A fully automated synthesis of [18F]-FEAU and [ 18F]-FMAU using a novel dual reactor radiosynthesis module

Article abstract of DOI:10.1002/jlcr.1674

2′-Deoxy-2′-[¹⁸F]fluoro-5-substituted-1-β-D- arabinofuranosyluracils, including 2′-deoxy-2′-[¹⁸F] fluoro-5-methyl-1-β-Darabinofuranosyluracil [¹⁸F]FMAU and [ ¹⁸F]FEAU are established radiolabeled probes to monit

Full text of DOI:10.1002/jlcr.1674

Research Article
Received 9 June 2009,
Revised 5 August 2009,
Accepted 6 August 2009
Published online 7 October 2009 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1674
A fully automated synthesis of [18F]-FEAU and
[18F]-FMAU using a novel dual reactor
radiosynthesis module
Ã
Vincenzo Paolillo,a Stefan Riese,b Juri G. Gelovani,a and Mian M. Alauddina
20-Deoxy-20-[18F]fluoro-5-substituted-1-b-D-arabinofuranosyluracils, including 20-deoxy-20-[18F]fluoro-5-methyl-1-b-D-
arabinofuranosyluracil [18F]FMAU and [18F]FEAU are established radiolabeled probes to monitor cellular proliferation and
herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene expression with positron emission tomography. For
clinical applications, a fully automated CGMP-compliant radiosynthesis is necessary for production of these probes.
However, due to multiple steps in the synthesis, no such automated synthetic protocols have been developed. We report
here a fully automated synthesis of [18F]-FEAU and [18F]-FMAU on a prototype dual reactor module TRACERlab FX FN. The
synthesis was performed by using a computer-programmed standard operating procedure, and the product was purified on
a semipreparative high-performance liquid chromatography (HPLC) integrated with the synthesis module using 12% EtOH
in 50 mM Na2HPO4. Finally, the percentage of alcohol was adjusted to 7% by adding Na2HPO4 and filtered through a
Millipore filter to make dose for human. The radiochemical yield on the fluorination was 40710% (n = 10), and the overall
yields were 471% (d. c.), from the end of the bombardment; [18F]FEAU (n = 7) and [18F]FMAU (n = 3). The radiochemical
purity was 499%, specific activity was 1200–1300 mCi/lmol. The synthesis time was 2.5 h. This automated synthesis
should be suitable for production of [18F]FIAU, [18F]FFAU, [18F]FCAU, [18F]FBAU and other 5-substitued thymidine
analogues.
Keywords: fluorine-18; nucleoside; PET; automated synthesis
the short half-life of [11C] (t1/2 = 20min) there was a demand
to develop [18F]-labeled compounds; and the radiosynthesis
Introduction
A number of radiolabeled 20-deoxy-20-fluoro-5-substituted-1-b-
D-arabinofuranosyluracil derivatives have been recognized as
efficient probes for imaging tumor proliferative activity1–7
and herpes simplex virus type 1 thymidine kinase (HSV1-tk)
reporter gene expression8–20 with positron emission
tomography (PET). Among these, 20-deoxy-20-[18F]fluoro-5-
methyl-1-b-D-arabinofuranosyl-uracil ([18F]-FMAU), 20-deoxy-20-
fluoro-5-[11C]methyl-1-b-D-arabinofuranosyl-uracil ([11C]-FMAU)
and 20-deoxy-20-[18F]fluoro-5-bromo-1-b-D-arabinofuranosylura-
cil ([18F]-FBAU) are markers for DNA synthesis through
phosphorylation by human and other mammalian nucleoside
kinases including thymidine kinase TK1 and TK2,3–5 and FMAU is
currently undergoing clinical studies in two centers for imaging
tumor proliferation in a variety of cancer types and DNA
synthesis.3–5,21 The other derivatives, such as 20-deoxy-20-[18F]-
fluoro-5-iodo-1-b-D-arabinofuranosyluracil ([18F]-FIAU), 20-deoxy-20-
[18F]fluoro-5-fluoro-1-b-D-arabinofuranosyl-uracil ([18F]-FFAU) and
20 - deoxy - 20 -[18F]- fluoro - 5 - chloro - 1 -b-D-arabinofuranosyl-ura-
cil ([18F]-FCAU) are excellent substrates for the viral kinases such
as herpes simplex virus (HSV) type 1 and 2,9,11 and FIAU is also a
substrate for hepatitis B virus22,23 and Epstein B virus (EBV)
thymidine kinase.24,25 These 20-fluoro-5-substitued arabinosylur-
acil derivatives were synthesized and evaluated earlier as antiviral
agents.26–28 The radiochemical synthesis of FMAU with PET
isotope ([11C]) was reported by Conti et al.29. However, due to
of [18F]-labeled FMAU and other 5-substituted thymidine
analogues was reported by Alauddin et al.30,31. Following
this synthesis another group of investigators also reported
the [18F]-labeled synthesis of these pyrimidine nucleoside
analogues.32
The radiosynthesis of these pyrimidine nucleoside analogues
with [18F] is a modification of the original synthesis reported
earlier.26–28 The radiosynthesis involves radiofluorination of
2-trifluoromethanesulfonyl-1,3,5-tri-O-benzoyl ribofuranose to
2-[18F]-fluoro-1,3,5-tri-O-benzoyl arabinofuranose derivative fol-
lowed by conversion to 1-bromo-2-[18F]-fluoro-1,3,5-tri-O-benzoyl
derivative, then coupling of the 1-bromo-2-[18F]fluoro-2,3,-di-O-
benzoyl-arabinofuranose with 2,4-bis-trimethylsilyluracil deriva-
tives. Finally, hydrolysis of the protecting groups from the sugar
moiety and high-performance liquid chromatography (HPLC)
purification produces the desired products. An ideal radio-
synthesis procedure involves a single step radiolabeling of a
precursor compound, followed by hydrolysis of protecting
aThe University of Texas MD Anderson Cancer Center, Houston, TX, USA
bGE Healthcare, Muenster, Germany
*Correspondence to: Mian M. Alauddin, 1515 Holcombe Blvd. T8.3895, Houston,
TX 77030, USA.
E-mail: alauddin@mdanderson.org, alauddin@di.mdacc.tmc.edu
J. Label Compd. Radiopharm 2009, 52 553–558
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V. Paolillo et al.
groups, if necessary, and purification of the crude mixture. semi-automated system the entire reaction mixture remains in
However, such an ideal method has not been successful when solution in the V-vial in a closed system without any solvent loss.
applied to the radiolabeling of 20-fluoro-arabino substituted During our synthesis in this box using a low-level radioactivity,
pyrimidine nucleosides. Multiple steps are required after radi- we used to shake the reactor manually to dissolve the reactants
olabeling of the sugar moiety. As a result, this method is difficult, in the reaction mixture and kept them in solution. As a result,
and many radiochemists have failed in routine production of we observed similar coupling efficiency as our semi-automated
these radiotracers. Therefore, we have been producing these synthesis. In the fully automated system, the manual shaking was
compounds on a routine basis by fluorination of the sugar in an not possible. A small magnetic bar provided with the module is
automated synthesis module, such as an FDG synthesis module, not sufficient to agitate and wash the reagents that get solidified
and then the subsequent steps are performed on a home built and adheres on the wall of the reactor. A larger magnetic bar may
semi-automated system operated by a switch box.33 A similar help to agitate and bring back the reagents into solution;
semi-automated radiosynthesis method of [18F]-FEAU has been however, more studies to be done for optimization of these steps
published recently by others.34 For clinical applications, an and yields in both fluorination reaction and coupling reaction.
efficient fully automated CGMP-compliant radiosynthesis system
In this automated synthesis system we used both the
for production of these probes is necessary. To our knowledge, commercial precursor compounds, such as sugar triflate 1 and
no automated synthesis of [18F]-FEAU or [18F]-FMAU using a the 2,4-bis-trimethylsilyl-5-ethyluracil 4 (ABX), as well as pre-
commercial synthesis module has been reported yet. In this pared in house. Precursors from both the sources were suitable
article we report for the first time a fully automated synthesis of for the synthesis; however, the 2,4-bis-trimethylsilyl-5-ethyluracil
[18F]-FEAU and [18F]-FMAU using a prototype dual reactor 4 from ABX produced a small amount of white precipitate after
radiosynthesis module, TRACERlab FX FN (GE Healthcare), which dissolving in the reaction solvent (dichloroethane). The white
can produce radiotracers for clinical applications in a CGMP precipitate is 5-ethyluracil produced from the 2,4-bis-trimethyl-
compliant way.
silyl-5-ethyluracil 4 by decomposition. This low-level decom-
position of the bis-trimethylsilyl-ether 4 did not reduce the yield
in the coupling reaction significantly, as this reagent was used in
4- to 6-fold excess than the sugar triflate 1. In the radio
Results and discussion
Figure 1 represents the schematic diagram of the automated fluorination step, we optimized the amount of sugar triflate 1 by
synthesis module and Figure 2 represents the scheme for the using as low as 5 mg/synthesis and high as 10 mg. The
synthesis of the pyrimidine nucleoside analogues, [18F]-FEAU, radiochemical yields were comparable in both low and high
[18F]-FMAU and other 5-substituted compounds. The chemistry quantities of triflate; therefore, we preferred to use 5 mg of the
and the synthetic steps are identical as reported earlier.30,31 The sugar triflate in the synthesis. It should be noted that if higher
difference between this automated synthesis and the previously quantity of the sugar friflate 1 is used for radiolabeling, the
developed semi-automated synthesis33 is that a computer pyrimidine base 4 should also be higher (4- to 6-fold) to get high
operated fully automated synthesis compared to a partial coupling efficiency (55–65%). Although the use of excess triflate
automated and partial manual synthesis. For the fully automated may help to produce slightly higher yield in the fluorination
synthesis we used a modified dual reactor TRACERlab FX FN, step, the problem arises during purification of the product by
which is completely different from the semi-automated system.
HPLC. Using high-level of triflate and larger quantity of the
The overall radiochemical yield in this automated synthesis pyrimidine base, a significant amount of the pyrimidine (5-EU or
was 471% (d. c.) from the end of bombardment in ten runs. thymine) is eluted as a tail in the desired product during HPLC
This yield is lower than that reported by others on a semi- purification. Therefore, it is necessary to reduce the amount of
automated system (571),34 and much lower than our own triflate 1 at the fluorination step to avoid 5-EU in the desired
synthesis yields (15–20%).33 We could estimate the radio- product. We found that 5 mg/synthesis is optimal, because it
chemical yields in the radiofluorination step on the sugar triflate produces a reasonably high yield (30–50%) of the fluorosugar 2
1 to produce 2, which was in the range of 30–50% with an and reduces the amount of the 5-EU in the final product.
average of 40%710. However, we could not estimate the yields
The lower yields observed with the fully automated synthesis
in the bromination of 2 to produce 3 and coupling between 3 module should be resolved either by using a smaller reactor or
and 4, rather, we could calculate the overall yield of the final some mechanical mixing/shaking device in a large reactor to
product 6, which was 4%71 (d. c.) from the end of keep the reaction mixture uniform in solution. Additional
bombardment. The radiochemical yields in the fluorination step studies will be required to optimize this step. At this stage,
and coupling between the fluorosugar and the protected base we have demonstrated that the dual reactor module TRACERlab
were significantly lower compared with the manual synthesis FX FN is suitable for automated production of these nucleo-
and semi-automated synthesis. The main reason of the overall sides for clinical application, although the yields are slightly
lower yield is the inefficient coupling between 3 and 4, which is lower.
due to the differences in automation components between the
fully automated synthesis module and the semi-automated or
manual synthesis. One of the reasons is that a significant
amount of the solvent from the reactor is evaporated during
Experimental
Reagents and instrumentation
fluorination (801C for 15 min), and coupling between the base
and sugar (1001C for 1 h), and the evaporated solvent enters into All reagents and solvents were purchased from Aldrich Chemical
the Teflon tubing. The solvent is condensed and remains as Co. (Milwaukee, WI, USA), and used without further purification.
liquid in the tubing, as a result a part of the reaction mixture Solid phase extraction cartridges (silica gel, 900 mg) were
from the surface of the reactor adheres on the wall as white purchased from Alltech Associates (Deerfield, IL, USA). Ion
solid, which does not react. On the other hand, in the manual/ exchange cartridges were purchased from ABX (Germany).
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J. Label Compd. Radiopharm 2009, 52 553–558

V. Paolillo et al.
2-Trifluoromethanesulfonyl - 1,3,5-tri-O-benzoyl-a-D-ribofuranose the collection flask to a receiving vial. Valves 34, 35 and 36 are
(precursor) 1 and bis-2,4-trimethylsilyl-5-ethyluracil
4 were spare valves and they are connected with the respective
prepared in house or purchased from ABX (Germany). reservoirs.
Nonradioactive compounds FEAU and FMAU were prepared in
house for HPLC standards.
Methods
HPLC was performed on a pump (integrated with the
The automated syntheses were performed according to the
synthesis module) with UV detector operated at 254 nm, and a
built in radioactivity detector (GE Healthcare, Germany) using a
semipreparative C18 reverse phase column (GE Health care,
16 ꢀ 250 mm2, Germany) and an analytical C18 column (Alltech,
4.6 ꢀ 250 mm2, (Deerfield, IL, USA)). A solution of 12% ethanol in
aqueous Na2HPO4 (50 mM, pH 6.5) was used for purification of
[18F]-FEAU, and 10% ethanol in aqueous Na2HPO4 (50 mM, pH
6.5) was used for purification of [18F]-FMAU. A solution of 10%
MeCN in water and an 8% MeCN in water was used for quality
control analysis of [18F]-FEAU and [18F]-FMAU, respectively, on
analytical HPLC.
The dual reactor automated synthesis module TRACERlab FX
FN was provided by GE Healthcare (Germany) as a part of
academic–industrial collaboration. The synthesis module is
composed of nine reagent reservoirs operated by electric valves
and an HPLC system (Figure 1). Two reactors are connected to
the reagent reservoirs and vacuum pump. The valves from V1 to
V9 control the solvent and reagent containing reservoirs 1–9.
Reservoirs 2, 3 and 4 are directly connected with reactor 1 (R1),
and reservoirs 5, 6, 7, 8 and 9 are connected with reactor 2 (R2).
Reservoirs 3–9 are connected with a nitrogen or argon gas line.
Reservoir 1 is connected with reactor 1 through several control
valves. Both reactors R1 and R2 are connected with vacuum
pump, and reactor 2 is also connected with the injection port of
the HPLC system. Beside these valves 1–9, there are other valves,
each control the appropriate operations as designated and
necessary such as transferring reagents or solvents, injection of
the crude product to the HPLC, collection of fraction
during HPLC purification and transfer of the final product from
synthetic scheme (Figure 2). All reagents were stored in the
reservoirs sequentially with the appropriate reagents and
solvents (Figure 1) under nitrogen before receive the [18F]-
fluoride from the target of the cyclotron. After receiving the
radioactivity in the synthesis module, the automated synthesis
was started using the computer-programmed standard operat-
ing procedure (time-list). Radioactivity in 18O-water was
transferred from the receiving vial (Figure 1 left bottom) to the
ion exchange cartridge to trap the [18F]-radioactivity, and then
eluted with K2CO3/kryptofix solution (1.2 mL; K2CO3 2.75mg/mL
water, and kryptofix 12mg/mL MeCN) from reservoir 1 into the
reactor one (R1) through V1, V10, V11 and V13. Water and solvent
were evaporated from the radioactive fluoride by heating at 951C
and in combination with nitrogen flow and vacuum. The residual
water was removed by azeotropic evaporation with MeCN
transferred through V2, under vacuum and nitrogen flow. To
the dry fluoride (reactor 1) sugar triflate (compound 1) in MeCN
(5mg/mL, 1 mL) was transferred through V3 and heated for
15min at 851C. After cooling the reactor (R1) to 401C, the reaction
mixture was transferred to reactor two (R2) through a silica gel
sep-pack cartridge. The cartridge was washed with 2.5 mL EtOAc
through V4, and collected into reactor 2. Solvent was evaporated
and HBr/AcOH in dichloroethane (0.2mL in 0.7 mL) was
transferred to reactor 2 through V5, and heated for 10min
at 801C. The reactor 2 was cooled to 551C, solvent and
excess reagents were evaporated by vacuum under nitrogen,
and then toluene was added through V6 to evaporate any
residual AcOH. Reagent
4
(2,4-bis-trimethylsilyl-5-ethyluracil)
Figure 1. Schematic diagram (screen picture) of the automated synthesis module TRACERlab FX FN.
J. Label Compd. Radiopharm 2009, 52 553–558
Copyright r 2009 John Wiley & Sons, Ltd.
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V. Paolillo et al.
OTMS
RO
RO
RO
O
O
O
MeCN
OR
OR OR'
R1
CH2Cl-CH2Cl
18F
N
18F
+
18F -
Br
OR
HBr/AcOH
TMSO
N
OR
OR
4
3
1
R=benzoate
R'=Triflate
R1= CH3, CH2-CH3 etc.
2
CH2Cl-CH2Cl
O
O
R1
R1
HN
MeOH
HN
NaOMe
O
O
N
N
HO
RO
O
O
18F
18F
OH
OR
5
6
Figure 2. Synthetic scheme of 20-deoxy-20-[18F]fluoro-5-substituted-1-b-D-arabino-furanosyluracil ([18F]FEAU, [18F]FMAU, etc.).
Figure 3. HPLC chromatogram for purification of [18F]-FEAU on a semipreparative column; solvent 12% ethanol in aqueous Na2HPO4 (50 mM, pH 6.5), flow 10 mL/min.
Two coupled anomeric products a and b are shown, b being [18F]-FEAU.
was then transferred to the reactor 2 through V7, and the and then injected to the HPLC column through V16. The column
reaction mixture was heated for 1 h at 1001C. The reactor was eluted with 12% EtOH/50 mM Na2HPO4 (pH 6.5). Figure 3
2 was cooled to 401C, evaporated solvent, NaOMe (0.5M, 0.2 mL) represents a semipreparative HPLC chromatogram. The appro-
in MeOH (0.8 mL) was added through V8, and then reactor priate fraction was collected into the collection flask and then
2 was heated for 7 min at 801C. Reactor 2 was finally cooled to transferred to the receiving vial. A solution of Na2HPO4 (75% v/v
401C and the solvent was evaporated, and this ended the of the collected product) was added to reduce the percent of
synthesis.
ethanol (o7%), and the product was filtered through a Millipore
HPLC purification: The automated synthesis module was set at filter. The product was co-injected with an authentic unlabeled
the manual operation mode, HPLC solvent was transferred to sample onto an analytical column to confirm its identity and
reactor 2 through V9 and the solution was stirred for a minute radiochemical purity (Figure 4).
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J. Label Compd. Radiopharm 2009, 52 553–558

V. Paolillo et al.
Figure 4. HPLC chromatogram of [18F]-FEAU, co-injected with standard FEAU: analytical C18 column; 10% MeCN/H2O; flow 1.0 mL/min.
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Conclusion
A fully automated synthesis of [18F]-FEAU and [18F]-FMAU has
been achieved for the first time in reasonable yields and high
purity using a prototype dual-reactor synthesis module TRA-
CERlab FX FN for clinical applications. The synthesis module can
be applied for the production of other 20-[18F]fluoro-20-deoxy-
arabino-5-substituted pyrimidine nucleoside analogues.
[11] M. M. Alauddin, A. Shahinian, R. Park, M. Tohme, J. D. Fissekis,
P. S. Conti, J. Nucl. Med. 2005, 45, 2063.
Acknowledgements
[12] A. Hajitou, M. Trepel, C. E. Lilley, S. Soghomonyan, M. M. Alauddin,
F. C. Marini, B. H. Restel, M. G. Ozawa, C. A. Moya, R. Rangel,
Y. Sun, K. Zaoui, M. Schmidt, C. V. Kalle, M. D. Weitzman,
J. G. Gelovani, R. Pasqualini, W. Arap, Cell 2006, 125, 385.
[13] M. M. Alauddin, A. Shahinian, R. Park, M. Tohme, J. D. Fissekis,
P. S. Conti, Eur. J. Nucl. Med. Mol. Imaging 2007, 34, 822.
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S. Soghomonyan, M. M. Alauddin, R. S. Benjamin, R. E. Pollock, J. G.
Gelovani, R. Pasqualin, W. Arap, Proc. Natl. Acad. Sci. 2008, 105,
4471.
This work was supported by start up funds of Drs Mian M.
Alauddin and Juri G. Gelovani from The University of Texas MD
Anderson Cancer Center in collaboration with GE Healthcare.
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