Synthesis of 18F-labeled cyclooxygenase-2 (COX-2) inhibitor as a potential PET imaging agent

Article abstract of DOI:10.1002/jlcr.1074

A new PET tracer for COX-2 imaging, the 6-ethoxy-3-(4- methanesulfonylphenyl)-4-(4-[¹⁸F]fluorophenyl)pyran-2-one ([ ¹⁸F]EFMP), was synthesized. For F-18 radiolabeling, a trimethylammonium precursor and a brominated precursor were syn

Full text of DOI:10.1002/jlcr.1074

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 583–593.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1074
Research Article
18
Synthesis of F-labeled cyclooxygenase-2 (COX-2)
inhibitor as a potential PET imaging agent
Haibin Tian and Zhenghong Lee*
Biomedical Engineering and Radiology, Case Western Reserve University, Cleveland,
OH 44106, USA
Summary
A new PET tracer for COX-2 imaging, the 6-ethoxy-3-(4-methanesulfonylphenyl)-4-
(4-[18F]fluorophenyl)pyran-2-one ([18F]EFMP), was synthesized. For F-18 radiolabel-
ing, a trimethylammonium precursor and a brominated precursor were synthesized
from 1,1,2,3-tetrachlorocycloprop-2-ene in 6 steps. The radiolabeling was achieved
through nucleophilic substitution using no-carrier-added (n.c.a.) fluorine-18. Solid-
phase extraction and semi-preparative-HPLC purification produced [18F]EFMP in
14.6 ꢀ 3.3% (n ¼ 4) decay corrected radiochemical yield with a specific activity of
487 ꢀ 85.1 (n ¼ 4) Ci/mmol and greater than 98% radiochemical purity. Copyright
# 2006 John Wiley & Sons, Ltd.
Received 12 December 2005; Revised 28 March 2006; Accepted 29 March 2006
Key Words: fluorine-18; COX-2 inhibitor; nucleophilic substitution
Introduction
Cyclooxygenase-2 (COX-2) is an enzyme that converts arachidonic acid to
prostaglandin H2. COX-2 is expressed in normal brain and kidney, activated
macrophages, synoviocytes during inflammation, and malignant epithelial
cells of several major cancers. COX-2 expression is stimulated by a number of
inflammatory cytokines, growth factors, oncogenes, lipopolysaccharides, and
tumor promoters.1,2 Generally, COX-2 expression in humans is assessed by
*Correspondence to: Zhenghong Lee, Radiology and Biomedical Engineering, Case Western Reserve
University, Cleveland, OH 44106, USA. E-mail: zhenghong.lee@case.edu
Contract grant sponsor: Ohio Biomedical Research and Technology Transfer
Contract grant sponsor: NIH Research Resource (R24); contract/grant number: CA110943
Copyright # 2006 John Wiley & Sons, Ltd.

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H. TIAN AND Z. LEE
ex vivo laboratory analysis of tissue samples acquired by biopsy or autopsy.3
Because COX-2 messenger RNA (mRNA) and protein are unstable, the
accuracy of ex vivo COX-2 analysis strongly depends on the interval between
tissue sampling and analysis.4 A noninvasive imaging method to monitor
COX-2 expression in vivo is thus needed to overcome this problem. In vivo
imaging of COX-2 would also provide a valuable tool to gain more insight in
pathophysiology of diseases involving COX-2. Over-expression of COX-2 in
arthritis, organ rejection, myocardial infraction, cancer, pain sensation, stroke,
and neurodegenerative diseases has been reported,5–8 which makes COX-2 a
potential target for therapeutic intervention and diagnosis based on
noninvasive medical imaging technique such as positron emission tomography
(PET). Although attempts have been made to develop PET probes for COX-2
imaging, currently no satisfactory COX-2 PET imaging agents are available
for in vivo imaging of COX-2 expression. McCarthy et al.9 reported the
radiosynthesis of 18F-SC58125 as a COX-2 PET tracer for investigation of the
COX-2 pathway in inflammatory diseases. But, it showed high nonspecific
binding in vivo, which would limit the usefulness of this imaging probe. de
Vries et al.10 reported [18F]-Desbromo-DuP-697, another radiolabeled COX-2
inhibitor that was evaluated in a rat model for carrageenan-induced
hyperalgesia, which exhibited substantial nonspecific uptake in fat and
intestine. Isakson et al.11 reported the synthesis of several labeled COX-2
inhibitors without demonstrating specific binding in vivo. Toyokuni et al.12
reported the synthesis of [18F]fluoromethyl analogue of valdecoxib, and
biodistribution studies in mice revealed rapid defluorination and accumulation
of the radioactive label in bone, which made it unfit for imaging to COX-2 in
this species. However, studies in vervet monkeys revealed much later and
much less prominent defluorination, suggesting its potential role for imaging
in humans. More recently, F-18 labeled Rofecoxib,13 C-11 labeled Celecoxib14
and C-11 labeled Etoricoxib15 have been synthesized as COX-2 selective
radiotracers. However, in vivo studies have not been published with these
compounds.
In this study, we investigated feasibility of labeling a new generation of
COX-2 inhibitors as radiotracers for PET imaging to quantitatively assess
COX-2 expression in vivo. We select to synthesize [18F]EFMP, an F-18
labeled COX-2 inhibitor for PET imaging studies of COX-2 in vivo. The
structure of the COX-2 inhibitor, 6-ethoxy-4-(4-fluorophenyl)-3-(4-methane-
sulfonyl-phenyl)-pyran-2-one (EFMP) is shown in Figure 1. It exhibits
excellent potency (IC50 ¼ 0:10 mM) and selectivity (SI ¼ 2880) for COX-216
better than Desbromo-DuP-697, SC-58125, etc. Its anti-inflammatory activity
was also studied revealing a much better anti-inflammatory activity than that
of the celecoxib.16 The structure of EFMP permits incorporation of 18F
through a nucleophilic reaction between [18F]fluorine and a trimethylammonium
Copyright # 2006 John Wiley & Sons, Ltd.
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SYNTHESIS OF 18F-LABELED COX-2
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Figure 1. Selective COX-2 inhibitors: EFMP
precursor. This manuscript summarizes the radio-synthesis procedure. We
plan to use microPET imaging along with other assays to extensively evaluate
the potential of this new COX-2 imaging agent on mouse models in the near
future. One of the models is transgenic, in which the erbB2/HER-2/neu
oncogene was expressed under tissue-specific transcriptional control of the
mouse mammary tumor virus promoter (MMTV-LTR) and represents a
suitable model of mammary carcinogenesis paw. The relationship between
COX-2 and breast cancer has been proposed,17 and PET imaging using the
new tracer reported here will directly measure COX-2 expression in breast
cancer. Similar PET imaging will also be used for assessing COX-2 level in a
mouse model of colorectal cancer since COX-2 is over-expressed in 85% of
colon cancers.18
Results and discussion
For F-18 radiolabeling, the trimethylammonium precursor 5 and brominated
precursor 3b, were synthesized as depicted in Scheme 1. Aryltrimethylammo-
nium is often used by many as a leaving group in the nucleophilic substitution
of n.c.a. [18F]fluoride.19 Our initial strategy was to introduce trimethyl-
ammonium directly starting with dimethylaniline (Scheme 1, R ¼ NMe3).
Unfortunately, when we tried to prepare 2-(4-dimethylamino-phenyl)-3-
(4-methanesulfonyl-phenyl)-cycloprop-2-enone
(1c)
through
tandem
Friedel–Crafts arylation reaction of 1,1,2,3-tetrachlorocycloprop-2-ene with
N,N-dimethylbenzenamine in the presence of AlCl3, no product of 1c was
obtained. This might be due to the fact that the benzene ring of 1c was not
sufficiently active upon protonation of dimethylamine group in the presence of
the acid solution. An alternative approach was then taken, in which 2-(4-
bromo-phenyl)-3-(4-methanesulfonyl-phenyl)-cycloprop-2-enone 2b was first
prepared with a yield of 69.0%. The 4-(4-bromophenyl)-6-ethoxy-3-(4-
methanesulfonyl-phenyl)-pyran-2-one 3b was prepared with a yield of 17.2%
by condensation of 2b with a pyridinium salt 6 in the presence of
Copyright # 2006 John Wiley & Sons, Ltd.
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H. TIAN AND Z. LEE
Scheme 1. Synthesis of 6-ethoxy-4-(4-fluorophenyl)-3-(4-methanesulfonyl-
phenyl)-pyran-2-one (EFMP) and trimethylammonium precursor 5 and bromi-
nated precursor 3b
triethylamine. The pyridinium salt 6 was prepared from ethyl bromoacetate
with pyridine according to a previously published method.20
For the synthesis of trimethylamino derivative 5, palladium-catalyzed
coupling reaction was used, which proved to be an efficient method for
substitution of aryl halogen atoms by amine according to a previous report.21
The palladium (0)/imidazolium salt catalyzed amination of aryl bromides was
achieved at room temperature. To effectively accelerate the reaction rate, a
palladium-substrate ratio of 1:2 was used and led to an isolated yield (30.3%).
As shown in Scheme 1, 4-(4-dimethylamino-phenyl)-6-ethoxy-3-(4-methane-
sulfonyl-phenyl)-pyran-2-one 4 was prepared based on the amination reaction
catalyzed by Pd2(dba)3/IPr.HCl. The treatment of 4 with methyl triflate thus
produced the desired trimethylammonium salts 5.
Following the production of [18F]fluoride through 18O(p,n) nuclear reaction,
EFMP was radiolabeled by the nucleophilic substitution reaction using the
Copyright # 2006 John Wiley & Sons, Ltd.
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SYNTHESIS OF 18F-LABELED COX-2
587
Table 1. Effect of temperature of fluorination trimethylammonium salt in acetonitrile
Reaction time (min)
Temperature (8C)
Labeling yield
(% ꢀ SD) n ¼ 3
20
20
20
100
130
140
28.4 ꢀ 6.85
86.8 ꢀ 2.01
75.1 ꢀ 6.53
n represents number of runs, SD: standard deviation.
Figure 2. The separation of semi-preparative HPLC-chromatograms of
[18F]EFMP
trimethylammonium precursor in CH3CN. The labeling yields at different
temperatures were examined. It appeared that the labeling reaction at 1308C
was appropriate for trimethylammonium substitution (Table 1). Following
rapid Sep-Pak (C-18) extraction, the radiolabeled product was further purified
by HPLC (Alltech Econosil C18, 250 ꢁ 10 mm, 5 mm column, 0.1% TFA:
acetonitrile, 50:50 mixture as an eluent at a flow rate of 3.0 ml/min) with a
radiochemical yield of 14.6 ꢀ 3.3% (n ¼ 4)(decay corrected) (Figure 2). The
total synthesis took 60–70 min (EOB). The radiochemical purity of [18F]EFMP
was verified by co-elution of the radioactive peak with nonlabeled standard.
The specific activity was determined at 487 ꢀ 85.1 (n ¼ 4) Ci/mmol at EOS.
Similarly, radiofluorination of brominated precursor was also studied in
DMSO at 1608C. As shown in Scheme 2, [18F]EFMP was obtained in 4%
Copyright # 2006 John Wiley & Sons, Ltd.
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DOI: 10.1002/jlcr

588
H. TIAN AND Z. LEE
Scheme 2. Radiofluorination of trimethylammonium precursor and brominated
precursor
radiochemical yield following purification by semi-preparative HPLC.
However, this approach was not optimized as it was difficult to separate the
brominated precursor from the final product, resulting in decreased specific
activity of [18F]EFMP.
Experimental
Materials and methods
Chemicals for the syntheses were purchased from commercial sources (Sigma-
Aldrich) and were used without further purification. Solvents of the highest
grade were used. Infrared (IR) spectra were recorded using a Digilab FTS-60
FTIR system. 1H NMR spectra were obtained on a Varian Gemini-2000(200-
MHz) instrument in CDCl3 using tetramethylsilane as the internal standard.
High-resolution mass-spectrometry (HRMS), fast atom bombardment (FAB)
mode (glycerol matrix) was obtained at 20–40 eV on a Kratos MS-25A
instrument. HPLC analysis and purification were performed on Hewlett-
Packard 1050 using an in-line UV detector (254 nm), and a NaI crystal flow-
count radioactivity detector (Beckman Model 170 Radioisotope Detector).
A dose calibrator (model CRC-7, Capintec) was used for all radioactivity
measurements. Compounds 1a, 2a, 3a were synthesized according to
previously reported procedures with some modification.16 [18F]fluoride was
Copyright # 2006 John Wiley & Sons, Ltd.
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SYNTHESIS OF 18F-LABELED COX-2
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produced by bombardment of [18O]H2O using a Scanditronix MC-17
cyclotron. Flash chromatography was performed using silica gel (230–400
mesh, Merck).
Chemistry
2-(4-bromo-phenyl)-3-(4-methylthiophenyl)cycloprop-2-en-1-one (1b). To a
suspension of dried AlCl3 (4.50 g, 33 mmol) in 1,2-dichloroethane (80 ml)
was added 1,1,2,3-Tetrachlorocycloprop-2-ene (5.31 g, 30 mmol) at 08C.
Under stirring bromobenzene (4.68 g, 30 mmol) was added to the reaction
mixture. There action was allowed to proceed at 258C for 24 h while the color
of the reaction mixture was changed from yellow to red. Thioanisole (3.72 g,
30 mmol) was then added and the reaction mixture was stirred for an
additional 24 h at 258C, while the color of mixture was changed from red to
deep green. Eventually green solid was precipitated. Ice water (100 g) was then
added to the reaction mixture and the organic and aqueous layers were
separated. The aqueous layer was extracted with 1,2-dichloroethane
(2 ꢁ 40 ml), and the combined organic fractions were washed successively
with NaHCO3 (50 ml of 5% wt/vol) and water (50 ml) and dried over Na2SO4.
Removal of the solvent in vacuo gave the crude product as a yellow solid.
Recrystallization of the mixture from MeOH-ether (twice) afforded 8.36 g
1
(84.1%) of the product 1b. IR(KBr): 1854 cmꢂ1(C=O), 1610 cmꢂ1(C=C); H
NMR(CDCl3): d ¼ 2:57(s, 3 H, SCH3), 7.34(dd, 2H, fluorophenyl H-3,
H-5), 7.44(d, 2H, methylthiophenyl H-3, H-5), 7.76(d, 2H, methylthiophenyl
H-3, H-5), 7.88(dd, 2H, fluorophenyl H-2, H-6).
2-(4-bromo-phenyl)-3-(4-methanesulfonyl-phenyl)-cycloprop-2-enone (2b). A
solution of oxone (6.25 g, 10.1 mmol) in water (30 ml) was added slowly to a
solution of 1b (0.27 g, 8.1 mmol) dissolved in MeOH/THF (50 ml of 1:1, vol/
vol) at ice-bath temperature. While stirring, the reaction mixture was allowed
to warm to 258C, and proceed for 24 h. White solid was then precipitated.
Removal of the solvent in vacuo gave a residue, which was dissolved in water
(25 ml) and CHCl3 (100 ml). The organic phase was separated and washed with
water and then brine before it was dried over Na2SO4. Removal of the solvent
from the organic fraction in vacuo gave a light yellow solid that was purified by
silica gel column chromatography using EtOAc-hexane (2:1, vol/vol) as
eluents to afford 0.205 g (69%) of the product as white needle. IR(KBr):
1854 cmꢂ1(C=O), 1624 cmꢂ1(C=C); 1H NMR(CDCl3): d ¼ 3:12(s, 3H,
SO2CH3), 7.75(dd, 2H, bromophenyl H-3, H-5), 7.82(d, 2H, methylsulfonyl-
phenyl H-2, H-6), 8.08(dd, 2H, bromophenyl H-2, H-6), 8.14(d, 2H,
methylsulfonylphenyl H-3, H-5). MS, m/z, M+ 360.760, calculated for
C16H1177BrO3S: 360.230.
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N-(ethoxycarbonylmethyl)-pyridinium bromides (6). To a stirred solution of
dry pyridine (9.0 ml, 11.0 mmol) in anhydrous THF (50 ml) was added ethyl
bromoacetate (1.84 g, 11.0 mmol) under an argon atmosphere. The reaction
mixture was stirred for 4 h at 258C till white solid was precipitated. The solvent
was removed in vacuo, and the solid product obtained was purified by
recrystallization from methanol/ether to give 1.31 g (51.5%) of the product as
white solid m.p.132–1348C (lit.,20 134–1368C); 1H NMR(DMSO-d6):
d ¼ 1:23(t, 3H, OCH2CH3), 4.25(q, 2H, OCH2CH3), 5.75 (s, 2H, N+CH2),
8.22(dd, 2H, pyridine H-3, H-5), 8.70(dd, 1H, pyridine H-4), 9.10(d, 2H,
pyridine H-2, H-4).
6-ethoxy-3-(4-methanesulfonylphenyl)-4-(4-bromophenyl)pyran-2-one(3b). To a
solution of the N-(ethoxycarbonylmethyl)-pyridinium bromides (2.09 g,
8.5 mmol) in anhydrous benzene (150 ml) at 258C was added dry triethylamine
(3.3 ml, 23 mmol), followed by addition of 2b (3.0 g, 8.3 mmol). The reaction
mixture was stirred for 24 h at 258C, while the color of the mixture was changed
from yellow to deep green. The solvent was evaporated under reduced pressure,
and the residue was purified by flash column chromatography using hexanes-
ethyl acetate (5:5, v/v) as eluents to afford 637 mg (17.2%) of the product as
1
green solid. IR (KBr): 1722 cmꢂ1(C=O), 1147 cmꢂ1(SO2); H NMR(CDCl3):
d ¼ 1:49(t, 3H, OCH2CH3), 3.05(s, 3H, SO2CH3), 4.38(q, 2H, OCH2CH3),
5.55(s, 1H, pyranone H-5), 6.95(dd, 2H, bromophenyl H-3, H-5), 7.30(dd, 2H,
bromophenyl H-2, H-6), 7.38(d, 2H, methylsulfonylpheny H-2, H-6), 7.78(d, 2H,
methylsulfonylpheny H-3, H-5). MS, m/z, M+ 446.298, calculated for C20H17
77BrO5S: 446.310.
6-ethoxy-3-(4-methanesulfonylphenyl)-4-(4-dimethylamino-phenyl)pyran-2-one(4).
The Pd2(dba)3 (6.6 mg, 0.0115 mmol) and 1Pr.HCl (19.6 mg, 0.046 mmol) were
added into the mixture of 1,4,-dioxane (20 ml), NaOH (240 mg, 6.0 mmol), 3b
(520 mg, 1.15 mmol), and dimethylamine hydrochloride (123 mg, 1.5 mmol) under
nitrogen atmosphere. The reaction mixture was stirred for 24 h at room
temperature. The mixture was then diluted with water then extracted with diethyl
ether. The extracts were combined, washed with saturated saline solution, and
then dried over Na2SO4. The solvent was removed under reduced pressure and the
residue was purified by flash chromatography, the desired product 4 was obtained
1
in 30.3% yield as yellow solid. H NMR(CDCl3): d ¼ 1:49(t, 3H, OCH2CH3),
3.05(s, 3H, SO2CH3), 3.10(s, 6H, dimethylaminophenyl) 4.38(q, 2H, OCH2CH3),
5.55(s, 1H, pyranone H-5), 6.95(dd, 2H, dimethylaminophenyl H-3, H-5), 7.30(dd,
2H, dimethylaminophenyl H-2, H-6), 7.38(d, 2H, methylsulfonylpheny H-2, H-6),
7.78(d, 2H, methylsulfonylpheny H-3, H-5). MS, m/z, M+ 413.230, calculated for
C22H23NO5S: 413.085.
Copyright # 2006 John Wiley & Sons, Ltd.
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SYNTHESIS OF 18F-LABELED COX-2
591
6-ethoxy-3-(4-methanesulfonylphenyl)-4-(4-trimethylammonium trifluoromethane
sulfonate phenyl)pyran-2-one(5). To a solution of 4 (40 mg, 0.07 mmol)
dissolved in 5 ml of anhydrous methylene chloride was added methyl
trifluoromethanesulfonate (9 ml, 0.08 mmol). The reaction solution was stirred
at room temperature overnight. At the end of the reaction, the solvent was
evaporated under reduced pressure and the residue was recrystallized from
MeOH/Et2O to give 12.3 mg (22.5%) of the product as brown solid.
1H NMR(CDCl3): d ¼ 1:49(t, 3H, OCH2CH3), 3.05(s, 3H, SO2CH3), 3.10(s,
9H, trimethylaminophenyl ) 4.38(q, 2H, OCH2CH3), 5.55(s, 1H, pyranone H-
5), 6.95(dd, 2H,trimethylaminophenyl H-3, H-5), 7.30(dd, 2H, trimethylami-
nophenyl H-2, H-6), 7.38(d, 2H, methylsulfonylpheny H-2, H-6), 7.78(d, 2H,
methylsulfonylpheny H-3, H-5). MS, m/z, M+ 577.233, calculated for
C24H26F3NO8S2: 577.590.
Radiosynthesis of 6-ethoxy-4-(4-[18F]fluorophenyl)-3-(4-methanesulfonyl-phenyl)-
pyran-2-one ([18F]EFMP). To a 10-ml V-vial containing 4.0 mg of potassium
carbonate, 50 ml of water, and 22 mg of Kryptofix-2.2.2 in 200 ml of acetonitrile
was added [18F]fluoride. The water was then removed through evaporation
with anhydrous acetonitrile under argon flow on a 1208C oil bath. To the
above-mentioned test vial containing the anhydrous [18F]fluoride ion was
added 2 mg of precursor 5 dissolved in 0.5 ml of acetonitrile. The vial was
sealed and heated on the oil bath at 1308C for 20 min. The reaction mixture
was cooled to room temperature and diluted with 1.0 ml acetonitrile and
passed through a C-18 Sep-Pak@ cartridge activated with methanol and water.
After the column was washed with 5 ml water, [18F]EFMP was then eluted
with 5 ml of acetonitrile. The solvent was removed under argon flow. Upon
dissolving in HPLC mobile phase, the mixtures were injected onto the
preparative HPLC column. Reversed phase semi-preparative HPLC (Alltech
Econosil C18, 250 ꢁ 10 mm, 5 mm column) was performed with 0.1% TFA:
acetonitrile, 50:50 mixtures as an eluent at a flow rate of 3.0 ml/min. The
effluent in semi-preparative HPLC was monitored with an ultraviolet detector
at 254 nm coupled with a gamma-radioactivity detector, and the radioactive
fraction having a retention time of 7.8–9.2 min was collected in a flask. After
collection and evaporation to dryness, the product was dissolved in 3.0 ml of
sterile normal saline and filtered through a sterile 0.2 mm filter into a sterile
evacuated vial. Radiochemical purity and specific activity of the product
[18F]EFMP was determined by analytical reversed phase HPLC (Alltech
Econosil C18, 250 ꢁ 4.6 mm, 5 mm column).
Radiofluorination of the brominated precursor 3b was conducted similarly.
The reaction was conducted in DMSO at 1608C for 30 min. The reaction
mixture was then cooled to room temperature and diluted with 1.0 ml water
before being passed through a C-18 Sep-Pak@ cartridge activated with
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methanol and water. The column was washed with 5.0 ml water. [18F]EFMP
was then eluted with 5 ml of acetonitrile and the solvent was removed under
argon flow. After being dissolved in HPLC mobile phases, the crude product
was injected onto the preparative HPLC column for further purification and
analysis.
Conclusion
In summary, [18F]EFMP, a potential F-18 labeled radiotracer for in vivo PET
imaging of COX-2 expression, has been successfully synthesized via a
trimethylammonium precursor. The radiosynthesis appeared to be superior
to that via a brominated precursor. After short reaction and fast purification,
the radiotracer was obtained with high specific activity and radiochemical and
chemical purity.
Acknowledgements
The authors would like to thank Prof. Yanming Wang, Dr Edward M. Plut
and Dr Shengyin Zhao for helpful discussion, Mr Bradley N. Roff and James
Hovanec for assistance with radiosynthesis. This work is supported in part by
Ohio BRTT and NIH R24 (CA110943).
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