Synthesis of an iodine-123-labeled celecoxib analogue: A potential spect agent

Article abstract of DOI:10.1002/jlcr.923

Celecoxib (4[5-(4-methylphenyl)-3-(trifluoromethy)-1H-pyrazol-1yl]- benzenesulfonamide) is an effective inhibitor of the cyclooxygenase-2 (COX-2). The synthesis of a no-carrier-added iodine-123-labeled analogue of celecoxib was accomplished in four steps for potential use in single photon tomography. Copyright

Full text of DOI:10.1002/jlcr.923

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 295–300.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.923
Research Article
Synthesis of an iodine-123-labeled celecoxib analogue:
a potential spect agent
George W. Kabalka1,*, Arjun R. Mereddy1 and Hildegard M. Schuller2
1 Departments of Chemistry and Radiology, The University of Tennessee, Rm. 612,
Buehler/Dabney Hall, Knoxville, TN 37996, USA
2 Department of Pathology, The University of Tennessee College of Veterinary
Medicine, Veterinary Teaching Hospital, Rm. A201A, Knoxville, TN 37996, USA
Summary
Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1yl]-benzenesulfonamide)
is an effective inhibitor of the cyclooxygenase-2 (COX-2). The synthesis of a
no-carrier-added iodine-123-labeled analogue of celecoxib was accomplished in four
steps for potential use in single photon tomography. Copyright # 2005 John Wiley &
Sons, Ltd.
Key Words: celecoxib; SPECT; radioiodination; radio-TLC; colon cancer
Introduction
The arachidonic acid (AA)-metabolizing enzyme cyclooxygenase-2 (COX-2) is
frequently but not always over-expressed in adenocarcinomas of the lungs,
pancreas, colon, stomach, breast and prostate, leading to the increased
formation of AA-metabolites that stimulate tumor growth.1,2 In vitro studies
with cell lines derived from such cancers and experiments in relevant animal
models as well as epidemiological studies in humans have provided evidence
that non-selective COX inhibitors (e.g. aspirin, ibuprofen) as well as selective
COX-2 inhibitors (e.g. celecoxib) can significantly reduce the risk for the
development of this cancer family.3À14 COX-2 inhibitors are therefore
currently being tested in cancer prevention and treatment trials. COX-2
inhibitors are also widely used for treatment of arthritis15,16 and they are being
tested as preventive agents for Alzheimer’s disease.17
*Correspondence to: G. W. Kabalka, Departments of Chemistry and Radiology, The University of
Tennessee, Rm. 612, Buehler/Dabney Hall, Knoxville, TN 37996, USA. E-mail: kabalka@utk.edu
Contract/grant sponsor: National Institutes of Health; contract/grant number: R01-CA 096128-01A1
Contract/grant sponsor: Robert H. Cole Foundation
Copyright # 2005 John Wiley & Sons, Ltd.
Received 25 October 2004
Revised 4 November 2004
Accepted 3 December 2004

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G. W. KABALKA ET AL.
H C
3
CF3
N
N
O
S
H2N
1
Figure 1. Structure of celecoxib
A potential problem with the chronic use of COX-2 agents is the fact that
physiological levels are necessary to ensure the proper balance of AA-
metabolites that are critical mediators of cardiovascular and kidney function
as well as platelet aggregation.18,19 Recent reports have revealed that chronic
use of the selective COX-2 inhibitor VIOXX significantly increased
cardiovascular mortality.19,20 This finding emphasizes the need to monitor
COX-2 levels in patients subjected to chronic treatments with this family of
drugs prior to therapy as well as during treatment. Non-invasive nuclear
medicine imaging with a suitable radiolabeled COX-2 inhibitor would be an
ideal tool to achieve this goal. Our research efforts have focused on the
synthesis of a no-carrier-added radioiodinated analogue of celecoxib (1, Figure
1) for use as a single photon emission tomography (SPECT) imaging agent.
Results and discussion
The iodine-123-labeled 4-iodo analogue of celecoxib (2, Figure 2) was chosen
for the study, based on the fact that substitution of a halogen for the 4-methyl
group did not significantly alter the COX-2/COX-1 selectivity in the initial
report. Thus, the chloro analogue of 1 showed a binding affinity of Ki=0.01
and 17.8 mM for COX-2 and COX-1, respectively. Thus, the 4-chloro analogue
proved to be more selective than celecoxib, which showed a binding affinity of
Ki=0.04 and 15.0 mM for COX-2 and COX-1.21
The synthesis of the no-carrier-added iodine-123-labeled analogue of
celecoxib, 2, is outlined in Scheme 1. 4-Iodoacetophenone, 3, was converted
into the requisite tin precursor in three steps. The initial reaction involving
conversion of 3 to 4, in the presence of NaOMe/MeOH proceeded in good
yield (79%). Intermediate 4 was refluxed with 4-(sulfamoylphenyl)hydrazine
hydrochloride in ethanol to give 5 in 91% yield.21 Compound 5 was subjected
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 295–300

I-123 COX-2 INHIBITOR
297
123I
CF3
N
N
O
S
O
H2N
2
Figure 2. Radioiodinated analogue of celecoxib
O
O
OH
CF3
H2NO2S
NHNH HCl
CH3
NaOMe/MeOH
CH3CH2OH
H
CH3OCOCF3
MTBE
I
I
3
4
Sn
O
I
Sn2(CH3)6
Pd(PPh3)4
CF3
CF3
N
N
N
N
S
H2NO2S
H2N
O
6
5
123I
Na123
CH3COOOH
I
CF3
N
N
O
S
H2N
O
2
Scheme 1. Synthesis of analogue 2
to a palladium-catalyzed deiodostannylation using hexamethylditin and
tetrakis(triphenylphosphine)palladium(0) in refluxing dioxane to generate 6
in 90% yield.22 The no-carrier-added radioiodination of trimethylstannyl
derivative 6 was conducted by conventional electrophilic iododestannylation
using Na123I and dilute peracetic acid, which produced 2 in a decay corrected
radiochemical yield of 90% and a radiochemical purity >98%. Product
purification can be achieved by thin layer chromatography (silica gel, ethyl
Copyright # 2005 John Wiley & Sons, Ltd.
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G. W. KABALKA ET AL.
ether/hexane = 3:1) since the Rf of 2 (0.61) is significantly different from that
of tin precursor 6 (0.72).
Experimental
Elemental analyses were performed by Atlantic Micro Labs, Inc., Norcross
Georgia. Melting points were recorded on an electrothermal Digital Melting
Point Apparatus and are uncorrected. 1H and 13C spectra were recorded on a
Bruker AC 250 MHz NMR spectrometer. The chemical shift values are
expressed in parts per million (d) relative to tetramethylsilane. Radio thin layer
chromatography was carried out using a Bioscan, AR-2000 imaging scanner.
All starting materials were purchased from Aldrich Chemical Company.
Na123I was obtained from Nordion Inc., Vancouver, Canada. All reactions
were carried out using dry solvents under an inert atmosphere.
4,4,4-Trifluoro-1-(4-iodophenyl)-butane-1,3-dione (4)
To a solution of methyl trifluoroacetate (4.23 g, 33.0 mmol) in 60 ml of methyl
tert-butyl ether (MTBE) was added a 25% solution of NaOMe in MeOH
(8.82 ml, 39.0 mmol). A solution of 4-iodoacetophenone (7.38 g, 30.0 mmol) in
115 ml of MTBE was then added dropwise to the mixture using an addition
funnel. After stirring for 48 h at room temperature, 3 N HCl (14.0 ml) was
added and the organic layer extracted into ether, washed with water and then
brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give
a brownish solid that was recrystallized from isooctane to yield 8.11 g (79%) of
product. m.p. 378C; 1H NMR (CDCl3) d 6.53(s, 1H), 7.64 (d, 2H, J=8.5 Hz),
7.87 (d, 2H, J=8.6 Hz); 13C NMR(CDCl3) d 92.2, 102.2, 117.0, 128.8, 132.3,
138.4, 177.5, 185.1. Analytically calculated for C10H6F3IO2: C, 35.11; H, 1.77;
I, 37.10. Found: C, 35.19; H, 1.74; I, 36.90.
4-[5-(4-Iodophenyl)-3-trifluoromethyl-pyrazol-1-yl]benzenesulfonamide (5)
To a stirred solution of diketone 4 (4.10 g, 12.0 mmol) in 120 ml of ethanol was
added 4-(sulfamoylphenyl)hydrazine hydrochloride (2.95 g, 13.2 mmol). The
mixture was refluxed for 24 h. After cooling to room temperature, the reaction
mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate,
washed with water and then brine, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo to give a pale brown solid. The crude product was
purified by column chromatography (30% ethyl acetate in hexane) to give
1
5.39 g (91%) of 5 as a white solid. m.p. 1808C; H NMR (CDCl3) d 5.04 (s,
2H), 6.78 (s, 1H), 6.97 (d, 2H, J=8.4 Hz), 7.46 (d, 2H, J=8.7 Hz), 7.73 (d, 2H,
J=8.4 Hz), 7.93 (d, 2H, J=8.7 Hz); 13C NMR(CDCl3) d 95.9, 106.6, 116.6,
125.6, 127.6, 128.0, 130.3, 138.3, 141.8, 142.1, 144.0, 144.9. Analytically
calculated for C16H11F3IN3O2S : C, 38.96; H, 2.25; N, 8.52; I, 25.73. Found:
C, 38.98; H, 2.26; N, 8.42; I, 25.49.
Copyright # 2005 John Wiley & Sons, Ltd.
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I-123 COX-2 INHIBITOR
299
4-[5-(4-Trimethylstynnyltinphenyl)-3-trifluoromethyl-pyrazol-1-yl]-benzenesul-
fonamide ( 6 )
Hexamethylditin (0.98 g, 3.0 mmol) and 5 (0.99 g, 2.0 mmol) were added
sequentially to a suspension of tetrakis(triphenylphosphine)palladium (0)
(0.10 g, 0.09 mmol) in anhydrous 1,4-dioxane (15 ml). The reaction mixture
was stirred at reflux under nitrogen for 0.5 h. After cooling, the mixture was
filtered, the insoluble black material was washed with dioxane (20 ml) and the
dioxane layers were combined. Removal of dioxane solvent gave a gummy
residue, which was purified by chromatography (silica gel, ethyl acetate:
hexane (1:1). The solid product was recrystallized from ethyl acetate/
petroleum ether. Yield (0.95 g, 90%); m.p. 888C; Rf=0.72 (silica gel, ethyl
1
ether:hexane=3:1). H NMR (CDCl3) d 0.30 (s, 9H), 5.47 (brs, 2H), 6.75 (s,
1H), 7.15 (d, 2H, J=8.1 Hz), 7.45 (d, 2H, J=8.5 Hz), 7.50 (d, 2H, J=7.9 Hz),
7.69 (d, 2H, J=8.5 Hz); 13C NMR(CDCl3) d À6.6, 106.5, 125.5, 127.4, 128.0,
128.1, 136.4, 141.5, 142.3, 143.7, 144.3, 145.0, 145.3. Analytically calculated
for C19H20F3N3O2SSn: C, 43.04; H, 3.80; N, 7.93. Found: C, 43.02; H, 3.78;
N, 7.94.
4-[5-(4-[123I]Iodophenyl)-3-trifluoromethyl-pyrazol-1-yl]benzenesulfonamide (2)
Precursor 6 (2.8 mg, 5.2 mmol, in 100 ml methanol) was placed in a 2 ml
Wheaton vial containing no-carrier-added Na123I (37 MBq in 0.1% aqueous
NaOH). To this was added peracetic acid (100 ml, 0.3% solution in methanol).
The reaction vial was sealed, covered with aluminum foil and the mixture
stirred for 5 min at room temperature. A drop of 10% aqueous sodium
thiosulfate was added to decompose the excess iodine and the radioiodinated
product was isolated by passing it through a silica gel Sep-pak using ethyl
acetate:hexane (2:1) as eluent. This process removed all ionic materials
including residual iodide. Product separation and radiochemical purity of the
product were achieved using radio-TLC (aluminum-backed silica gel plate,
ethyl ether:hexane=3:1); Rf=0.61. The decay-corrected radiochemical yield
was determined to be 90% and radiochemical purity was >98%. The total
synthesis time was 15 min.
Conclusion
In summary, a no-carrier-added iodine-123-labeled analogue of celecoxib, 2, a
potential SPECT agent for imaging a variety of cancers, was synthesized via
iododestannylation in excellent yield and high radiochemical purity.
Acknowledgements
We wish to thank the National Institutes of Health (R01-CA 096128-01A1)
and the Robert H. Cole Foundation for supporting this research.
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