An improved synthesis of 1′-[18F]fluoroethyl-β- D -Lactose ([18F]-FEL) for positron emission tomography imaging of pancreatic cancer

Article abstract of DOI:10.1002/jlcr.3042

Introduction Earlier, we reported syntheses of ethyl-β-d- galactopyranosyl-(1,4′)-2′-deoxy-2′-[¹⁸F]fluoro- β-d-glucopyranoside (Et-[¹⁸F]FDL) and 1′-[ ¹⁸F]fluoroethyl-β-d-lactose ([¹⁸F]-FEL) for positron emission tomography (PET) of pancreatic carcinoma. Et-[¹⁸F]FDL requires a precursor, which involves 11 steps to synthesize and produces overall low yields. Synthesis of precursors for [¹⁸F]-FEL requires four steps, but those precursors produced low radiochemical yields. Here, we report new precursors and an improved synthesis of [¹⁸F]-FEL. Method Two precursors, 1′-(methanesulfonyl)ethyl-2′,3′,6′,2,3,4,6- hepta-O-acetyl-β-d-lactose 2a and 1′-(p-nitrophenyl-sulfonyl)ethyl- 2′,3′,6′,2,3,4,6-hepta-O-acetyl-β-d-lactose 2b, were synthesized from lactose in four steps. Radiofluorination reactions were performed using K¹⁸F/kryptofix and the crude product [ ¹⁸F]-3 was purified by HPLC. Basic hydrolysis of [¹⁸F]-3 produced 1′-[¹⁸F]fluoroethyl-β-d-lactose [ ¹⁸F]-4, which was neutralized, diluted with saline, filtered on a 0.22-μm filter, and analyzed by radio-TLC. Results The average radiochemical yields of [¹⁸F]-4 (d. c.) from 2a and 2b were 21% (n = 6) and 65% (n = 6), respectively, with >99% radiochemical purity and specific activity of 55.5 GBq/μmol. Synthesis time was 90-95 min from the end of bombardment. Conclusion An improved synthesis of [¹⁸F]FEL has been achieved in high yields, with high purity and specific activity. Precursor 2b with this method should be applicable for high yield automated production in a commercial synthesis module for clinical application. Copyright

Full text of DOI:10.1002/jlcr.3042

Research Article
Received 05 February 2013,
Accepted 14 February 2013
Published online 22 March 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3042
An improved synthesis of 10-[18F]fluoroethyl-
b-D-lactose ([18F]-FEL) for positron emission
tomography imaging of pancreatic cancer
a
Nashaat Turkman,a,b Juri G. Gelovani,a,b and Mian M. Alauddin
*
Introduction: Earlier, we reported syntheses of ethyl-b-D-galactopyranosyl-(1,40)-20-deoxy-20-[18F]fluoro-b-D-glucopyranoside
(Et-[18F]FDL) and 10-[18F]fluoroethyl-b-D-lactose ([18F]-FEL) for positron emission tomography (PET) of pancreatic carcinoma.
Et-[18F]FDL requires a precursor, which involves 11 steps to synthesize and produces overall low yields. Synthesis of
precursors for [18F]-FEL requires four steps, but those precursors produced low radiochemical yields. Here, we report new
precursors and an improved synthesis of [18F]-FEL.
Method: Two precursors, 10-(methanesulfonyl)ethyl-20,30,60,2,3,4,6-hepta-O-acetyl-b-D-lactose 2a and 10-(p-nitrophenyl-
sulfonyl)ethyl-20,30,60,2,3,4,6-hepta-O-acetyl-b-D-lactose 2b, were synthesized from lactose in four steps. Radiofluorination
reactions were performed using K18F/kryptofix and the crude product [18F]-3 was purified by HPLC. Basic hydrolysis of
[
18F]-3 produced 10-[18F]fluoroethyl-b-D-lactose [18F]-4, which was neutralized, diluted with saline, filtered on a 0.22-mm
filter, and analyzed by radio-TLC.
Results: The average radiochemical yields of [18F]-4 (d. c.) from 2a and 2b were 21% (n = 6) and 65% (n = 6), respectively, with
>99% radiochemical purity and specific activity of 55.5GBq/mmol. Synthesis time was 90–95 min from the end of bombardment.
Conclusion: An improved synthesis of [18F]FEL has been achieved in high yields, with high purity and specific activity.
Precursor 2b with this method should be applicable for high yield automated production in a commercial synthesis module
for clinical application.
Keywords: fluorine-18; lactose; HIP/PAP; pancreatic carcinoma; PET
to that of Et-[18F]FDL for PET imaging of these cancers
Introduction
[unpublished data]. Alternatively, the synthesis of precursors for
[18F]-FEL required only four steps and produced high yields.
Early detection of pancreatic cancer with highly sensitive
diagnostic imaging modality could save many thousands of
However, those precursors produced low radiochemical yields
(9–11%) of [18F]-FEL. Therefore, a convenient high-yield synthesis
patients by increasing resectability and survival rates. We have
been developing novel probes for positron emission
of [18F]-FEL is needed for routine production of the radiotracer
tomography (PET) in early detection of pancreatic cancer and
and to pursue pre-clinical and clinical applications.
To improve the radiochemical yield of [18F]-FEL, we have
hepatocellular carcinoma. In previous studies, we reported the
synthesis of ethyl-b-D-galactopyranosyl-(1,40)-20-deoxy-20-[18F]
designed and synthesized two new precursors and evaluated them
fluoro-b-D-glucopyranoside (Et-[18F]FDL),1 its PET imaging
results on orthotopically implanted pancreatic cancer in nude
mice,2 and the radiosynthesis of 10-[18F]fluoroethyl-b-D-lactose
([18F]-FEL)3 for PET imaging of pancreatic carcinoma. These
compounds, Et-[18F]FDL and [18F]-FEL, were developed
based on the fact that D-lactose and its analogues bind with
the hepatocarcinoma-intestine-pancreas/pancreatitis-associated
protein (HIP/PAP),4–6 which is overexpressed (130-fold) in
peritumoral pancreatic acinar cells compared with normal
pancreas7,8 and in hepatocellular carcinomas.9–13 Our previous
studies revealed that Et-[18F]FDL is an excellent PET imaging
agent for detection of pancreatic cancer by targeting HIP/PAP
in the peritumoral region.2 However, the synthesis of Et-[18F]
FDL was performed using a precursor, which requires 11 steps
to synthesize and produced overall low yields. Preliminary
studies of pancreatic cancer in an orthotopic nude mouse model
and chemically induced hepatocellular carcinoma in swine liver
using [18F]-FEL showed that the efficacy of [18F]-FEL was similar
for radiosynthesis of [18F]-FEL using K18F/kryptofix 2.2.2 in
dry MeCN. In this article, we report a high-yield (>sixfold)
radiosynthesis of [18F]-FEL using
a
new precursor, 10-(p-
nitrophenylsulfonylethyl)-20,30,60,2,3,4,6-hepta-O-acetyl-b-D-lactose.
This precursor should be suitable for routine production of high-
yield [18F]-FEL, and the method may be adapted to a commercially
available automated synthesis module for pre-clinical and clinical
applications of the probe.
aDepartment of Experimental Diagnostic Imaging, The University of Texas MD
Anderson Cancer Center, Houston, TX 77030, USA
bWayne state University, Detroit, MI, USA
*Correspondence to: Mian M. Alauddin, Ph. D., Department of Experimental
Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1515
Holcombe Blvd. T8.3895, Box 059, Houston, TX 77030 USA.
E-mail: alauddin@mdanderson.org
J. Label Compd. Radiopharm 2013, 56 351–355
Copyright © 2013 John Wiley & Sons, Ltd.

N. Turkman et al.
(m, 1H), 3.92–3.88 (m 1H), 3.85–3.72 (m, 2H), 3.64–3.57 (m, 1H), 2.17
(s, 3H, acetate), 2.14 (s, 3H, acetate), 2.08 (s, 3H, acetate), 2.07 (s, 3H, acetate),
2.06 (s, 3H, acetate), 2.05 (s, 3H, acetate), 1.98 (s, 3H, acetate). HRMS:
calculated for C34H43NO23SNa (M + Na) 888.1839, found 888.1873.
Experimental
Reagents and instrumentation
Reagents and solvents were purchased from Aldrich Chemical Co.
(Milwaukee, WI, USA) and used without further purification. K18F/
kryptofix 2.2.2. was purchased from Cyclotope Inc. (Houston, TX, USA)
as an aqueous solution. Silica gel solid-phase extraction cartridges
(Sep-Pak, 900 mg) were purchased from Alltech Associates (Deerfield,
IL, USA). Thin layer chromatography (TLC) was performed on precoated
Kieselgel 60 F254 (Merck, Darmstadt, Germany) glass plates. Proton and
19F NMR spectra were recorded using tetramethylsilane as an internal
reference or hexafluorobenzene as an external reference at The
University of Texas MD Anderson Cancer Center using a Bruker
300 MHz spectrometer. High-resolution mass spectra (HRMS) were
obtained on a Bruker BioTOF II mass spectrometer at the University of
Minnesota using electrospray ionization.
High-performance liquid chromatography was performed using a
1100 series pump (Agilent Technologies, Stuttgart, Germany) with a
built-in ultraviolet detector operated at 210 nm and a radioactivity
detector with a single-channel analyzer (Bioscan, Washington, DC, USA).
Crude product was purified on a semipreparative C18 reverse-phase
column (Alltech, Econosil, 10 ꢀ 250 mm), and quality control analyses
were performed on an analytical C18 column (Alltech, Econosil,
4.6 ꢀ 250 mm). An acetonitrile/water solvent system (45% MeCN/H2O)
was used for purification of the radiolabeled product at a flow of 4 mL/
min. Quality control analyses were performed using 55% MeCN/H2O
solvents at a flow of 1 mL/min. Radio-TLC plates were scanned on an
AR-2000 imaging scanner (Bioscan, Washington, DC, USA).
Preparation of 10-fluoroethyl-20,30,60,2,3,4,6-hepta-O-acetyl-b-
D-lactose: 3
Compound 3 was prepared from 2a and 2b by fluorination with Bu4NF; a
representative preparation from 2a is described here. Compound 2a
(10 mg, 13.2 mmol) was dissolved in MeCN (1.0 mL) in a V-vial. To this
solution, 26 mL of Bu4NF in tetrahydrofuran (1 M solution, 2 equiv.) was
added, and the reaction mixture was heated at 90 ꢁC for 20 min, when
TLC showed no starting material remained. The reaction mixture was
cooled at room temperature, the solvent was evaporated, and the crude
product was chromatographed on a small silica gel column using 40%
acetone/hexane. The solvent was evaporated, and 6.0 mg of the product
3 was obtained in 65% yield. Precursor 2b produced 85% yield of 3 with
all spectral data identical as reported earlier.3
Preparation of 10-fluoroethyl-b-D-lactose: 4
Compound
4
was prepared as previously reported3 and fully
characterized by spectroscopic methods, and the spectral data were
consistent with those previously reported in the literature.3
Radiosynthesis of 10-[18F]fluoroethyl-20,30,60,2,3,4,6-hepta-O-
acetyl-b-D-lactose: [18F]-3
This compound was also prepared as previously reported.3 A brief
Preparation of 10-(methanesulfonylethyl)-20,30,60,2,3,4,6-hepta- description using precursor 2b is presented here. The aqueous solution of
K[18F]/kryptofix 2.2.2 was evaporated with acetonitrile (1.0mL) by an
O-acetyl-b-D-lactose: 2a
azeotropic removal of water at 90 ꢁC under a stream of argon. A solution
10-(Hydroxyethyl)-20,30,60,2, 3, 4,6-hepta-O-acetyl-b-D-lactose 13 (68.0 mg,
0.1 mmol) was dissolved in dry pyridine (3.0 mL) in a small flask and
cooled to 0 ꢁC under argon. Methanesulfonyl chloride (12 mL, 1.5 equiv.)
was added, and the reaction mixture was stirred for 10 min and then
stirred for 1 h at room temperature. An aliquot was taken out, and
pyridine was removed using a high-vacuum pump; the material was
redissolved in CH2Cl2 and analyzed by TLC, which showed that no
starting material remained. The rest of the reaction mixture was
evaporated using a high-vacuum pump. The crude product was purified
by flash chromatography on a silica gel column and eluted with 40%
acetone in hexane. The solvent was evaporated to afford 2a (65 mg) in
86% yield as a white solid. 1H NMR (CDCl3) d: 5.36 (d, J = 2.4 Hz, 1H),
5.22 (t, J = 9.3 Hz, 1H), 5.13 (2d, J = 7.8, 8.1 Hz, 1H), 4.9–4.89 (m, 2H),
4.56–4.49 (m, 3H), 4.36 (t, J = 4.5 Hz, 2H), 4.16–4.03 (m, 4H), 3.91–3.79
(m, 3H), 3.66–3.64 (m, 1H), 3.04 (s, 3H, Ms), 2.17 (s, 3H, acetate), 2.15
(s, 3H, acetate), 2.08 (s, 3H, acetate), 2.07 (s, 3H, acetate), 2.06 (s, 6H,
acetate), 1.98 (s, 3H, acetate). HRMS: calculated for C29H42O21SNa
(M + Na) 781.1832, found 781.1850.
of 2b (4–5 mg) in dry acetonitrile (0.4mL) was added to the dry K18F/
kryptofix 2.2.2. The reaction mixture was heated at 80ꢁC for 20min. The
crude reaction mixture was passed through a silica Sep-Pak cartridge and
eluted with 10% MeOH/CH2Cl2 (2.5mL). The solvent was evaporated, and
the residue was dissolved in 60% acetonitrile/water (1.0mL) and purified
by HPLC. The product [18F]-3 was collected between 16.5 and 18.0min,
and an aliquot was analyzed on an analytical HPLC to verify its identity
and purity by coinjection with the nonradioactive authentic sample 3.
Preparation of 10-[18F]fluoroethyl-b-D-lactose: [18F]-4
The product [18F]-3 was dried under reduced pressure, dissolved in CH2Cl2,
and transferred to a V-vial; then, the solvent was evaporated. The residue
was dissolved in methanol (0.4mL), 0.5M NaOMe/MeOH solution (0.1mL)
was added, and the mixture was heated at 80 ꢁC for 7min, when HPLC
showed complete hydrolysis of [18F]-3. The solvent was evaporated, and
the residue, [18F]-4, was neutralized with HCl, diluted with saline, and
filtered through a 0.22-mm Millipore filter. Compound [18F]-4 was analyzed
by TLC as previously reported,3 which showed >99% pure product with
the same Rf value as the authentic compound.
Preparation of 10-(p-nitrophenylsulfonylethyl)-20,30,60,2,3,4,6-
hepta-O-acetyl-b-D-lactose: 2b
Results and discussion
10-(Hydroxyethyl)-20,30,60,2,3,4,6-hepta-O-acetyl-b-D-lactose
1 (68.0 mg,
0.1 mmol) was dissolved in dry pyridine (3.0 mL) in a small flask and Scheme 1 describes the non-radioactive synthesis of 10-fluoroethyl-
b-D-lactose 4 and radiosynthesis of [18F]-FEL [18F]-4. Compound 1
was prepared from lactose using methods described previously3,14
and characterized by 1H NMR spectroscopy and MS, which were
consistent with those previously reported in the literature.3,14
Compound 2a was obtained in 86% yield; its identity was fully
cooled to 0 ꢁC under argon. p-Nitrophenylsulfonyl chloride (55 mg,
2.5 equiv.) was dissolved in dry CH2Cl2 (1.0 mL) and added slowly to
the reaction mixture and stirred for 1 h at 0 ꢁC. TLC showed that no
starting material remained. The reaction mixture was evaporated using
a high-vacuum pump, and the crude product was purified by flash
chromatography on a silica gel column and eluted with 40% acetone in
hexane. The solvent was evaporated to afford 2b (55 mg) in 64% yield
as a white solid. 1H NMR (CDCl3) d: 8.44 (d, J = 8.8 Hz, 2H, aromatic), 8.1
(d, J = 8.9 Hz, 2H, aromatic), 5.37 (d, J = 2.4 Hz, 1H), 5.20–5.089 (m, 2H),
4.98 (dd, J = 10.5 Hz, 3.6 Hz, 1H), 4.77 (dd, J = 7.8 Hz, 7.8 Hz, 1H),
1
1
characterized by H NMR spectroscopy and HRMS. The H NMR
spectrum showed a new peak (s) at 3.04 ppm with an integration
of 3H, suggesting the presence of the mesylate and the HRMS
showed M+ Na ion at m/z 781.1850. Compound 2b was obtained
1
4.51–4.46 (m, 3H), 4.29–4.25 (m, 2H), 4.16–4.06 (m, 3H), 4.04–3.39 in 64% yield, and this compound was also characterized by H
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Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 351–355

N. Turkman et al.
OAc
OAc
AcO
AcO
AcO
AcO
OAc
O
OAc
O
AcO
O
OH
pyridine
RCl
O
AcO
O
OR
O
O
O
OAc
OAc
OAc
OAc
2a R=Ms
2b R=Ns
1
MeCN, K18F/Kryptofix
OAc
OH
OAc
HO
HO
AcO
AcO
18F
OH
O
18F
HO
O
AcO
O
O
O
O
O
O
OH
OAc
MeOH/NaOMe
OH
OAc
4
3
Scheme 1. Scheme for synthesis and radiosynthesis of 10-[18F]fluoroethyl-b-D-lactose [18F]-4.
NMR spectroscopy and HRMS. The NMR spectrum showed new of CH2-F. Both 1H NMR and 19F NMR spectra of 3 were consistent,
characteristic peaks in the aromatic region with an integration of as previously reported.3 The reaction of 2b with Bu4NF at 80 ꢁC
2H each, and the HRMS showed M + Na ion at m/z 888.1873. and 90 ꢁC produced 3 in 85% yields. NMR spectra of 3 from 2a
Compound 2b was highly reactive as opposed to 2a; for example, and 2b were identical, and 3 from both precursors had the same
when pyridine was evaporated from the crude reaction mixture at retention time (tR) in the HPLC chromatograms.
an elevated temperature (50ꢁC), the product was converted to a
After deacetylation of peracetyl-10-fluoroethyl-b-lactose 3 by
1
new compound, which was characterized by H NMR and MS as reaction with 0.5 M sodium methoxide, 10-fluoroethyl-b-lactose
the 10-chloroethyl-20,30,60,2,3,4,6-hepta-O-acetyl-b-D-lactose. The 4 was produced in quantitative yield.
chloride ion generated from the reaction of nosyl chloride acted
For synthesis of [18F]-3 and eventually [18F]-4, both precursors 2a
as a nucleophile to produce the new derivative. About 80% of and 2b were radiofluorinated with K18F/kryptofix 2.2.2. in dry
the product was converted to the 10-chloroethyl derivative at MeCN (Scheme 1) at different temperatures. Compound 2a was
50 ꢁC. However, the problem was resolved by keeping the reaction radiofluorinated at 90ꢁC and 100ꢁC, and 2b was radiofluorinated
mixture at 0 ꢁC and evaporating pyridine at a lower temperature at 80 ꢁC and 90ꢁC. Because the higher temperatures did not render
(7–10 ꢁC). With this precautionary measure, the yield could be any improvement in yields, we maintained the lower temperatures;
improved to 64%.
thus, 2a was reacted at 90 ꢁC and 2b reacted at 80 ꢁC for 20 min.
The reaction of 2a with Bu4NF at 90 ꢁC and 100 ꢁC produced 3 in Passing [18F]-3 through a silica gel cartridge helped to remove
1
65% yields. The H NMR spectrum of 3, as previously reported,3 unreacted fluoride that may have co-eluted with the desired
was quite complex in the region where the CH2-F protons resonate. product during HPLC purification. The precursor 2a produced
The 19F NMR spectrum (coupled), however, was clear, showing a [18F]-3 in 15–27% yields at 90 ꢁC after HPLC purification, and the
peak at – 224.22 ppm as a multiplet, which supports the presence precursor 2b produced [18F]-3 in 58–69% yields at 80 ꢁC. Figure 1
ADC1 A, ADC1 CHANNEL A (LAC425\LACTOSE2.D)
mAU
65
Radioactivity
60
55
50
45
0
2.5
5
7.5
10
12.5
15
17.5
20
min
VWD1 A, Wavelength=254 nm (LAC425\LACTOSE2.D)
mAU
3500
3000
2500
2000
1500
1000
500
UV
0
0
2.5
5
7.5
10
12.5
15
17.5
20
min
Figure 1. HPLC purification of 10-[18F]fluoroethyl-20,30,60,2,3,4,6-hepta-O-acetyl-b-D-lactose, [18F]-3: semipreparative C18 Column; 45% MeCN and 55% H2O; flow 4.0mL/min.
J. Label Compd. Radiopharm 2013, 56 351–355
Copyright © 2013 John Wiley & Sons, Ltd.
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N. Turkman et al.
ADC1 A, ADC1 CHANNEL A (LAC714\LAC00029.D)
mAU
65
62.5
60
57.5
55
Radioactivity
52.5
50
47.5
0
2
4
6
8
min
DAD1 C, Sig=210,8 Ref=360,100 (LAC714\LAC00029.D)
mAU
80
70
60
50
40
30
20
10
0
UV
0
2
4
6
8
min
0
2
4
6
8
1
Figure 2. HPLC chromatogram of 10-[18F]fluoroethyl-20,30,60,2,3,4,6-hepta-O-acetyl-b-D-lactose, [18F]-3, co-injected with standard 10-fluoroethyl-20,30,60,2,3,4,6-hepta-O-
acetyl-b-D-lactose 3: Analytical C18 Column; 55% MeCN and 45% H2O; flow 1.0 mL/min.
represents the HPLC chromatogram for the purification of [18F]-3 of any byproduct, and in this synthesis, nosylate at 80 ꢁC should
from the nosylate precursor. The nosylate produced much a be used for routine production. Thus, nosylate produced the
cleaner product, and the recovery from the HPLC column was highest radiochemical yield at 65%, whereas mesylate produced
about 75%, much higher than that previously reported.3 Analysis 21% yield, which is lower than that of nosylate but still higher
of [18F]-3 by HPLC on an analytical column showed a single than those obtained from bromo- and tosylate precursors, 9%
radioactive peak co-eluted with an authentic nonradioactive and 11%, respectively.3
standard (Figure 2). The nosylate precursor 2b appeared to be
much better and produced high yields. Thus, 2b at 80 ꢁC for
20 min seems to be ideal for the routine production of [18F]- Conclusion
fluoroethyl lactose. One experiment was performed at 70 ꢁC, which
We have achieved an improved synthesis of the lactose
also produced high yields, thereby suggesting that this
analogue, [18F]-FEL, in high yields, with high purity and high
specific activity. The product is suitable for PET imaging of early
temperature may be applicable; however, further experiments
should be performed.
pancreatic carcinomas. Nosylate precursor 2b with this method
Hydrolysis of [18F]-3 with NaOMe produced the final product,
should be applicable for automated production in a commercial
[18F]-4, in quantitative yield. Hydrolysis was monitored by HPLC,
synthesis module for clinical application.
which showed that the hydrolysis was complete in 7 min. After
the solvent was evaporated from [18F]-4, the product required
neutralization with 1 M HCl solution followed by dilution with
25000
saline and finally filtration through a 0.22-mm Millipore filter.
Radio-TLC of [18F]-4 showed a single product with an Rf value
20000
of 0.82, consistent with that of the non-radioactive compound
(Figure 3). In general, about 10–12% of the product was
15000
lost during evaporation of the HPLC solvent from [18F]-3,
transfer, hydrolysis, and filtration of [18F]-4. The radiochemical
10000
purity was >99% with specific activity of 55.5 GBq/mmol at the
end of synthesis. The synthesis time was 90–95 min from the
5000
end of bombardment.
0
Mesylate at 90 ꢁC for 30 min produced 21% yield; on the other
0
50
100
150
200
hand, nosylate at 80 ꢁC produced 65% yield. At 90 ꢁC, nosylate
did not produce any higher yield. Lower temperatures are
preferred for any chemical reaction to eliminate the formation
Figure 3. Radio-TLC of 10-[18F]fluoroethyl-b-D-lactose [18F]-4: developing solvent;
MeOH:H2O (95:5).
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Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 351–355

N. Turkman et al.
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Acknowledgements
This work was supported by the NCI CCSG Core Grant CA 106672
and 1R01DA030333–01; NIH/NIDA.
Conflict of Interest
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