Fully automated, high yielding production of N-succinimidyl 4-[ 18F]fluorobenzoate ([18F]SFB), and its use in microwave-enhanced radiochemical coupling reactions

Article abstract of DOI:10.1002/jlcr.1785

A General Electric Medical Systems (GEMS) Tracerlab FX_FN fluorine-18 synthesis module has been reconfigured to allow rapid (45 min), fully automated production of N-succinimidyl 4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB) using the e

Full text of DOI:10.1002/jlcr.1785

Research Article
Received 3 March 2010,
Revised 30 March 2010,
Accepted 12 April 2010
Published online 17 June 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1785
Fully automated, high yielding production of
N-succinimidyl 4-[18F]fluorobenzoate
([18F]SFB), and its use in microwave-enhanced
radiochemical coupling reactions
Ã
Peter J. H. Scott and Xia Shao
A General Electric Medical Systems (GEMS) Tracerlab FXFN fluorine-18 synthesis module has been reconfigured to allow
rapid (45 min), fully automated production of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) using the established three-
step, one-pot synthesis procedure. Purification is by sep-pak only and [18F]SFB is routinely obtained in 38% non-decay
corrected yield,41 Ci/lmol specific activity, and 495% radiochemical purity (n = 20). Moreover, this report includes our
preliminary research efforts into improving peptide coupling reactions with [18F]SFB using microwave-enhanced
radiochemistry. Reaction times can be reduced by490%, when compared with traditional thermal reactions, with no
significant effect on radiochemical reaction yield.
Keywords: radiopharmaceutical chemistry; [18F]SFB; microwave-promoted radiochemistry
our hands. In this study, we report modifications to a GEMS
Tracerlab FXFN that enable the rapid (synthesis time = 45 min)
Introduction
and fully automated preparation of [18F]SFB in high radio-
The use of radiopharmaceuticals, in conjunction with positron
emission tomography (PET) imaging, to non-invasively elucidate
biochemical mechanisms, diagnose diseases, and monitor
chemical yield (38% non-decay corrected, n = 20),41 Ci/mmol
specific activity, and excellent radiochemical purity (495%).
patient response to therapy, is becoming increasingly popular.1
The radiopharmaceuticals are often tagged with fluorine-18
because the convenient half-life (110 min) allows for sophisti-
cated synthetic manipulations and scope for distribution to
satellite PET centers without a cyclotron. Small molecule
radiopharmaceuticals are typically labeled with fluorine-18, by
displacement of a leaving group with [18F]fluoride, using well-
established radiochemical reactions.2–4 However, this strategy is
not viable for radiolabeling larger biologically sensitive species
(e.g. proteins). In such cases, fluorine-18 is typically introduced by
reacting the bioactive molecule with a pre-formed, [18F]labeled,
bifunctional prosthetic group. Numerous prosthetic groups
have been developed for such applications2 and, to date,
N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB, 4) remains one of
the most widely used.
With a reliable method for producing [18F]SFB in hand, we use
it routinely in our laboratory to radiolabel large bioactive
molecules such as peptides. Typically, solutions of [18F]SFB and
peptide precursor are mixed in a vial and heated (heat gun) to
promote reaction. Recently however, coupling of [18F]SFB with
less reactive precursors has been taking impractically long
(440 min) to provide radiopharmaceuticals in high enough
radiochemical yield for use in pre-clinical studies. Therefore, we
have explored microwave-assisted radiochemistry, a promising
technique for enhancing radiochemical reactions that has been
recently reviewed,10–13 as a means of improving coupling
reactions with [18F]SFB. In this report, we present preliminary
results demonstrating that reaction times can be reduced
by490%, when compared with traditional thermal reactions,
with no significant effect on radiochemical reaction yield.
Initially, the preparation of [18F]SFB was hampered by lengthy
syntheses requiring multiple reaction vessels, and was not
trivial.5 Typically, such syntheses were done manually6 although
the process has also been automated.7 However, such automa-
tion requires access to multi-reaction vessel synthesis modules
and so, in the last decade, we and others8,9 have concentrated
on developing improved methods for preparing [18F]SFB. With
this in mind, we adapted the three-step, one-pot method for
preparing [18F]SFB, reported by Kabalka,8 for use with a General
Electric Medical Systems (GEMS) Tracerlab FXFN. This method
eliminates the need for HPLC purification, using only solid-phase
extraction (SPE) cartridges, and has proven extremely robust in
Results and discussion
Production of [18F]SFB
In considering a method for production of [18F]SFB to adapt for
use with a Tracerlab FXFN, we were particularly attracted by the
University of Michigan Medical School, Ann Arbor, MI, USA
*Correspondence to: Xia Shao, Department of Radiology, University of Michigan
Medical School, Ann Arbor, MI, USA.
E-mail: xshao@umich.edu
J. Label Compd. Radiopharm 2010, 53 586–591
Copyright r 2010 John Wiley & Sons, Ltd.

P. J. H. Scott and X. Shao
three-step, one-pot method for its production reported by shown in Figure 1. Luer lock fittings were incorporated into the
Kabalka (Scheme 1).8 This method is operationally simple and line that normally connected valve-18 to the round-bottomed
does not require HPLC purification.
dilution flask. These fittings offered a straightforward means of
To fully automate this synthesis of [18F]SFB in our laboratory, connecting the line out from the reactor (through valve-14)
simple modifications were made to a GEMS Tracerlab FXFN as directly to the round-bottomed dilution flask and bypassing the
Scheme 1.
Figure 1. Modified Tracerlab FXFN configuration for production of [18F]SFB.
J. Label Compd. Radiopharm 2010, 53 586–591
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

P. J. H. Scott and X. Shao
HPLC system. Such modifications enabled straightforward temperature controller. In a typical reaction, the peptide
switching between module configurations, allowing for easy precursor (0.2–0.5 mg) and diisopropylethylamine (DIPEA, 10 ml,
alteration and access to radiopharamceuticals prepared using Note: In our experience, addition of DIPEA is essential for the
different radiochemical strategies.
reaction to proceed) were dissolved in DMSO (0.1 ml). [18F]SFB in
Tracerlab FXFN Vials 1, 2, and 3 were loaded with potassium DMSO (0.1 ml) was then added and the reaction vial was heated
carbonate, kryptofix-2.2.2, and 4-(ethoxycarbonyl)-N,N,N-tri- at 601C for 30–40 min (Note: Prolonged heating at this stage can
methylbenzenaminium triflate precursor (1), respectively. Fluor- lead to decomposition of sensitive precursors and products).
ide-18 was delivered from the GEMS PETTrace cyclotron and After this time, reactions had typically reached their endpoint
trapped on a Waters QMA-light sep-pak to remove [18O]H2O. (determined from the analytical radio-HPLC trace) and crude
Fluoride-18 was then eluted into the reaction vessel using reaction mixtures were then purified by semi-preparative HPLC
aqueous potassium carbonate (3.0 mg in 0.4 ml). A solution of to provide radiolabeled peptides. If necessary, collected HPLC
kryptofix-2.2.2 (15 mg in 1 ml of MeCN) was added to the fractions were reformulated into isotonic solutions suitable for
reaction vessel and the fluoride-18 was dried by azeotropic injection using standard SPE techniques.
evaporation of the water/acetonitrile. Following drying, the
In connection with a project developing novel oncology PET
trimethylbenzeneaminium triflate precursor (5 mg in 0.5 ml of biomarkers to quantify over-expression of neuropilins, receptors
DMSO) was added to the reaction vessel and the fluorination of angiogenic vascular endothelial growth factor, we were
reaction was heated at 901C for 10 min to provide [18F]ethyl 4- recently attempting to label a number of novel peptides with
fluorobenzoate (2). After this time, tetrapropylammonium [18F]SFB. In most cases, the thermal set-up discussed above was
hydroxide (TPAH, 1.0 M solution in water, 20 ml in 0.5 ml of adequate for preparing pre-clinical doses of our experimental
MeCN) was added to saponify the ester. The saponification new biomarkers. However, with certain peptide precursors,
reaction was heated at 1201C for 3 min to yield [18F]4- which were found to be less reactive and somewhat thermally
fluorobenzoic acid (3) as the corresponding tetrapropylammo- unstable, longer reaction times resulted in decomposition
nium salt. On completion of the saponification, MeCN (1 ml) was leading to low yields, and we were struggling to obtain
added and evaporated to remove excess water from addition of sufficient amounts of biomarker for pre-clinical evaluation.
the aqueous solution of TPAH. O-(N-succinimidyl)-1,1,3,3-tetra- Therefore, alternative strategies for improving [18F]SFB coupling
methyluronium tetrafluoroborate (TSTU, 10 mg in 0.6 ml of reactions were considered and attention was turned to
MeCN) was then added and the reaction vessel was heated at microwave-promoted reactions. Microwave-accelerated radio-
901C for 5 min to provide [18F]SFB (4). The crude reaction chemical reactions have been shown to be more efficient than
mixture was cooled to 401C and transferred from the reactor to their thermal counterparts,10–13 and we were curious about
the round-bottomed dilution flask (pre-charged with 20 ml of what, if any, enhancement might be achieved by carrying out
1.5% acetic acid). The resulting solution was transferred through SFB coupling reactions in a microwave reactor.
a
Waters C18 Plus sep-pak to trap the crude reaction
Our laboratory is equipped with a Resonance Instruments
components. Following trapping, the C18 sep-pak was washed Model 521 Microwave Power Generator. The single vial
with 10% MeCN (10 ml), eluting unwanted hydrophilic impu- microwave reactor is attached to the control unit and the 521
rities (including unreacted fluoride-18) to waste. Subsequently, microwave is capable of providing variable microwave power
[18F]SFB was eluted off into the collection vial with neat MeCN from 10 to 150 W. Moreover, reactions can be heated from 30 to
(2 ml). Synthesis time was ꢀ45 min and typical yields of [18F]SFB 1801C. In order to gauge the impact of the microwave reactor
using this method were 38% (non-decay corrected, n = 20), on coupling reactions with [18F]SFB, two model test compounds
specific activity was 41 Ci/mmol, and radiochemical purity was ([18F]A7R (5) and [18F]RGD (6), Figure 2) were selected. RGD
always 495%. For the pre-clinical work described in this study, peptides such as 6 are known biomarkers for angiogenesis,14–16
no efforts were made to optimize specific activity. However, while radiolabeled heptapeptide ATWLPPR (A7R, 5) is a scaffold
there is scope for improving the specific activity (e.g. target of interest in our efforts to quantify over-expression of
rinsing prior to bombardment, etc.). The [18F]SFB was either neuropilins.17
used as the obtained solution in MeCN or, alternatively, was
Initially, A7R was chosen for preliminary experiments to
evaporated to dryness (heat gun) and re-dissolved in a solvent compare thermal heating to microwave irradiation. For the
more appropriate for the subsequent coupling reaction (e.g. microwave reactions, A7R precursor (0.2–0.5 mg) and DIPEA
DMSO).
(10 ml) were dissolved in DMSO (0.1 ml) in a small glass vial.
[18F]SFB (2–10 mCi) in DMSO (0.1 ml) was added, and the vial
was placed in the microwave reaction cavity. The microwave
power was set to 100 W and microwave radiation was then
Microwave-accelerated coupling reactions with [18F]SFB
Typically, solutions of [18F]SFB, obtained in acetonitrile, were applied for different time points. Note that unlike thermal
concentrated using a heat gun at 60–701C under a stream of reactions, in which multiple samples were removed from a single
nitrogen gas (15 ml/min). Note: Temperatures higher than 701C reaction vial over time for analysis, a fresh reaction was prepared
can decompose [18F]SFB so this step should be carefully in a new glass vial for each individual microwave time point
monitored. Following evaporation, [18F]SFB was re-dissolved in tested. Reaction temperature was measured using a digital
a smaller volume of DMSO (0.5 ml) and this solution was then thermometer and was found to be o1201C under these
divided between several reaction vials, allowing for multiple conditions. While this temperature is higher than the thermal
coupling reactions to be carried out in parallel. Until recently, we reaction, reaction time is significantly reduced and yield of
carried out coupling reactions using a manual setup. Solvent product is acceptable for pre-clinical use. Samples were removed
evaporation and reaction heating were simply achieved by from the vial, on completion of the irradiation, for HPLC analysis
suspending a vial above a heat gun and temperature was (Figure 3, Table 1). After 3 min of microwave irradiation (490%
controlled by varying power to the heat gun using
a
reduction in reaction time compared to 40min thermal reaction),
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Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2010, 53 586–591

P. J. H. Scott and X. Shao
Figure 2. Peptides labeled with [18F]SFB.
led to charring in the reaction vial and a drop off in yield, both
attributable to decomposition of the product. Reflecting our
experience with thermally mediated [18F]SFB coupling reactions,
addition of DIPEA was also essential for the microwave-promoted
reactions to proceed and eliminating it resulted in no product
formation. In contrast to the microwave-mediated reactions, it
took 30min to get comparable (37%, n = 20) conversion to
[18F]A7R using the conventional thermal reaction set-up.
Using analogous conditions, the coupling of RGD with
[18F]SFB was compared under both thermal and microwave-
mediated conditions, although for this particular peptide both
were found to be extremely efficient reactions. Microwave-
enhanced reactions were carried out in an analogous fashion to
that described above: RGD precursor (0.2–0.5 mg) and DIPEA
(10 ml) were dissolved in DMSO (0.1 ml) in a glass reaction vial.
[18F]SFB (2–10 mCi) in DMSO (0.1 ml) was then added and the
reaction was irradiated at 100 W for different time points.
Samples were removed from the vial, on completion of the
reaction, to monitor progress by HPLC analysis (Figure 3,
Table 1). Remarkably, 490% conversion occurred after 30 s of
microwave radiation (n = 3), while heating at 601C for 10 min
with a heat gun (n = 3) was required to achieve equivalent
conversions (Figure 3, Table 1). As with the A7R reactions
described above, yields began to drop off after prolonged
heating (30–40 min for thermal reactions). The crude microwave
reaction mixtures for [18F]labeled A7R and RGD were then
purified by semi-preparative HPLC, and reformulated using
standard C18 sep-pak techniques, as required.
Figure 3. Percentage conversion of [18F]SFB coupling reactions.
Table 1. Percentage conversion in microwave vs thermal
coupling reactions using [18F]SFB
A7R
Thermalb
RGD
Thermalb
MWa
MWa
Time
(min)
Time
(min)
Time
(min)
Time
(min)
%
%
%
%
1
2
3
7
10
15
9
5
10
20
30
40
6
0.5
1
2
92
94
95
96
5
10
20
30
40
87
92
94
96
94
Experimental
17
32
38
28
27
16
27
37
32
General considerations
3
Reagents and solvents were all commercially available and used,
as received, without further purification: Sterile Water for
Injection, USP was purchased from Hospira; acetic acid,
anhydrous acetonitrile, DMSO, DIPEA, potassium carbonate,
tetrapropylammonium hydroxide, and TSTU were purchased
from Sigma Aldrich; kryptofix-2.2.2 was purchased from Acros
Organics; SFB reference standard and precursor were purchased
from ABX Advanced Biochemicals; A7R and RGD precursors, and
unlabeled reference standards, were purchased from the
University of Michigan Protein Structure Facility. QMA and C18
Sep-pak cartridges were purchased from Waters, Inc. and
aMicrowave reactions carried out at 100 W power level,
([18F]RGD n = 3; [18F]A7R n = 3).
bThermal reactions carried using a heat gun out at 601C,
([18F]RGD n = 3; [18F]A7R n = 20)
high enough conversion (32%, n = 3) had occurred to allow
purification and subsequent use in pre-clinical experiments
although this could be increased to 38% by microwaving for conditioned with ethanol (10 ml) and sterile water (10 ml) prior
7 min. However, extending the reaction time much beyond 7 min
to use.
J. Label Compd. Radiopharm 2010, 53 586–591
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

P. J. H. Scott and X. Shao
Production of [18F]SFB
DMSO (0.1 ml) was added and the vial placed in our custom-
built heat gun apparatus. The heat gun was set to 601C and the
reaction was maintained at this temperature for up to 40 min
(Table 1). Samples were removed periodically for HPLC analysis
(as described in the section Quality control of [18F]SFB-labeled
peptides).
To prepare [18F]SFB, the Tracerlab was configured as shown in
Figure 1 and vials were loaded as follows: Vial 1: potassium
carbonate (3.0 mg in 0.4 ml of water); Vial 2: kryptofix-2.2.2 (15 mg
in 1 ml of MeCN); Vial 3: 4-(ethoxycarbonyl)-N,N,N-trimethylben-
zenaminium triflate precursor (5mg in 0.5 ml of DMSO); Vial 4:
TPAH (20 ml in 0.5 ml of MeCN); Vial 5: acetonitrile (1 ml); Vial 6:
TSTU (10mg in 0.6 ml of MeCN); Vial 7: MeCN (2ml); Vial 9: 10%
MeCN in water (10 ml); dilution flask: 20ml of 1.5% acetic acid.
Fluoride-18 was produced via the 18O(p,n)18F nuclear reaction
using a GEMS PETTrace cyclotron equipped with a high yield
fluorine-18 target. Fluoride-18 was delivered from the cyclotron
(in a 2-ml bolus of [18O]H2O) and trapped on a QMA-light sep-
pak to remove [18O]H2O. Fluoride-18 was then eluted into the
reaction vessel using aqueous potassium carbonate (3.0 mg in
0.4 ml of water). A solution of kryptofix-2.2.2 (15 mg in 1 ml of
acetonitrile) was then added to the reaction vessel and the
fluoride-18 was dried by evaporating the water–acetonitrile
azeotrope. Evaporation of the azeotrope was achieved by
heating the reaction vessel to 801C and drawing full vacuum for
4 min. After this time, the reaction vessel was cooled to 601C and
subjected to both an argon stream and vacuum draw
simultaneously for another 4 min.
Following drying of the fluoride, a solution of trimethylben-
zeneaminium triflate precursor (5 mg in 0.5 ml of DMSO) was
added and the reaction vessel was heated to 901C for 10 min to
provide [18F]ethyl 4-fluorobenzoate. After this time, tetrapropy-
lammonium hydroxide (TPAH, 20 ml in 0.5 ml of MeCN) was
added to saponify the ester group. Heating at 1201C for 3 min
provided [18F]4-fluorobenzoic acid as the corresponding TPA
salt. After saponification, 1 ml of acetonitrile was added and
evaporated (701C, 5 min) with a stream of argon to remove any
residual water left over from the saponification. O-(N-succinimi-
dyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU, 10 mg
in 0.6 ml of MeCN) was added and the reaction vessel was
heated at 901C for 5 min to provide [18F]SFB. The crude reaction
mixture was cooled down (401C) and transferred to the dilution
flask (pre-charged with 5 ml of 5% acetic acid and 15 ml of
water). The resulting solution was transferred through a Waters
C18 Plus sep-pak and the C18 sep-pak was then washed with
10% MeCN (10 ml). Following washing, elution into the collection
vial with neat MeCN (2ml) gave [18F]SFB in 38% radiochemical
yield (non-decay corrected, n = 20),41.0 Ci/mmol specific activity,
and495% radiochemical purity. The [18F]SFB could be used as
the obtained solution in MeCN or, alternatively, could be
evaporated to dryness (heat gun) and re-dissolved in DMSO.
Microwave-enhanced reactions
Peptide precursor (0.2–0.5 mg) and DIPEA (10 ml) were dissolved
in DMSO (0.1 ml) in a small glass vial. [18F]SFB (2–10 mCi) in
DMSO (0.1 ml) was added, and the vial was placed in the
reaction cavity of a Resonance Instruments Model 521 Micro-
wave Power Generator. Microwave radiation at 100 W was
applied for different lengths of time (Table 1). A new reaction
was prepared for each time point and samples were removed
from the reaction vial, on completion of microwave irradiation,
for HPLC analysis (as described in the section Quality control of
[18F]SFB-labeled peptides).
Quality control of [18F]SFB-labeled peptides
Radiochemical purity and identity were analyzed using a
Shimadzu LC-2010 HPLC equipped with a Bioscan FC3300
radioactivity detector and UV detector. Column: Chromolith
RP18, 100 Â 4.6 mm (Merck, Germany); Mobile Phase: 0.1% TFA
in 35% MeOH, flow rate: 1.0 ml/min; UV: 254 nm, RT: ꢀ6.5 min
for [18F]SFB, 6.0 min for [18F]RGD, and 20 min for [18F]A7R.
Conclusions
In conclusion, a GEMS Tracerlab FXFN synthesis module has been
modified to enable rapid, fully automated, preparation of
[18F]SFB. Synthesis time is 45 min and this method is routinely
employed in our laboratory to provide [18F]SFB in 38% yield
(non-decay corrected), 41.0 Ci/mmol specific activity, and
495% radiochemical purity. Moreover, we have demonstrated
that microwave-accelerated peptide coupling reactions using
[18F]SFB are far more efficient than their conventional thermal
counterparts. Reaction times can be reduced by more than 90%
without significant impact on radiochemical yield and, in light of
the positive results disclosed in this study, we anticipate
microwave-accelerated reactions to play an increasingly sig-
nificant role in our radiochemical laboratory in the future.
Acknowledgements
We gratefully acknowledge the Office of Biological and
Environmental Research (BER) of the Office of Science (SC),
U.S. Department of Energy (DE-FG02-08ER64645) for financial
support of this research.
Quality control of [18F]SFB
Radiochemical purity and identity were analyzed using a
Shimadzu LC-2010 HPLC equipped with a Bioscan FC3300
radioactivity detector and UV detector. Column: Chromolith
RP18, 100 Â 4.6 mm (Merck, Germany); Mobile Phase: 0.1% TFA
in 50% MeOH, flow rate: 0.8 ml/min; UV: 254 nm, RT:ꢀ3.0 min.
Non-radioactive [19F]SFB was used as the reference standard.
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