F- 18
on a carbon atom which would preserve the properties of the parentmolecule. The choice of C-2
for the fluoriue substituticmwas an obvious one. C-2, unlike other carbon atoms in the molecule,
can be modiEed without interferingwith either facilitatedtransportrequiredto bring the
molecule across the bloocl brainbarrier (BBB) or the hexokinase reaction. It was also reasonable
to assume that 2-deoxy-2-.fluoro-D-glucose (FDG) would not be a substratefor
phosphohexoseisomerase,, Thus it was predicted that2-deoxy-2-[18F]fluoro-D-glucose (’8FDG)
would be a good substratefor hexokinase and that,with the absence of a hydroxyl group on C-2.
the phoshorylated product would be intracellukirlytrapped at the site of metabolism providing a
record of metabolic activity which could be imaged externally(Figure .$). The development of
‘8FDG was fi.u-thersupported by the fact thatFDG had been synthesized in unlabeled form arid
shown to be a good substri~tefor hexokinase (Bessell et al, 1972). The importance of
substitutingthe fluorine atom on C-2 is illustratedby the dramaticreduction in affinity for
hexokinase with 3-deoxy-3-fluoro-D-glucose and 4-deoxy-4-fluoro-D-glucose (Table 1).
In order to test the hypothesis thatFDG would be a good model for 2-DG, FDG was
labeled with C-14 (Ido et al, 1978). Autoradiographicstudieswith [’4C]FDG in the rat gave
similarresults as those obtained for [’4C]2-DG and phosphorylation by hexokinase also
proceeded as predicted @eivich et al, 1979).
These studies formed the groundwork for developing a synthesis for 2-deoxy-2[’8F]fluoro-D-glucose (’8FDG) for studiesof brain glucose metabolism in humans. However,
‘8FDG’s unique high uptake in rapidly growing tumors (Sore et al, 1980) as a resultof enhanced
tumor glycolysis (Weber, 1977) coupled with its low body background resulted in a very high
signal to noise ratio to detect tumors in the body. The low body background from’8FDG is due
on partto the fact that ‘ 8FDG which is not phosphorylatedby hexokinase is excreted (Gallagher
et al, 1978). This contraststo the behavior of glucose which is not excreted due to resorption
from urine to plasma via active transportacross the renaltubule. The presence of a hydroxyl
group on C-2 which occurs in glucose but not ‘8FDG is required for active transport(Silverman,
1970). This property of low body background resultingfi-om ‘ 8FDG excretion which was not
anticipatedin the initialdesign of’8FDG for brainstudieshas elevated it to the forefi-ontas a
tracerfor managing the cancer patient (Coleman, 2000).
FIRST SYNTHESIS OF 18FDGFOR ANIMAL AND HUMAN STUDIES
WMl ‘8FDG as a goal, the options for rapid incorporationof F- 18 in the C-2 position
were assessed. Fortunately,there were two synthesesfor unlabeled2-deoxy-2-fiuoro-D-glucose
in the chemical literatureat the time that *8FDG was being developed. One of these involved the
electrophilic fluorination of 3,4,6-triacetylglucal with the electrophilic fluorination reagent
4
..
>’
trifluoromethylhypofluorite (CF30F) (Adarnson et al, 1970) which was used in the synthesisof
[14C]FDG (Ido et al, 1978). The other syntheticapproach to unlabeled FDG involved the use of
potassium bifluoride (ICHFZ)in a nucleophilic displacement reaction (Pacak et al, 1969).
Though neither CF30F nor KHFz nor the syntheticschemes was directly applicable to the
synthesisof’ 8FDG, it was likely that elemental fluorine (F2) could be substitutedfor CF30F
based on initialreports that its reactivity could be controlled in diluted form (Bartou 1976). This
approach was successfid and the fluorination of 3,4,6-tri-O-acetylglucal with elemental fluorine
representeda new syntheticroute to unlabeled FDG (Ido et al, 1977). Fortunatelythe
methodology for producing [’8F]F2by the irradiationof a neon target containing F2via the
2~e(d,cx)’8F reaction using specially prepared nickel irradiationvessel had already been
developed (Lambrecht and WOK, 1973) and applied to the first synthesisof 5-[’ 8F]fluorouracil
(Fowler et al, 1973). Thus electrophilic fluorinationof 3,4,6-tri-O-acetyl-D-glucal with [’8F]Fz
produced a 3:1 mixture of the F-18 labeled 1,2-difluoroglucose isomer and the 1,2-difluoromannose isomers which were separatedby preparativegas chromatography. The 1,2difluoroglucose isomer was hydrolyzed in HC1to give 18FDG(Figure 4). The yield was about
8Y0, the puritywas >98% and the synthesistime was about 2 hours.
Because ‘8FDG had never been administeredto a humansubject either in labeled or in
unlabeled forl~ there was no adequate safety data to support administrationto humans. The
literatureat the time had one report of an LDsOfor FDG of 600 mg/kg in rats (Bessell et al,
1973). This was not.sufficient to support human studies. Therefore toxicity studies were
performed in mice and dogs with unlabeled FDG (Sorn et al, 1980). Doses of FDG were 14.3
mg/kg and 0.72 mg/kg ach-ministered
intravenouslyat weekly intervalsfor 3 weeks for mice and
dogs respectively. There was a control group, which was injected with vehicle for each species.
5
I
I ‘---
‘,
‘,
Mice were weighed weekly and at the end of 3 weeks they were sacrtilced and their organs
examined grossly and microscopically. For dogs, baseline, 2-hour, 1-week and 2-week blood
and urine samples and a few CSF samples were obtained for analysis. At the end of 3 weeks the
dogs were sacrificed and their internalorgans were examined grossly and microscopically.
Neither mice nor dogs thatreceived FDG showed any gross or microscopic differences with their
respective control groups. These resultsindicated thatthe anticipateddose of 1 mg of 18FDG
(0.014 mglkg) could be safely administeredto humanvolunteers. This was a factor of 150 times
less thatthat administeredto dogs and 3000 times less thatthat administeredto mice without any
evidence of acute or chronic toxicity.
Radiation dosimetry was estimatedbased on the tissue distributionof *8FDG in dogs
sacrtilced at 60 minutes and at 135 minutespost injection of’8FDG (Gallagher et al, 1977). The
targetorgan in these initialestimateswas the bladder which received 289 mrern/mCi (Reivich et
al, 1979). These estimateswere laterrefined when human distributionand excretion data
became available (Jones et al, 1982).
These developments: the design of 18FDGbased on a knowledge of structure-activity
relationships;the synthesisof [’4C]FDG (Ido et al, 1978); autoradiographiccomparison of
[’4C]FDG and [’4C]2-DG (Reivich et al, 1979); the synthesisof ‘8FDG (Ido et al, 197S)
toxicological studies of FDG (Sore et a~ 1980); biodistributionof ‘.*FDG in mice and dogs
(Gallagher et al, 1977); and dosimetry calculations (Reivich et al, 1979) all combined to support
the ffist studies in humans.
IMPROVEMENTS
AND A MAJOR MILESTONE (1976-1986)
During the next 10 years after the development of the electrophilic route to 18FDG,its
utilityas a radiotracerin the neuroscience and in the diagnosis of heartdisease and cancer grew.
6
,,
1“
This stimulatedthe investigationsof difi?erentsyntheticmethods to improve yields thereby to
increase availability
y. Other electrophilic routes were developed and nucleophilic routes were
sought (Table 2). The most usefid of the electrophilic routes was labeled acetylhypofluorite
(CHSCOZ[’8F]which offered advantagesover [18F]Fzin terms of yield and experimental
simplicity. Labeled acetylhypofluorite was readily synthesized via in situ formation in acetic
acid or via gas-solid phase synthesisusing [*8F]F2. However, it was subsequently found thatthe
stereospecitlcity of acetylhypofluorite was dependenton reaction conditions and solvent with
one of the most commonly used methods giving ca. 15°/0of 2-deoxy-2-[’ 8F]fluoro-D-rnannose
(18FDM), an isomer with the fluorine atom occupying the axial position. Are-investigation and
analysis of the product distributionfrom other fluorinationreagents derived horn elemental
fluorine and showed thatthey all produce the mannose isomer in varying amounts (Bids et al,
1984). The synthesisproducing the most acceptable product purity involved the gaseous
CH3C02[]‘1?] fluorination of 3,4,6-tri-O-acetyLD-glucal in fireon-11. In this synthesis, the ratio
of’ 8FDG:’‘FDM was 95:5. Though the effect of using a mixture of’8FDG and.‘ 8FDM on
glucose metabolic rate in ithe humanbrainhas been reported to be negligible, the use of a mixture
was less than ideal because the rate constantsand the lumped constants for these two molecules
could differ in a non-predictable fashion introducinga variable in human studies. A kinetic
comparison of’ 8FDG and.‘ 8FDM in the rhesusmonkey indicates thatthere is a 20°/0reduction in
apparentcerebral metabolic rates for glucose when ‘‘FDM is used. If this is similar in humans, it
was estimatedthat a 15°/0impurityof’8FDM would lead to an underestimationof 3°/0in glucose
metabolic mte (Braun et al, 1994).
In addition to the production of the F-18 labeled rnannoseisomer, there were other
limitationsto the electrophilic route to ‘ 8FDG. The nuclear reaction commonly used to produce
J
‘c
‘r
[’8F]FZwas the 2~e(d,cz)’8F in a high pressureneon gas targetto which a small amount of Fz gas
was added (Casella et al, 1980). The targetryto produce [’8F]Fz and its maintenanceat the time
was curribersomeand handling elemental fluorine, the most reactive of all elements, required
special precautions. However, the major limitationwas thatunder the best circumstances, only
50% of the label is incorporated into the product. This is also the case in the use of CHSC02[18F]
because half of the label is lost in the conversion of [18F]Fzto CHSCOZ[18F].
In terms of F-18 yield, anothernuclearreaction the ‘80(p,n)’8F reactio% was fm superior
as can be seen when the cross sections are compared (Fi=wre5) (Ruth and Wolf 1979). The
adaptationof the’80@,n)1 *Freaction to a practicalproduction method which would conserve the
inventory of costly and occasionally rare O-18 enrichedwater stimulatedthe development of
small volume enriched water targetswhich produced F-18 as [’8F]fluoride in high yield (Wieland
et al, 1986; Kilbourn et al, 1984). Methods for recovering O-18 enriched water for re-use have
been reported including the use of an anion exchange resin (Dowex 1 x 10) which permits a 95%
recovery of[’8F]fluoride ion and a loss of’ ‘O-enriched water of less than 5 pl from a volume of
3 ml (Schlyer et al, 1990). With the availability of high yields of [’ ‘F] fluoride, the development
of a high yield nucleophilic route to ‘8FDG became even more compelling. A number of
approaches were reported prior to 1986 (Table 2). All of these were plagued with difficult steps
including low incorporation of F- 18 and difficulty in removing protective groups. Thus the
electrophilic route, with its limitations,remainedthe method of choice through 1985.
A major advance in the synthesis of 18FDGfrom [’ ‘F] fluoride was reported in 1986 when
it was discovered thatkryptofm [2.2.2] could be used to increasethe reactivity of [’ 8F]fluoride
(Hamacher et al, 1986). In essence, kryptofm masks the potassium ion which is the counterion
of the.[’ ‘F] fluoride. The reaction of [’ ‘F] fluoride with 1,3,4,6-tetra-O-acetyl-2-O-
8
,,
,“
trifluoromethanesulfonyl-+LD-manno-pyranoseto give 1,3,4,6-tetra-O-acetyl-2-[’8F]fluoro-~-Dgluco-pyranose gives a 95% incorporation of F- 18 and the overall synthesis including
purification procee@ in about 60% yield. The synthesisinvolves 2 steps, displacement with
[18F]fluofideand de-protmtion with HC1@igure 6). This was an almost perfect solution to the
need to produce ‘ 8FDG in high yield and in high purity. It also produced ‘ 8FDG in no-carrieradded form and laterion chromatographicanalysisof various preparationsfrom this route
showed the presence of FDG in a mass of 1-40 p.g(Allexoff et al, 1992). Thus this new method
served an ,kcreasing need,in the nuclear medicine and the neuroscience communities which were
discovering new uses for ‘8FDG. It is also simple and amenable to autonmtionand in the 15
years since it was reported, a number of automatedsynthesismodules have become
commercially available (Satyamurthyet al, 1999).
18FDG SYNTHESIS (1986-PRESENT)
No major new developments have been made following this simple, high-yield
nucleophilic route. However, a number of variantshave been investigated to improve the
displacement and the deprotection steps and considerable effort has been put into free-tuning.the
reaction and to identi&nig impuritiesand contaminantswhich are carried through to the final
product. This has become more critical with the increasinguse of’ 8FDG in clinical practice
where a pharmaceuticalquality product is required.
One of the goals has been to optimize the removal of kryptofix ‘2.2.2 which is used to
facilitate the displacement reaction. Methods have been reported for both the removal (Moerlei.n
et al, 1989; Alexoff et al, 1991) and the detection (Ferrieriet al, 1993; Chaly and Dahl, 1989) of
kryptof~. The simplest method to remove k.ryptofixis the incorporation of a short cation
9
exchange resin k! the synthesissystem so thatthe hydrolysate (HCl) passes through the cartridge
before final purification (Alexoff et al, 1991).
Alternativesto the use of kryptof~ 2.2.2 have been investigated in order to avoid its
appearanceas a contaminantin the final product. These include the use of tetrabutylammonium
as the counterion (Yuasa et al, 1997; Brodack et ~ 1988) as well as the development of a resinsupported form of[’8F]fluoride for on-column fluorination (Toorongian et a~ 1990). The latter
method is synergistic with the use of an anion exchange resin to recover O-18 enriched water for
re-use. Several kinds of polymer supported quaternaryammonium and phosphonium salts such
as dimethylaminopyridiniumor tributylphosphoniumhave been systematically examined for the
on-column synthesis of ‘8FDG (Ohsaki et al, 1998).
Alternatives to deprotectionwith HC1have also been investigated. The use of a cation
exchange resin was investigatedand reportedto efficiently hydrolyze the acetylated labeled
precursor in 10-15 minutes at 100 degrees thereby eliminatingthe need for a neutralizationstep
in the synthesis (Mulholland, 1995) and also serving to remove kryptofm 2.2.2. The use of base
hydrolysis in the deprotection step has also been investigatedas an approach to reduce the need
for high temperaturesand to decreasethe synthesistime. Though epimerization at C-2 is a
known reaction of aldoses underbasic conditions and in this case would produce ‘8FDM as a
radiochemical irnpurity (Varelis and Barnes, 1996), a systematicstudy of the reaction conditions
for basic hydrolysis determinedthat epimerizationcould be limited to 0.5% using 0.33 M sodium
hydroxide below 40 degrees for about 5 minutes.to avoid the neutralizationstep in the synthesis
(Meyer et al, 1999).
2-Deoxy-2-chloro-D-glucose (CIDG) was identified as an impurity during ion
chromatographic determinationof the speci.ilcactivity of 181?DGpreparations from the
10
,’
,
nucleophilic route (Alexoff et a~ 1992). CIDG is produced as a competing displacement reaction
with chloride ion which comes from different sources includingHC1used in the hydrolysis step.
In typical ‘gFDG preparations,CIDG is present in a total amount of <100 pg as is determinedby
ion chromatography and pulsed amperometricdetection. Larger amounts are produced when
larger amo~ts of the triflateprecursor are used. The amountof CIDG can be reduced by using
sulfhric acid instead of HC1for hydrolysis. The reduction of the amount of CIDG has also been
an impetus for avoiclingHC1in the hydrolysis step. Though CIDG does not present a toxicity
problem its presence is n~otdesireable from the standpointof pharmaceuticalquality.
OUTLOOK
Advances in chemistry and the remarkableproperties of’8FDG have largely overcome
the limitationsof the 110 minute half-ltie of fluorine-18 so that ‘ 8FDG is now available to most
regions of the US fi-om a :numberof centralproduction sites. This avoids the need for an on-site
cyclotron and chemistry laboratory and has opened up the use of’8FDG to institutionswhich
have a PET scanner (or other imaging device) but no cyclotron or chemistry irdiastructure.
Currently‘ 8FDG is used by many hospitals as an “off the shelf’ radiopharnuiceuticalfor clinical
diagnosis in heart disease, in seizure disorders and in oncology, the area of most rapid growth.
However, its ready availability has opened the possibility to also use it in more widespread
applications in the human.neuroscience including drug researchand development (Fowler et al,
1999). This is an importantapplimtion because with ‘ 817DGit is possible to determinewhich
brain regions are most sensitive to the effects of a given drug. Because glucose metabolism
reflects, in part, the energy involved in restorationof membranepotentials, regional patternsmay
be used to generate hypotheses as to which molecular targetsare mediating the effects of the
11
‘!
“!
drug. Also a baseline study can be run allowing intra-subjectcomparison before and after the
drug. Since subjects are awake and alert atthe time of the study, the behavioral and therapeutic
effects of the drug and their association with metabolic effects can be measured. Though the use
of a fictional
tracer like ‘ 8FDG is not as precise as the use of a radiotracer which is more
spec~lc for a given neurotransmittersyste~ it nonethelessprovides a measure of the final
consequences of the effects of the drug on the humanbrain. This is importantbecause even
though a drug may interactwith a particularneurotransmitter,it maybe the downstream
consequences of that interactionwhich are of relevance to its pharmacological effects. When
radiotraceravailabilitypermits, the ideal situationis to pair an’8FDG measurementwith a
neurotransmitterspecific measurementand in thatway to correlateneurotransmitter-spectic
effects with regional metabolic effects. ‘ 8FDGhas many advantages as a scientiilc tool for
preclinical studies in small animals when it is coupled with small animal imaging devices.
Because the ‘8FDG method requiresa -30 minuteuptakeperiod before the imaging is actually
done the animals can be awake duringthis period and anesthetizedimmediately before imaging,
thus avoiding the effect of anesthesiaon the behavior of the tracer.
Acknowledgment:
This researchwas performed in part at Brookhaven National
Laboratory under contract DE-AC02-98CH1 0886 with the U. S. Departmentof energy and was
supported by its Office of Biological and EnvironmentalResearch. The authors also thank
David Schlyer for his valuable comments.
12
,’
,’
Figure Ctiptions:
Figure 1.
(clockwise from upper left) Synthesisof ‘gFDG for the first human study,(left to
right, Tatsuo Ido, C-N Wan and AMed P. Wow; Delivery of’8FDG to
PhiladelphiaAirport (Tatsuo Ido and Vito Casella); ‘8FDG injection and imaging
in Mark IIV scanner(MartinReivich and Joel Greenberg); Brain images.
Figure 2.
Structureof glucose, 2-deoxy-D-glucose (2-DG) and 2-deoxy-2-fiuoro-D-glucose
(FDG) showing modifications at C-2.
Figure 3.
18FDGmodel compared to glucose and 2-DG. Note thatreplacement of the
hydroxyl 1(–OH)group at C-2 does not alterfacilitated transportor
phosphorylation by hexokinase (HK) but does prevent metabolism beyond the
phosphory]ation step.
Figure 4.
Synthesisof’ 8FDG via fluorinationwith [*8F]labeledelemental fluorine (Ido et al,
1978).
Figure 5.
Comparison of fluorine-18 yields fi-om the 2’?ie(d,u)’8F reaction and the
‘80(p,n)’8F reaction (Casella et al, 1980; Ruth and Wol~ 1979).
Figure 6.
SynthesisOf ‘8FDG via fluorination with [’8F]fluoride ion (Hamacher et al, 19S6).
13
‘,
Table 1. Substratespecificities for hexokinase. Note that substitutionsat C-2 retainspecificity
for hexokinase while substitutionson C-3 and C-4 resultin increases of more than 100
Substrate
Hexokinase
source
Km (Inrnol)
reference
D-glucose
Yeast
0.17
Bessell et a~ 1973
2-deoxy-D-glucose
Yeast
0.59M.11
Bessell et a~ 1973
2-deoxy-2-fluoro-D-glucose
Yeast
0.19*0.03
Bessell et al, 1973
2-deoxy-2-fluoro-D-glucose
Bovine brain
0.2
Machado De
Domenech and Sols,
1980
2-deoq-2-fluoro-D-mannose
Yeast
0.41M.05
Bessell et al, 1973
3-deoxy-3-fluoro-D-gluco se
Yeast
70*30”
Bessell et al, 1973
4-deoW-4-fluoro-D-glucose
Yeast
84
Bessell et al, 1973
14
—.
.“
.
Table 2. Syntheticroutes to ‘8FDG (1976-1986).
[[18F]Labeled
Substrate
Precursor
Electrophilic Methods
[’8F]F,
3.4.6-tri-O-acetvl-D-ducal
[’8F]F, -+ CHqCOz[18F]
D-glucal
[[18F]FZ+ [18F]XeFz
Nucleophilic Methods
H[18F]+ CS[18F]
H[18F]+ Et4N[*8F]
3,4,6-tri-O-acetyl-D-glucal
Methyl-4,6-O-benzylidene-3-O-methyl-2-Otrifluoromethanesulfonyl-~-D-mannopyranoside
Methyl or vinyl 4,6-O-benzylidene-cx-Dmannopyranoside-2,3-cyclic sulfate
H[18F] + KH[18F]FZ
1,2-anhydro-3,4:5,6-di-isopropylidene- l-C-nitroD-mannitol
H[lgF] +
K[18F]Kryptofix 2.2.2
1,2,4,6-tetra-O-acetyl-2-
trifluoromethanesulfonyl-~-D-mannopyranose
15
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Levy et al, 1982:
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Bessell EM, Foster AB, Westwood JH. (1972) The use of deoxyfluoro-D-glucopyranoses and
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Bessell EM, CourtenayVD, Foster AB, Jones M, Westwood JH. (1973) Some in vivo and in
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22
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