Radiosynthesis of new carbon-11-labeled nimesulide analogs as potential PET SAER tracers for imaging of aromatase expression in breast cancer

Article abstract of DOI:10.1080/00397910903013747

Carbon-11-labeled nimesulide analogs, N-[¹¹C]methyl-N-(2- benzyloxy-4-nitrophenyl)methanesulfonamide ([¹¹C]4a), N-[ ¹¹C]methyl-N-[2-(4'-methylbenzyloxy)-4-nitrophenyl] methanesulfonamide ([¹¹C]4b), N-[¹¹

Full text of DOI:10.1080/00397910903013747

Synthetic Communications1, 40: 749–758, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903013747
RADIOSYNTHESIS OF NEW CARBON-11-LABELED
NIMESULIDE ANALOGS AS POTENTIAL PET SAER
TRACERS FOR IMAGING OF AROMATASE
EXPRESSION IN BREAST CANCER
Min Wang,1 Mingzhang Gao,1 Kathy D. Miller,2
George W. Sledge,2 Gary D. Hutchins,1 and Qi-Huang Zheng1
1Department of Radiology, Indiana University School of Medicine,
Indianapolis, Indiana, USA
2Department of Medicine, Indiana University School of Medicine,
Indianapolis, Indiana, USA
Carbon-11-labeled nimesulide analogs, N-[11C]methyl-N-(2-benzyloxy-4-nitrophenyl)-
methanesulfonamide ([11C]4a), N-[11C]methyl-N-[2-(40-methylbenzyloxy)-4-nitrophenyl]-
methanesulfonamide
phenyl]methanesulfonamide ([11C]4c), N-[11C]methyl-N-[2-(40-nitrobenzyloxy)-4-nitro-
phenyl]methanesulfonamide
([11C]8a), N-[11C]methyl-N-[2-(b-naphthylmethoxy)-
([11C]4b),
N-[11C]methyl-N-[2-(40-fluorobenzyloxy)-4-nitro-
4-nitrophenyl]methanesulfonamide ([11C]8b), and N-[11C]methyl-N-[2-(20-phenylbenzy-
loxy)-4-nitrophenyl]methanesulfonamide ([11C]8c), have been synthesized as new potential
positron emission tomography (PET) selective aromatase expression regulator (SAER) radio-
tracers for imaging of aromatase expression in breast cancer. The target tracers were prepared
by N-[11C]methylation of their corresponding precursors using [11C]CH3OTf under basic con-
ditions (NaH) and isolated by reversed-phase high-pressure liquid chromatography (HPLC)
method in 30–50% radiochemical yields decay corrected to end of bombardment (EOB) with
25–30 min overall synthesis time and 111–148 GBq/lmol specific activity at end of synthesis
(EOS).
Keywords: Aromatase expression; breast cancer; imaging; nimesulides; positron emission tomography
(PET); radiosynthesis
Breast cancer is the most common cancer diagnosed in women and is the second
leading cause of death in women after lung cancer in the United States. The exact
cause of breast cancer remains unknown. Most breast cancer patients will survive
after conventional treatment modalities such as surgery, radiation therapy, chemo-
therapy, and=or a combination thereof if the breast cancer can be detected at an
early stage.[1] However, these treatments still fail to cure a significant number of
patients. Rapid and accurate early detection is highly desirable so that various
Received December 31, 2008.
Address correspondence to Qi-Huang Zheng, Department of Radiology, Indiana University
School of Medicine, 1345 West 16th Street, L-3 Room 202, Indianapolis, IN 46202-2111, USA. E-mail:
qzheng@iupui.edu
749

750
M. WANG ET AL.
therapeutic regiments can be given before the primary tumors become widespread.[2]
The improved therapies with fewer side effects and early detection with advanced
imaging technology may help to decrease the overall death rate of breast cancer.
Novel strategies are eagerly needed. To this end, aromatase inhibitor therapy has
received wide attention in treating breast cancer,[3] because aromatase inhibitors
are equivalent or superior to tamoxifen, a well-known selective estrogen receptor
modulator currently in advanced clinical trials or on the market for treatment of
hormone-dependent breast cancer, as a first-line therapy for metastatic breast cancer
and as neoadjuvant treatment for primary breast cancer. Moreover, aromatase inhi-
bitors can be administered instead of tamoxifen as a single agent for 5 years or
sequentially with tamoxifen for 5 or 10 years as shown in the randomized studies.[4]
The enzyme aromatase converts androgen to estrogen and is a particularly attractive
target in the treatment of estrogen-receptor-positive breast cancer[5,6] and the devel-
opment of enzyme-based cancer-imaging agents for a biomedical imaging technique,
positron emission tomography (PET). Recently, a new series of nimesulide analogs
has been developed as potent selective aromatase expression regulators (SAERs),
which suppress aromatase enzyme activity and selectively decrease aromatase gene
expression in breast cancer cells without causing cytotoxic or apoptotic effects.[5,6]
We investigated whether 11C-labeled analogs of nimesulides could be used to map
breast cancer aromatase in vivo. In our previous work, we synthesized carbon-11-
labeled sulfonanilides as potential PET breast cancer aromatase imaging agents
and performed their preliminary biological evaluation.[7] In this ongoing study, we
designed and synthesized carbon-11-labeled nimesulide analogs, N-[11C]methyl-
N-(2-benzyloxy-4-nitrophenyl)methanesulfonamide ([11C]4a), N-[11C]methyl-N-[2-(40-
methylbenzyloxy)-4-nitrophenyl]methanesulfonamide ([11C]4b), N-[11C]methyl-N-[2-(40-
fluorobenzyloxy)-4-nitrophenyl]methanesulfonamide
([11C]4c),
N-[11C]methyl-N-
[2-(40-nitrobenzyloxy)-4-nitrophenyl]methanesulfonamide ([11C]8a), N-[11C]methyl-N-
[2-(b-naphthylmethoxy)-4-nitrophenyl]methanesulfonamide ([11C]8b), and N-[11C]-
methyl-N-[2-(20-phenylbenzyloxy)-4-nitrophenyl]methanesulfonamide ([11C]8c), as
new potential PET SAER radiotracers for imaging of aromatase expression in
breast cancer.
The precursors (3a–c, 7a–c) and their corresponding standard compounds
(4a–c, 8a–c) were synthesized as shown in Schemes 1 and 2 with a modification of
the literature procedure.[6] As outlined in Scheme 1, the synthesis started with ben-
zylation of 2-amino-5-nitrophenol by various substituted benzyl bromides in the
presence of K2CO3 to provide 2-benzyloxy-4-nitroanilins 1a–c. Compound 1a
reacted with excess of methanesulfonyl chloride under basic conditions (NaH) in
dimethylformamide (DMF) to afford N,N-bimethanesulfonimide 2a, which was
hydrolyzed with 3 N NaOH under reflux to provide monomethanesulfonamide 3a.
However, compound 1b or 1c reacted with excess of methanesulfonyl chloride,
resulting in a mixture of N,N-bimethanesulfonimide and N-methanesulfonamide.
The mixture was hydrolyzed with 3 N NaOH to obtain monomethanesulfonamide
3b or 3c. Methylation of the precursors 3a–c with CH3I in the presence of NaH in
DMF to provide standard compounds 4a–c.
Scheme 2 presents an alternative pathway for achieving the precursors 7a–c
and standard compounds 8a–c. Benzyl ether 2a was debenzylated with BF3 ꢀ OEt2-
Me2S in CH2Cl2 to give the corresponding parent phenol 5 in a good yield.[8]

RADIOSYNTHESIS OF CARBON-11-LABELED NIMESULIDES
751
Scheme 1. Synthesis of nimesulide precursors and standards 3a–c and 4a–c.
Alkylation of the phenolic hydroxyl group of compound 5 by substituted benzyl or
naphthylmethyl bromides provided compounds 6a–c. Hydrolysis of N,N-bimethane-
sulfonimides (6a with K2CO3 in CH3CN and 6b and 6c with 3 N NaOH) gave mono-
methanesulfonamides 7a–c. The precursors 7a–c reacted with CH3I in the presence
of NaH or K2CO3 in DMF to form their corresponding standard compounds 8a–c.
Scheme 2. Synthesis of nimesulide precursors and standards 7a–c and 8a–c.

752
M. WANG ET AL.
Scheme 3. Synthesis of carbon-11-labeled nimesulides [11C]4a–c.
Synthesis of the tracers [11C]4a–c and [11C]8a–c is outlined in Schemes 3 and 4.
The precursors 3a–c and 7a–c were labeled by [11C]methyl triflate ([11C]CH3OTf)[9,10]
through N-[11C]methylation and isolated by reversed-phase high-performance liquid
chromatography (HPLC)[7] to produce the corresponding pure radiolabeled com-
pounds [11C]4a–c and [11C]8a–c in 30–50% radiochemical yields, based on
[11C]CO2 with decay corrected to end of bombardment (EOB). Overall synthesis time
was 25–30 min from EOB. The radiosynthesis was performed in an automated multi-
purpose 11C-radiosynthesis module, allowing measurement of specific activity during
synthesis.[11,12] The specific activity measured by the on-the-fly technique was in a
range of 222–296 GBq=mmol at EOB and 111–148 GBq=mmol at the end of synthesis
(EOS), respectively. Chemical purity and radiochemical purity were determined by
analytical HPLC method.[13] The chemical purity of the precursors and reference
standards was >95%. The radiochemical purity of the target tracers was >99%,
determined by radio-HPLC through c-ray (PIN diode) flow detector, and the chemi-
cal purity of the target tracers was >93% determined by reversed-phase HPLC
through an ultraviolet (UV) flow detector.
In conclusion, an efficient and convenient synthesis of new carbon-11-labeled
nimesulide analogs has been developed. The synthetic methodology employed classi-
cal organic chemistry such as benzylation, methanesulfonylation, debenzylation,
alkylation, hydrolysis, and methylation to produce nimesulide precursor and
standard compounds. Carbon-11-labeled nimesulides were prepared by N-
[11C]methylation of their corresponding monomethanesulfonamide precursors using
Scheme 4. Synthesis of carbon-11-labeled nimesulides [11C]8a–c.

RADIOSYNTHESIS OF CARBON-11-LABELED NIMESULIDES
753
a reactive [11C]methylating agent, [11C]CH3OTf, and isolated by HPLC purification
procedure in high radiochemical yields, short overall synthesis time, and great spe-
cific radioactivities. These results combined with the reported in vitro biological
data[5,6] encourage further in vivo biological evaluation of new carbon-11-labeled
nimesulide analogs as potential PET SAER radiotracers for imaging of breast cancer
aromatase expression.
EXPERIMENTAL
All commercial reagents and solvents from Aldrich and Sigma were used
without further purification. [11C]CH3OTf was prepared according to a literature
procedure.[10] Melting points were determined on a Mel-Temp II capillary tube
apparatus and were uncorrected. 1H NMR spectra were recorded on a Bruker
Avance II 500-MHz NMR spectrometer using tetramethylsilane (TMS) as an inter-
nal standard. Chemical shift data for the proton resonances were reported in parts
per million (ppm, d scale) relative to internal standard TMS (d 0.0), and coupling
constants (J) were reported in hertz (Hz). Thin-layer chromatography (TLC) was
run using Analtech silica gel GF uniplates (5 ꢁ 10 cm2). Plates were visualized under
UV light. Preparative TLC was run using Analtech silica-gel UV 254 plates
(20 ꢁ 20 cm2). Normal-phase flash-column chromatography was carried out on
EM Science silica gel 60 (230–400 mesh) with a forced flow of the chromatographic
solvent proportions (volume–volume). All moisture- and=or air-sensitive reactions
were performed under a positive pressure of nitrogen maintained by a direct line
from a nitrogen source.
Analytical HPLC was performed using a Prodigy (Phenomenex) 5-mm C18
column, 4.6 ꢁ 250 mm; 3:1:1 CH3CN=MeOH=20 mM, pH 6.7 phosphate (buffer sol-
ution) mobile phase, flow rate 1.5 mL=min, and UV (254 nm) and c-ray (PIN diode)
flow detectors. Semi-preparative HPLC was performed using a YMC-Pack ODS-A,
S 5 mm, 12 nm, 10 ꢁ 250 mm i.d. (Waters) C-18 column; 3:1:1 CH3CN=MeOH=
20 mM, pH 6.7 phosphate mobile phase, 5.0 mL=min flow rate, UV (254 nm) and
c-ray (PIN diode) flow detectors. Sterile vented Millex-GS 0.22-mm filter unit was
obtained from Millipore Corporation, Bedford, MA.
2-Benzyloxy-4-nitroaniline (1a)
Yellow solid, 86% yield, mp 144–145 ꢂC (lit.[6] 148–149 ꢂC). 1H NMR
(500 MHz, CDCl3): d 7.83 (dd, J ¼ 2.5, 8.5 Hz, 1H, Ar-H), 7.79 (d, J ¼ 2.5 Hz, 1H,
Ar-H), 7.47–7.35 (m, 5H, Ar-H), 6.78 (d, J ¼ 8.5 Hz, 1H, Ar-H), 5.16 (s, 2H,
PhCH2O).
2-(40-Methylbenzyloxy)-4-nitroaniline (1b)
Yellow solid, 86% yield, mp 145–146 ꢂC (lit.[6] 149–150 ꢂC). 1H NMR
(500 MHz, CDCl3): d 7.82 (dd, J ¼ 2.3, 8.5 Hz, 1H, Ar-H), 7.78 (d, J ¼ 2.5 Hz, 1H,
Ar-H), 7.35 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.20 (d, J ¼ 7.5 Hz, 2H, Ar-H), 6.78 (d,
J ¼ 8.7 Hz, 1H, Ar-H), 5.16 (s, 2H, PhCH2O), 2.38 (s, 3H, PhCH3).

754
M. WANG ET AL.
2-(40-Fluorobenzyloxy)-4-nitroaniline (1c)
Yellow solid, 84% yield, mp 120–121 ꢂC (lit.[6] 125–127 ꢂC). 1H NMR
(500 MHz, DMSO-d6): d 7.74 (dd, J ¼ 2.0, 9.0 Hz, 1H, Ar-H), 7.69 (d, J ¼ 2.0 Hz,
1H, Ar-H), 7.58 (t, J ¼ 7.3 Hz, 2H, Ar-H), 7.23 (t, J ¼ 9.0 Hz, 2H, Ar-H), 6.69 (d,
J ¼ 9.0 Hz, 1H, Ar-H), 6.44 (br s, 2H, NH2), 5.22 (s, 2H, PhCH2O).
N,N-(2-Benzyloxy-4-nitrophenyl)dimethanesulfonamide (2a)
Pale yellow solid, 98% yield, mp 186–187 ꢂC (lit.[6] 188–189 ꢂC). 1H NMR
(500 MHz, DMSO-d6): d 8.03 (d, J ¼ 2.5 Hz, 1H, Ar-H), 7.91–7.86 (m, 2H, Ar-H),
7.53 (d, J ¼ 7.0 Hz, 2H, Ar-H), 7.42 (t, J ¼ 7.0 Hz, 2H, Ar-H), 7.38–7.35 (m, 1H,
Ar-H), 5.40 (s, 2H, PhCH2O), 3.46 (s, 6H, 2 ꢁ SO2CH3).
N-(2-Benzyloxy-4-nitrophenyl)methanesulfonamide (3a)
Yellow solid, 87% yield, mp 158–160 ꢂC (lit.[6] 150–152 ꢂC). 1H NMR
(500 MHz, CDCl3): d 7.94 (dd, J ¼ 2.3, 8.8 Hz, 1H, Ar-H), 7.89 (d, J ¼ 2.5 Hz, 1H,
Ar-H), 7.68 (d, J ¼ 9.0 Hz, 1H, Ar-H), 7.47–7.40 (m, 5H, Ar-H), 7.23 (br s, 1H,
NH), 5.21 (s, 2H, PhCH2O), 3.07 (s, 3H, SO2CH3).
N-[2-(40-Methylbenzyloxy)-4-nitrophenyl]methanesulfonamide (3b)
Yellow solid, 55% yield, mp 152–153 ꢂC (lit.[6] 151–152 ꢂC). 1H NMR
(500 MHz, CDCl3): d 7.93 (dd, J ¼ 2.3, 8.8 Hz, 1H, Ar-H), 7.89 (d, J ¼ 2.5 Hz, 1H,
Ar-H), 7.66 (d, J ¼ 8.5 Hz, 1H, Ar-H), 7.30 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.24 (d,
J ¼ 8.0 Hz, 2H, Ar-H), 7.22 (br s, 1H, NH), 5.16 (s, 2H, PhCH2O), 3.06 (s, 3H,
SO2CH3), 2.39 (s, 3H, PhCH3).
N-[2-(40-Fluorobenzyloxy)-4-nitrophenyl]methanesulfonamide (3c)
Yellow solid, 71% yield, mp 155–157 ꢂC (lit.[6] 162–164 ꢂC). 1H NMR
(500 MHz, CDCl3): d 7.95 (dd, J ¼ 2.3, 8.8 Hz, 1H, Ar-H), 7.88 (d, J ¼ 2.5 Hz, 1H,
Ar-H), 7.67 (d, J ¼ 8.5 Hz, 1H, Ar-H), 7.42–7.40 (m, 2H, Ar-H), 7.21 (br s, 1H,
NH), 7.16–7.12 (m, 2H, Ar-H), 5.17 (s, 2H, PhCH2O), 3.08 (s, 3H, SO2CH3).
N-Methyl-N-(2-benzyloxy-4-nitrophenyl)methanesulfonamide (4a)
Pale yellow solid, 66% yield, mp 131–133 ꢂC (lit.[6] 138–140 ꢂC). 1H NMR
(500 MHz, CDCl3): d 7.94 (d, J ¼ 2.5 Hz, 1H, Ar-H), 7.89 (dd, J ¼ 2.5, 8.5 Hz, 1H,
Ar-H), 7.55 (d, J ¼ 8.5 Hz, 1H, Ar-H), 7.45–7.41 (m, 5H, Ar-H), 5.21 (s, 2H,
PhCH2O), 3.26 (s, 3H, SO2CH3), 2.81 (s, 3H, NCH3).
N-Methyl-N-[2-(40-methylbenzyloxy)-4-nitrophenyl]methane-
sulfonamide (4b)
Yellow solid, 76% yield, mp 116–118 ꢂC (lit.[6] 123–124 ꢂC). 1H NMR
(500 MHz, CDCl3): d 7.93 (d, J ¼ 2.5 Hz, 1H, Ar-H), 7.87 (dd, J ¼ 2.5, 8.5 Hz, 1H,

RADIOSYNTHESIS OF CARBON-11-LABELED NIMESULIDES
755
Ar-H), 7.54 (d, J ¼ 8.5 Hz, 1H, Ar-H), 7.32 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.24 (d,
J ¼ 8.0 Hz, 2H, Ar-H), 5.16 (s, 2H, PhCH2O), 3.25 (s, 3H, SO2CH3), 2.80 (s, 3H,
NCH3), 2.39 (s, 3H, PhCH3).
N-Methyl-N-[2-(40-fluorobenzyloxy)-4-nitrophenyl]-
methanesulfonamide (4c)
Yellow solid, 72% yield, mp 168–169 ꢂC (lit.[6] 168–169 ꢂC). 1H NMR
(500 MHz, CDCl3): d 7.92 (d, J ¼ 2.0 Hz, 1H, Ar-H), 7.89 (dd, J ¼ 2.3, 8.8 Hz, 1H,
Ar-H), 7.54 (d, J ¼ 8.5 Hz, 1H, Ar-H), 7.45–7.42 (m, 2H, Ar-H), 7.15–7.12 (m,
2H, Ar-H), 5.18 (s, 2H, PhCH2O), 3.25 (s, 3H, SO2CH3), 2.82 (s, 3H, NCH3).
N,N-(2-Hydroxy-4-nitrophenyl)dimethanesulfonamide (5)
1
Yellow solid, 82% yield, mp 251 ꢂC (dec.) [lit.[6] 249–253 ꢂC (dec.)]. H NMR
(500 MHz, DMSO-d6): d 11.63 (s, 1H, OH), 7.76–7.74 (m, 1H, Ar-H), 7.73 (s, 1H,
Ar-H), 7.69 (dd, J ¼ 2.5, 9.0 Hz, 1H, Ar-H), 3.55 (s, 6H, 2 ꢁ SO2CH3).
N,N-[2-(40-Nitrobenzyloxy)-4-nitrophenyl]-
dimethanesulfonamide (6a)
1
Yellow solid, 68% yield, mp 265 ꢂC (dec.) [lit.[6] 265–269 ꢂC (dec.)]. H NMR
(500 MHz, DMSO-d6): d 8.28 (d, J ¼ 9.0 Hz, 2H, Ar-H), 8.04 (d, J ¼ 2.5 Hz, 1H,
Ar-H), 7.94 (dd, J ¼ 2.0, 8.5 Hz, 1H, Ar-H), 7.89 (d, J ¼ 8.5 Hz, 1H, Ar-H), 7.80
(d, J ¼ 9.0 Hz, 2H, Ar-H), 5.59 (s, 2H, PhCH2O), 3.50 (s, 6H, 2 ꢁ SO2CH3).
N,N-[2-(b-Naphthylmethoxy)-4-nitrophenyl]-
dimethanesulfonamide (6b)
Pale yellow solid, 90% yield, mp 185–186 ꢂC (lit.[6] 184–185 ꢂC). 1H NMR
(500 MHz, DMSO-d6): d 8.10 (d, J ¼ 2.5 Hz, 2H, Ar-H), 7.97 (d, J ¼ 8.5 Hz, 2H,
Ar-H), 7.95–7.88 (m, 3H, Ar-H), 7.64 (dd, J ¼ 1.5, 8.5 Hz, 1H, Ar-H), 7.57–7.53
(m, 2H, Ar-H), 5.58 (s, 2H, PhCH2O), 3.50 (s, 6H, 2 ꢁ SO2CH3).
N,N-[2-(20-Phenylbenzyloxy)-4-nitrophenyl]-
dimethanesulfonamide (6c)
White solid, 90% yield, mp 184–185 ꢂC (lit.[6] 182–184 ꢂC). 1H NMR (500 MHz,
DMSO-d6): d 7.87 (d, J ¼ 1.0 Hz, 2H, Ar-H), 7.79 (s, 1H, Ar-H), 7.71 (dd, J ¼ 1.0,
7.5 Hz, 1H, Ar-H), 7.50–7.38 (m, 8H, Ar-H), 5.20 (s, 2H, PhCH2O), 3.45 (s, 6H,
2 ꢁ SO2CH3).
N-[2-(40-Nitrobenzyloxy)-4-nitrophenyl]methanesulfonamide (7a)
Yellow solid, 70% yield, mp 151–152 ꢂC (lit.[6] 168–169 ꢂC). 1H NMR
(500 MHz, DMSO-d6): d 9.75 (s, 1H, NH), 8.29 (d, J ¼ 9.0 Hz, 2H, Ar-H), 7.92

756
M. WANG ET AL.
(s, 1H, Ar-H), 7.90 (d, J ¼ 2.5 Hz, 1H, Ar-H), 7.87 (d, J ¼ 9.0 Hz, 2H, Ar-H), 7.61 (d,
J ¼ 8.0 Hz, 1H, Ar-H), 5.51 (s, 2H, PhCH2O), 3.17 (s, 3H, SO2CH3).
N-[2-(b-Naphthylmethoxy)-4-nitrophenyl]methanesulfonamide (7b)
Pale yellow solid, 83% yield, mp 143–144 ꢂC [lit.[6] 239–243 ꢂC (dec.)]. 1H NMR
(500 MHz, CDCl3): d 7.95 (s, 1H, Ar-H), 7.94–7.92 (m, 2H, Ar-H), 7.89–7.87 (m, 3H,
Ar-H), 7.68 (d, J ¼ 9.0 Hz, 1H, Ar-H), 7.56–7.53 (m, 2H, Ar-H), 7.50 (dd, J ¼ 1.5,
8.5 Hz, 1H, Ar-H), 5.37 (s, 2H, PhCH2O), 3.06 (s, 3H, SO2CH3).
N-[2-(20-Phenylbenzyloxy)-4-nitrophenyl]methanesulfonamide (7c)
Pale yellow solid, 55% yield, mp 138–140 ꢂC (lit.[6] 116–119 ꢂC). 1H NMR
(500 MHz, CDCl3): d 7.87 (dd, J ¼ 2.5, 9.0 Hz, 1H, Ar-H), 7.61 (s þ d, J ¼ 7.0 Hz,
2H, Ar-H), 7.51–7.34 (m, 9H, Ar-H), 7.02 (br s, 1H, NH), 5.16 (s, 2H, PhCH2O),
3.02 (s, 3H, SO2CH3).
N-Methyl-N-[2-(40-nitrobenzyloxy)-4-nitrophenyl]-
methanesulfonamide (8a)
Pale yellow solid, 68% yield, mp 215–216 ꢂC (lit.[6] 209–211 ꢂC). 1H NMR
(500 MHz, DMSO-d6): d 8.30 (d, J ¼ 9.0 Hz, 2H, Ar-H), 8.00 (d, J ¼ 2.5 Hz, 1H,
Ar-H), 7.89 (dd, J ¼ 2.5, 8.5 Hz, 1H, Ar-H), 7.81 (d, J ¼ 8.5 Hz, 2H, Ar-H), 7.64
(d, J ¼ 8.5 Hz, 1H, Ar-H), 5.53 (s, 2H, PhCH2O), 3.22 (s, 3H, SO2CH3), 3.04 (s,
3H, NCH3).
N-Methyl-N-[2-(b-naphthylmethoxy)-4-nitrophenyl]-
methanesulfonamide (8b)
Pale yellow solid, 54% yield, mp 119–120 ꢂC (lit.[6] 119–121 ꢂC). 1H NMR
(500 MHz, CDCl3): d 8.00 (d, J ¼ 2.5 Hz, 1H, Ar-H), 7.93 (s, 1H, Ar-H), 7.91–7.86
(m, 4H, Ar-H), 7.57–7.52 (m, 4H, Ar-H), 5.37 (s, 2H, PhCH2O), 3.27 (s, 3H,
SO2CH3), 2.81 (s, 3H, NCH3).
N-Methyl-N-[2-(20-phenylbenzyloxy)-4-nitrophenyl]-
methanesulfonamide (8c)
Pale yellow solid, 87% yield, mp 124–125 ꢂC (lit.[6] 128–129 ꢂC). 1H NMR
(500 MHz, CDCl3): d 7.83 (dd, J ¼ 2.5, 8.5 Hz, 1H, Ar-H), 7.64 (d, J ¼ 2.0 Hz, 1H,
Ar-H), 7.54 (dd, J ¼ 1.0, 7.5 Hz, 1H, Ar-H), 7.51–7.39 (m, 9H, Ar-H), 5.17 (s, 2H,
PhCH2O), 3.22 (s, 3H, SO2CH3), 2.81 (s, 3H, NCH3).
General Method for the Preparation of the Carbon-11-Labeled
Nimesulide Analogs
[11C]CO2 was produced by the 14N(p,a)11C nuclear reaction in a small-volume
(9.5 cm3) aluminum-gas target (CTI) from an 11-MeV proton cyclotron on

RADIOSYNTHESIS OF CARBON-11-LABELED NIMESULIDES
757
research-purity nitrogen (þ1% O2) in a Siemens radionuclide delivery system
(Eclipse RDS-111). The precursor (3a, 3b, 3c, 7a, 7b, or 7c) (0.1–0.3 mg) was dis-
solved in CH3CN (300 mL). NaH (0.5–1 mg) was added to this solution. The mixture
was transferred to a small reaction vial. No-carrier-added (high specific activity)
[11C]CH3OTf [produced by the gas-phase production method[10] from [11C]CO2
through [11C]CH4 and [11C]CH3Br with silver triflate (AgOTf) column] was passed
into the reaction vial until radioactivity reached a maximum (ꢃ2 min), and then
the reaction vial was isolated and heated at 80 ꢂC for 3 min. The contents of the
reaction vial were diluted with NaHCO3 (1 mL, 0.1 M) and injected onto the
semi-preparative HPLC column with a 2-mL injection loop. The product fraction
was collected, the solvent was removed by rotatory evaporation under vacuum,
and the final product, [11C]4a, [11C]4b, [11C]4c, [11C]8a, [11C]8b, or [11C]8c, was
formulated in saline, filtered through a sterile vented Millex-GS 0.22-mm cellulose
acetate membrane, and collected into a sterile vial. Total radioactivity was assayed,
and total volume was noted for tracer dose dispensing. The overall synthesis, puri-
fication, and formulation time was 25–30 min from EOB. The radiochemical yields
decay-corrected to EOB, from [11C]CO2, were 30–50%. Retention times in the
analytical HPLC system were tR 3a ¼ 2.80 min, tR 4a ¼ 3.13 min, tR [11C]4a ¼
3.13 min; tR 3b ¼ 3.23 min, tR 4b ¼ 3.80 min, tR [11C]4b ¼ 3.80 min; tR 3c ¼ 2.75 min,
tR 4c ¼ 3.03 min, tR [11C]4c ¼ 3.03 min; tR 7a ¼ 2.73 min, tR 8a ¼ 3.05 min, tR
[11C]8a ¼ 3.05 min; tR 7b ¼ 3.80 min, tR 8b ¼ 4.13 min, tR [11C]8b ¼ 4.13 min, and tR
7c ¼ 4.35 min, tR 8c ¼ 4.80 min, and tR [11C]8c ¼ 4.80 min. Retention times in the
semi-preparative HPLC system were tR 3a ¼ 5.12 min, tR 4a ¼ 7.33 min, tR
[11C]4a ¼ 7.33 min; tR 3b ¼ 6.55 min, tR 4b ¼ 8.23 min, tR [11C]4b ¼ 8.23 min; tR
3c ¼ 5.35 min, tR 4c ¼ 7.28 min, tR [11C]4c ¼ 7.28 min; tR 7a ¼ 4.98 min, tR 8a ¼
6.75 min, tR [11C]8a ¼ 6.75 min; tR 7b ¼ 5.34 min, tR 8b ¼ 8.03 min, tR [11C]8b ¼
8.03 min; and tR 7c ¼ 6.18 min, tR 8c ¼ 8.54 min, tR [11C]8c ¼ 8.54 min.
ACKNOWLEDGMENTS
This work was partially supported by the Susan G. Komen for the Cure, Breast
Cancer Research Foundation, and Indiana Genomics Initiative (INGEN) of Indiana
University, which is supported in part by Lilly Endowment Inc. The authors thank
Dr. Bruce H. Mock and Barbara E. Glick-Wilson for their assistance in production
of [11C]CH3OTf.
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