Substituted halogenated arylsulfonamides: A new class of σ receptor binding tumor imaging agents

Article abstract of DOI:10.1021/jm9800447

The discovery of a series of novel halogenated arylsulfonamides (HAS) as new σ receptor binding tumor imaging agents is described. Several substituted halogenated sulfonamides have been prepared and characterized. Target compounds were examined for their

Full text of DOI:10.1021/jm9800447

J . Med. Chem. 1998, 41, 2445-2450
2445
Expedited Articles
Su bstitu ted Ha logen a ted Ar ylsu lfon a m id es: A New Cla ss of σ Recep tor Bin d in g
Tu m or Im a gin g Agen ts
,
†
†
‡
†
‡
Christy S. J ohn,* Benjamin B. Lim, Bertold J . Vilner, Brian C. Geyer, and Wayne D. Bowen
Radiopharmaceutical Chemistry Section, Department of Radiology, The George Washington University Medical Center,
Washington, D.C. 20037, and Unit on Receptor Biochemistry and Pharmacology, Laboratory of Medicinal Chemistry, National
Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Received J anuary 21, 1998
The discovery of a series of novel halogenated arylsulfonamides (HAS) as new σ receptor binding
tumor imaging agents is described. Several substituted halogenated sulfonamides have been
prepared and characterized. Target compounds were examined for their affinity for σ
receptor subtypes using guinea pig brain membranes and rat liver membranes, respectively.
A number of substituted halogenated sulfonamides displayed subnanomolar affinities for σ
sites and low nanomolar affinities for σ subtype receptors. A limited structure-activity
relationship study of this chemical series is discussed. The radioiodination (I-125) of one
1
and σ
2
1
2
congener member (4-[1 I]iodo-N-[2-(1′-piperidinyl)ethyl]benzenesulfonamide, 4-[ I]IPBS) was
25
125
1
25
accomplished in high yields. The in vitro competition binding studies of 4-[ I]IPBS in guinea
pig brain membranes with σ receptor binding ligands confirmed its σ pharmacology. The rank
order of potency was BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)-
ethylamine) > 4-IPBS > haloperidol > (+)-pentazocine > DTG (1,3-di-o-tolylguanidine) > (-)-
pentazocine. The inhibition constants (IC50) were 0.70, 1.46, 6.28, 10.4, 87.2, and 152 nM,
respectively, and are consistent with labeling of σ
1
receptors. The tumor imaging potential of
-[ I]IPBS was studied in C57 black mice bearing B16 melanoma xenograft. A high tumor
1
25
4
1
25
uptake of 4-[ I]IPBS was observed (7.40% ID/g) at 1 h postinjection. The wash out of activity
from the tumor was slow at 6 h postinjection (7.22% ID/g). The tumor also had the highest
amount of radioactivity (1.54% ID/g) at 24 h postinjection. These results demonstrate that
radiohalogenated benzenesulfonamides could be a potentially useful class of compounds in
nuclear oncologic scintigraphy.
σ receptor binding ligands consist of a variety of
structurally unrelated compounds such as benzomor-
phans, guanidines, arylethylenediamines, substituted
high density of σl and σ2 receptors is present on human
malignant melanoma, breast carcinoma, prostate tumor,
and nonsmall cell lung cancer, among other cell lines.12
The number of σ receptors is found to range between
1
-8
benzamides, phenylpiperidines, and phenylpiperazines.
On the basis of the opposite enantioselectivity for
benzomorphans, different molecular weights, and phar-
macological binding studies, two types of σ receptors (σ1
and σ2) have been defined.9 The endogenous σ ligand-
2
00000 and about a million receptors/cell, depending
upon the nature of the tumor cell line. Furthermore,
the in vitro binding experiments from the membrane
preparations of human biopsied solid tumors such as
brain, breast, and renal carcinomas also revealed a high
density of σ receptors as compared to the normal
(
s) are not known; however, progesterone has been
1
0
suggested to be a candidate.
The pharmacological
significance of σ receptor binding sites remain elusive
due to lack of functional and structural information.
However, recently the σl binding site, a 30 kDa protein
from guinea pig liver, has been purified and cloned. The
amino acid sequence of this protein showed no homology
to any known mammalian proteins, but a partial ho-
mologic resemblance with a fungal protein involved in
1
3-15
organs.
σ-receptor binding ligands have also shown
the inhibition of proliferation in mammary adenocarci-
noma (MCF-7, MDA) and colon carcinoma (LIM l2l5,
WIDr) cells as well as melanoma cells and neural tumor
1
6,17
cells in culture.
These results have implicated that
σ binding sites may play an important role in cell
growth, differentiation, and cell proliferation as well.
Furthermore, a recent study using mouse mammary
adenocarcinoma cells (line 66) showed the potential of
σ receptor binding radioligands as biomarkers of pro-
liferation in breast cancer cells. It was also shown that
sterol synthesis was observed.1
1
σ receptors have also been shown to be expressed in
a variety of human and rodent tumor cell lines. A very
*
Address correspondence to: Christy S. J ohn, Ph.D., 2300 I. St.
NW, 661 Ross Hall, Radiology Research, The George Washington
University Medical Center, Washington, D.C. 20037. Tel: (202)-994-
the density of σ2 receptors in proliferative cells was
5
031. Fax: (202)-994-8855. E-mail: radcsj@gwumc.edu.
18
†
about 10-fold higher than quiescent cells.
These
The George Washington University Medical Center.
‡
National Institutes of Health.
studies suggested the potential use of σ receptor ligands
S0022-2623(98)00044-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/05/1998

2
446 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
J ohn et al.
in oncological imaging and in evaluation of proliferating
breast tumors.
Sch em e 1. Synthetic Routes for Substituted
Haloarylsulfonamides
a
We have an ongoing research program involving the
development of σ receptor binding ligands for noninva-
sive imaging/therapy of σ receptor positive tumors.
Several radioiodinated benzamides have been evaluated
for their potential for imaging neoplasms in animal
1
9-21
models.
On the basis of the encouraging preclinical
results, several clinical studies have recently been
performed in Europe employing radioiodinated benza-
1
23
mides such as N-[2-(diethylamino)ethyl]-4-[ I]iodo-
1
23
bezamide, 4-[ I]DAB, and N-[2-(diethylamino)ethyl]-
1
23
123
3
-[ I]iodo-4-methoxybenzamide, 3-[ I]MBA, in mela-
2
2,23
noma patients.
These patient studies have revealed
the fast clearance of radiopharmaceuticals from the
blood pool and other nontarget organs that possess σ
receptors (such as liver, kidneys, and brain) and a high
uptake and retention in tumors. It has been proposed
that the uptake of radioiodinated benzamides in mela-
noma tumors may be related to the melanin content of
the melanoma cells. While the mechanism of uptake
a
Reagents: (a) N,N-diethylethylenediamine or 1-(2-aminoeth-
yl)pyrrolidine/piperidine/homopiperidine; (b) 1-(2-aminoethyl)-
piperidine or N-methyl-2-(1′-homopiperidinyl)ethylamine; (c)
Tl(CO2CF3)3/CF3COOH; (d) I2.
Ta ble 1. Mass Spectroscopic and Combustion Analyses Data
for Selected Halogenated Arylsulfonamides
in melanoma appears controversial, a recent clinical
CIMS
study using 4-[123I]DAB showed a good uptake of tracer
elemental analysis calcd (found)
emperical
formula
m/z
+
no.
(MH )
C
H
N
in nonsmall cell lung cancer patients as well, probably
due to σ receptor binding in human nonsmall cell lung
1
2
3
4
5
6
7
8
9
C
C
C
C
C
C
C
C
C
C
C
C
12
12
12
12
13
13
14
14
15
15
14
16
H
H
H
H
H
H
H
H
H
H
H
H
19
19
17
17
19
19
21
21
23
23
21
25
N
N
N
N
N
N
N
N
N
N
N
N
2
2
2
2
2
2
2
2
2
2
2
2
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
2
2
2
2
2
2
2
2
2
2
3
3
Br
I
Br
I
Br
I
Br
I
335
383
335
381
347
395
361
409
376
423
425
453
43.00 (42.80) 5.71 (5.83) 8.35 (8.30)
37.70 (37.71) 5.01 (4.74) 7.33 (7.04)
43.25 (43.42) 5.14 (5.17) 8.41 (8.42)
37.90 (38.05) 4.50 (4.19) 7.30 (7.25)
44.96 (44.91) 5.51 (5.56) 8.07 (8.00)
39.60 (39.86) 4.85 (4.60) 7.10 (7.06)
46.54 (46.62) 5.86 (5.77) 7.75 (7.63)
41.21 (41.47) 5.18 (4.97) 6.80 (6.67)
48.00 (47.73) 6.18 (5.94) 7.46 (7.41)
42.66 (42.44) 5.49 (5.18) 6.63 (6.41)
38.63 (38.39) 4.99 (4.85) 6.60 (6.28)
cancer.24 The number of patient studies has been very
few, and extensive clinical trials need to be performed
before the clinical use of σ receptor binding radiophar-
maceuticals is fully realized. In this study, we report
the discovery of halogenated arylsulfonamide (HAS), a
new class of high-affinity σ receptor binding ligands. The
synthesis, characterization, and pharmacological in vitro
binding studies in guinea pig brain membranes and
membrane preparations from rat liver, radioiodination
Br
I
I
10
1
2
1
1
a
I
nd
a
1
25
nd ) not determined.
of one member of this class of compounds, 4-[ I]iodo-
1
25
N-[2-(1′-piperidinyl)ethyl]benzenesulfonamide, 4-[ I]-
IPBS, and its in-vivo tumor imaging potential in a black
mouse melanoma tumor model are described.
Sch em e 2. Preparation of
-[ I]Iodo-N-[2-(1′-piperidinyl)ethyl]benzenesulfonamide,
-[ I]IPBS
125
4
4
125
a
Ch em istr y
Several substituted HAS, 1-10, were synthesized by
condensation of 1-(2-aminoethyl)pyrrolidine or 1-(2-
aminoethyl)piperidine or 1-(2-aminoethyl)homopiperi-
dine or N-methyl-2-(1′-homopiperidinyl)ethylamine with
4
-bromo- or 4-iodobenzenesulfonyl chloride in the pres-
ence of aqueous saturated sodium bicarbonate (Scheme
). N-[2-(1′-Piperidinyl)ethyl]-3-iodo-4-methoxybenze-
nesulfonamide, 11, was prepared by condensation of
-methoxybenzenesulfonyl chloride with 1-(2-amino-
ethyl)piperidine in the presence of base. The resulting
-methoxybenzenesulfonamide was then iodinated by
an electrophilic thallation procedure using thallium
trifluoroacetate-trifluoroacetic acid with molecular io-
dine. No attempts were made to isolate the resulting
intermediate arylthallium ditrifluoroacetate derivative.
Some of the halogenated arylsulfonamides were char-
acterized using NMR, mass spectroscopy, and combus-
tion analysis. The results of mass spectroscopy and
combustion analyses are summarized in Table 1. To
obtain a high yield in radioiodinations and high specific
activity of the radioiodinated product, the tri-n-butyl-
stannyl precursor, 6a , was prepared from its corre-
sponding iodo derivative 6 using bis(tri-n-butyltin) in
the presence of a catalytic amount of tetrakis(tri-
a
Reagents: (e) (SnBu3)2, Pd(PPh3)4, NEt3; (f) NaI-125, Chloram-
1
ine-T.
4
phenylphosphine)palladium(0) in triethylamine. The
radioiodination was achieved by an oxidative iodo-
destannylation reaction of 4-(tributylstannyl)benzene-
4
1
25
sulfonamide, 6a, and Na I (carrier free) using chloram-
1
25
ine-T as an oxidizing agent (Scheme 2). 4-[ I]Iodo-N-
[2-(1′-piperidinyl)ethyl]benzenesulfonamide, 4-[1 I]IPBS,
6b, was characterized by HPLC and radio-TLC. The
radiolabeled arylsulfonamide was purified using reversed-
phase HPLC. The radiochemical yield by solvent ex-
traction was found to range between 89 and 93% (n )
3), and the specific activity was found to be about 1600
Ci/mmol.
25
Resu lts a n d Discu ssion
On the basis of our SAR studies from halogenated
benzamides and SAR studies of de Costa et al.1 on

Substituted Halogenated Arylsulfonamides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2447
Ta ble 2. Receptor Binding Data for Halogenated Arylsulfonamides (HAS)a
3
3
compd
X
R
Y
R2
Ki (nM) σ1 guinea pig brain [ H]-(+)-pent
Ki (nM) σ2 rat liver [ H]DTG
1
2
3
4
5
6
7
8
9
1
1
1
Br
I
Br
I
Br
I
Br
I
Br
I
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
I
Et2
Et2
-(CH2)4-
-(CH2)4-
-(CH2)5-
-(CH2)5
-(CH2)6-
-(CH2)6-
-(CH2)6-
-(CH2)6-
-(CH2)5-
-(CH2)6-
10.1 ( 0.3
4.97 ( 0.54
6.65 ( 0.87
4.25 ( 0.66
1.54 ( 0.09
0.46 ( 0.07
0.63 ( 0.01
1.32 ( 0.93
0.18 ( 0.13
0.14 ( 0.03
41.8 ( 5.6
3.11 ( 1.6
3.70 ( 0.6
27.7 ( 4.3
3.1 ( 0.3
2826 ( 67
2393 ( 187
1487 ( 26
1002 ( 55
459 ( 15
206 ( 58
198 ( 5.2
189 ( 0.8
44.4 ( 5.6
23.5 ( 1.1
449 ( 29
Me
Me
H
0
1
2
Me
I
337 ( 31
haloperidol
DTG
12.0 ( 1.7
12.8 ( 2.1
1540 ( 313
(+)-pentazocine
a
Twelve concentrations of unlabeled test ligand ranging from 0.05 to 10 000 nM were incubated with guinea pig brain membranes and
[3
H](+)-pentazocine (σ1 receptors) or with rat liver membranes and [ H]DTG in the presence of 1 µM dextrallorphan (σ2 receptors) as
3
described in Methods. IC50 values were determined using iterative curve-fitting program GraphPAD InPlot (San Diego, CA). IC50 values
were then converted to apparent Ki values using the Cheng-Prusoff equation and radioligand Kd values. Values are the averages of two
or three experiments, (SEM. Each experiment was carried out in duplicate.
Ta ble 3. Inhibition Constants (IC50, nM; (SEM) for
a
arylethylenediamines, we had noticed that (aminoeth-
1
25
4
-[ I]IPBS Binding in Guinea Pig Brain Membranes
yl)piperidine and (aminoethyl)homopiperidine possess-
ing iodobenzamides/arylethylenediamines had the high-
est potency for σ1 and σ2 receptor subtypes. On the basis
of these results, we hypothesized that the aromatic
group occupies the lipophilic pocket of the receptors and
the alkylamino group represent the pharmacophore;
therefore substituted sulfonamides possessing amino-
ethyl piperidines and aminoethylhomopiperidines should
have high binding affinities for σ receptors. The results
of our binding experiments showed that aromatic sul-
fonamides such as 4-iodo-N-[2-(1′-piperidinyl)ethyl]ben-
zenesulfonamide, 6, and N-[2-(1′-homopiperidinyl)ethyl]-
compd
BD1008
4-IPBS
haloperidol
IC50
0.70 ( 0.18
1.46 ( 0.13
6.28 ( 0.11
10.4 ( 1.1
87.2 ( 15
(
+)-pentazocine
DTG
(-)-pentazocine
152 ( 0.2
a
Confirmation of σ-like pharmacological profile of 4-[125I]IPBS
binding was carried out in guinea pig brain membranes. Guinea
pig brain membranes (300-500 µg of membrane protein) were
incubated with 0.3 nM 4-[1 I]IPBS and 12 concentrations of
unlabeled test ligand ranging from 0.05 to 10 000 nM. Incubations
were carried out in 50 mM Tris-HCl, pH 8.0, at 25 °C for 60 min
in a final volume of 0.25 mL. Nonspecific binding was determined
in the presence of 10 µM haloperidol. All other procedures and
data analysis were described in caption to Table 1 for assays using
tritiated ligand, with the exception that counting was carried out
in a gamma counter (LKB model 1272 CLINIGAMMA). Values
are the averages of two experiments, (SEM. Each experiment was
carried out in duplicate. The data are presented as IC50 values
and not Ki since the Kd value for 4-[1 I]IPBS in guinea pig brain
membranes was not directly determined. However, due to the low
concentration of radioligand used, the Ki values will closely
approximate the IC50 values.
25
4
-iodobenzenesulfonamide, 8, had high affinities for σ1
sites (Ki ) 0.75 and 2.14 nM, respectively). Potency for
σ2 sites for both 6 and 8 were modest (Ki ) 206 and 189
nM, respectively). The binding affinity for the corre-
sponding diethyl and pyrrolidine derivatives 2 and 4,
however, were lower for σ1 as well as σ2 sites (Table 2).
This is consistent with our previous findings with
iodobenzamides. Tertiary sulfonamides 9 and 10 both
had subnanomolar affinity for σ1 receptor subtypes (Ki
25
)
0.18 and 0.14 nM, respectively) and also an 8-9-fold
increase in σ2 affinities (44.4 and 23.5 nM, respectively)
over the corresponding secondary sulfonamide 7 and 8.
The incorporation of a 4-methoxy substituent in the
σ ligands and guinea pig brain membranes. The rank
order of potency was BD1008 (N-[2-(3,4-dichlorophenyl)-
ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) > IPBS >
haloperidol > (+)-pentazocine > DTG (1,3-di-o-tolylguani-
dine) > (-)-pentazocine. The inhibition constants (IC50)
were 0.70, 1.46, 6.28, 10.4, 87.2, and 152 nM, respec-
tively (Table 3). These IC50 values and the rank order
of potency are consistent with the labeling of σ1 recep-
tors.
3
-iodinated arylsulfonamides 11 and 12 reduced the
receptor binding affinity for σ1 and σ2 sites as well. The
reduced affinity for σ sites was also observed for the
methoxy-substituted benzamides.25 A patent literature
search indicated that several substituted arylhalosul-
2
7,28
fonamides have been reported as antiarrhythmics.
The preparation of 4-[1 I]iodo-N-[2-(1′-piperidinyl)-
ethyl]benzenesulfonamide, 6b, was achieved in high
yields starting from the stannylated derivative 6a . The
radioiodinated benzenesulfonamide was purified using
reversed phase HPLC. The retention time of the labeled
compound using MeOH/phosphate buffer (10 mM): 80/
25
To evaluate the tumor imaging potential of HAS, the
1
25
biodistribution of 4-[ I]IPBS was studied in C57 black
mice bearing B16 murine melanoma tumors. A recent
study found that the melanoma uptake in the C57 black
mice animal model compared well with melanoma
2
2
patients.
For this reason, the C57/B16 melanoma
2
0 was about 9 min. The σ receptor pharmacology was
model was chosen for this study. A high tumor uptake
of the radiopharmaceutical was found (7.40% ID/g) at
established by in vitro competition binding studies using

2
448 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
J ohn et al.
Ta ble 4. Tissue Distribution of
Carroll (Research Triangle Institute, Research Triangle Park,
NC). Haloperidol, Tris-HCl, and polyethyleneimine were
purchased from Sigma Chemical Co. (St. Louis, MO).
N-(2-(Diet h yla m in o)et h yl)-4-b r om ob en zen esu lfon a -
m id e, 1. N,N-Diethylethylenediamine (0.422 g, 3.63 mmol)
1
25
4
4
-[ I]Iodo-N-[2-(1′-piperidinyl)ethyl]benzenesulfonamide,
-[ I]IPBS, in C57 Black Mice Bearing B16 Melanoma Tumor
1
25
Xenograft (%ID/g ( SD; n ) 4)
organ
1 h
6 h
24 h
was suspended in CHCl
3
(50 mL) and 50% aqueous NaHCO
3
blood
heart
liver
lung
kidneys
spleen
stomach
sm intest
lg intest
brain
3.67 ( 1.27
5.21 ( 2.69
3.54 ( 1.56
10.90 ( 4.97
6.48 ( 3.23
10.84 ( 5.19
5.89 ( 2.43
7.67 ( 3.15
3.00 ( 1.25
3.85 ( 2.15
7.40 ( 0.52
2.26 ( 1.49
2.02 ( 0.32
3.15 ( 0.60
5.24 ( 0.98
3.43 ( 0.52
10.45 ( 1.35
3.83 ( 1.08
6.23 ( 0.70
7.91 ( 1.31
7.7 ( 2.68
0.31 ( 0.21
0.09 ( 0.03
0.15 ( 0.06
0.18 ( 0.12
0.77 ( 0.49
0.13 ( 0.04
0.23 ( 0.18
0.35 ( 0.29
0.30 ( 0.11
0.06 ( 0.01
1.54 ( 0.22
(50 mL), and 4-bromobenzenesulfonyl chloride (1.0 g, 3.92
3
mmol) in CHCl (10 mL) was added to the mixture. The
solution was stirred at room temperature for 15 h. The organic
layer was separated, washed with water, and evaporated to
dryness. The resulting oil was chromatographed on a silica
gel column and eluted with EtOAc/NEt
3
: 100/2 (v/v). The
desired fractions were pooled and the volatiles removed in
1
vacuo to give a colorless oil (1.1 g, 95%). H NMR (CDCl
0.85-0.90 (t, 6H, NCH CH ); 2-30-2.35 (q, 4H, NCH CH
2.47-2.51 (m, 2H, NCH ); 2.95-2.99 (m, 2H, NCH ); 7.62-
.64 (d, 2H, arom); 7.70-7.74 (d, 2H, arom).
N -(2-(Die t h y la m in o)e t h yl)-4-iod ob e n ze n e su lfon a -
3
)
3
);
2
3
2
tumor
7.22 ( 1.70
2
2
7
ratio
tumor/blood
2.02 ( 0.41
3.19 ( 1.14
4.97 ( 1.05
m id e, 2. This compound was prepared by the same procedure
as above from 4-iodobenzenesulfonyl chloride (1.0 g, 3.3 mmol)
1
h postinjection (Table 4). The tumor activity was
and N,N-diethylethylenediamine (0.42 g, 3.7 mmol) in 88%
1
yield as a colorless oil (1.2 g). H NMR (CDCl
3
): 0.85-0.90
); 2.41-2.44 (t, 2H,
); 7.54-7.57 (d, 2H, arom);
found to be constant (7.22% ID/g) at 6 h postinjection,
indicating slow wash out of the activity from the tumor.
Although there was a relatively slow clearance from
blood and other normal organs at 1 and 6 h postinjec-
tion, tumor had the highest (1.54% ID/g) activity at 24
h postinjection. Tumor to blood and tumor to liver
ratios were about 5 and 10, respectively, at 24 h
postinjection. These results show that 4-[1 I]iodo-N-
(
t, 6H, CH
NCH ); 2.79-2.83 (t, 2H, NCH
.83-7.86 (d, 2H, arom).
N-[2-(1′-P yr r olid in yl)et h yl]-4-b r om ob en zen esu lfon a -
3
); 2.30-2.37 (q, 4H, NCH
2
2
2
7
m id e, 3. This compound was prepared by the same procedure
as above from 4-bromobenzenesulfonyl chloride (1.0 g, 3.92
mmol) and 1-(2-aminoethyl)pyrrolidine (0.45 g, 3.94 mmol) in
25
1
88% yield as a white solid (1.1 g), mp 76-78 °C. H NMR
(
CDCl
NCH
.62-7.65 (d, 2H, arom); 7.70-7.73 (d, 2H, arom).
N -[2-(1′-P yr r olid in yl)e t h yl]-4-iod ob e n ze n e su lfon a -
3
): 1.66-1.73 (m, 4H CH
2
CH
2
2
); 2.29-2.34 (m, 4H, CH -
[2-(1′-piperidinyl)ethyl]benzenesulfonamide clearly has
2
); 2.48-2.51 (m, 2H, NCH
2
); 2.95-2.99 (m, 2H, NCH );
2
potential for imaging melanoma tumors.
7
In conclusion, the discovery of a new σ receptor
binding ligand class, HAS, is reported. Several halo-
arylsulfonamides possessed high affinity for σ binding
sites, particularly σ1 sites where subnanomolar affinity
was observed. A radioiodinated benzenesulfonamide,
m id e, 4. This was prepared using same procedure as 1 from
4-iodobenzenesulfonyl chloride (1.0 g, 3.3 mmol) and 1-(2-
aminoethyl)pyrrolidine (0.42 g 3.7 mmol) in 89% yield as beige
1
solid (1.1 g), mp 71-73 °C. H NMR (CDCl
3
): 1.65-1.70 (m,
); 2.49-2.54 (m, 2H, NCH );
); 7.52-7.58 (d, 2H, arom); 7.84-7.87
d, 2H, arom). This compound has been previously reported
1
25
4H, CH
2
); 2.30-2.34 (m, 4H, NCH
2
2
4
-[ I]IPBS, was synthesized in high yields. A pilot
2
(
.94-3.0 (m, 2H, NCH
2
biodistribution study in C57 black mice possessing a
melanoma xenograft showed high tumor uptake and
slow wash out of the activity from tumor, showing the
neoplastic disease imaging potential of radioiodinated
benzenesulfonamides. Further SAR/biodistribution stud-
ies are in progress in order to develop an optimal
compound that may be clinically useful.
27,28
in the patent literature.
N-[2-(1′-P ip er id in ylet h yl)]-4-b r om ob en zen esu lfon a -
m id e, 5. This compound was prepared from 4-bromoben-
zenesulfonyl chloride (1.0 g, 3.92 mmol) and 1-(2-aminoethyl)-
piperidine (0.50 g, 3.9 mmol) in 92% yield (1.2 g), mp 91-92
1
°
2
2
C. H NMR (CDCl
3
): 1.39-1.43 (m, 6H, pip CH
NCH
); 7.62-7.64 (d, 2H, arom); 7.69-7.73
2
s); 2.16-
.34 (bm, 4H, piperidinyl CH
.91-2.95 (t, 2H, NCH
d, 2H, arom).
2
2
); 2.30-2.34 (t, 2H, NCH );
2
2
Exp er im en ta l Section
(
Gen er a l Exp er im en ta l Meth od s. Reagents for organic
syntheses were purchased from Aldrich Chemical Co., Mil-
waukee, WI, and used without further purification. HPLC
grade solvents were purchased from Fisher Scientific Co. and
used without further distillation. Proton NMR spectra were
recorded on a Bruker 300 AM spectrometer. NMR peak
patterns were described by the following abbreviations: s )
singlet, b ) broad, d ) doublet, t ) triplet, q ) quartet, m )
multiplet, and arom ) aromatic protons. Chemical shifts were
N -[2-(1′-P ip e r id in yl)e t h yl]-4-iod ob e n ze n e su lfon a -
m id e, 6. This compound was prepared from 4-iodobenzene-
sulfonyl chloride (1.0 g, 3.3 mmol) and 1-(2-aminoethyl)-
piperidine (0.43 g, 3.4 mmol) in 92% yield (1.2 g), mp 100-
102 °C. 1H NMR (CDCl
(bm, 4H, NCH
NCH ); 7.55-7.58 (d, 2H, arom); 7.84-7.86 (d, 2H, arom).
): 1.40-1.49 (m, 6H, CH
); 2.18-2.21
3
2
2
); 2.34-2.37 (m, 2H, NCH ); 2.94-2.98 (m, 2H,
2
2
N-[2-(1′-P ip er id in yl)et h yl]-4-t r i-n -b u t ylst a n n ylb en -
zen esu lfon a m id e, 6a . N-[2-(1′-Piperidinylethyl)]-4-iodoben-
zenesulfonamide (500 mg, 1.3 mmol) in NEt /THF (25/15 mL),
3
expressed as ppm using CDCl
3
as internal standard. Low-
resolution chemical ionization mass spectra were performed
on a Finnigan 1015 mass spectrometer. Thin-layer chroma-
tography (TLC) was performed on Analtech uniplate silica gel
tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.2 equiv),
and bis(tri-n-butyltin) (1.1 g, 1.9 mmol, 1.5 equiv) were heated
at reflux for 4 h. Additional bis(tributyltin) (0.55 g) was added
to the reaction mixture and heated at reflux overnight. The
solvents were removed in vacuo, and the residue was dissolved
in a small quantity of hexanes/EtOAc (50/50, v/v) and loaded
on a silica gel column packed with hexanes and eluted with
hexanes/EtOAc. The fractions containing the desired com-
pound were pooled together, and the volatiles were removed
GF plates (250 µm, 10 × 20 cm) and developed with CHCl
3
/
MeOH: 90/10. Elemental analysis were performed by Quan-
titative Technologies Inc. (Whitehouse, NJ ). Radio-thin-layer
chromatography (radio-TLC) was performed using a radio-
chromatogram scanner (Packard 7220/21). Sodium iodide-I-
1
25
1
25, Na I, was obtained from Amersham (Arlington Heights,
IL). Radioactivity was measured using a Capintec radioisotope
to give a light yellow oil (0.18 g, 25%). 1H NMR (CDCl
0.90 (m, 9H, CH ); 1.03-1.09 (t, 6H, CH
from nBu); 1.25-
1.50 (m, 18H, CH
s from nBu and piperidinyl ring); 2.0-2.2
(bm, 5H, NCH ); 2.3-2.4 (m, 2H, NCH ); 2.8-2.9 (m, 2H, CH );
7.56-7.59 (d, 2H, arom); 7.74-7.77 (d, 2H, arom).
3
): 0.83-
3
3
calibrator CRC-4. 1,3-[ H]Di-o-tolylguanidine, ([ H]DTG, 35.4
3
2
3
Ci/mmol) was bought from DuPont/NEN (Boston, MA). [ H]-
2
(
+)-Pentazocine (51.7 Ci/mmol) was synthesized as described
2
2
2
2
6a,b
previously.
Dextrallorphan was provided by Dr. F. I.

Substituted Halogenated Arylsulfonamides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2449
N-[2-(1′-Hom op ip er id in yl)eth yl]-4-br om oben zen esu l-
fon a m id e, 7. 7 was prepared from 4-bromobenzenesulfon-
yl chloride (1.3 g, 5.1 mmol) and 1-(2-aminoethyl)homopiperi-
heated at reflux for 1.5 h, and the volatiles were then
removed in vacuo. The residue was taken up in ice cold
water (20 mL), and 10% NaOH solution (10 mL) and CHCl
3
1
dine (0.73 g, 5.1 mmol) in 95% yield (1.7 g), mp 82-84 °C. H
(40 mL) was added. The mixture was stirred at room
temperature for 30 min to give a brown precipitate. This
solid was filtered, and the organic layer was separated,
NMR (CDCl
homopip NCH
NCH
3
): 1.52 (bs, 8H, homopip CH
2
); 2.40-2.42 (m, 4H,
); 2.88-2.92 (m, 2H,
2
); 2.48-2.51 (m, 2H, NCH
2
2
); 7.62-7.64 (d, 2H, arom); 7.71-7.74 (d, 2H, arom).
dried, and evaporated in vacuo to give a light yellow oil
1
N-[2-(1′-Hom opiper idin yl)eth yl]-4-iodoben zen esu lfon a-
m id e, 8. This was prepared from 4-iodobenzenesulfonyl
chloride (1.0 g, 3.33 mmol) and 1-(2-aminoethyl)homopiperi-
(1.2 g, 85%).
H
2
NMR (CDCl
s); 2.63-2.71 (m, 6H, NCH
); 3.93 (s, 3H, OCH
3
3
): 1.56 (bm, 8H,
); 2.77 (s,
);
homopiperidine CH
); 3.07-3.13 (m, 2H, NCH
6.84-6.87 (dd, 1H, arom); 7.77-7.80 (dd, 1H, arom); 8.15
2
3 H, NCH
3
2
dine (0.52 g, 3.6 mmol) to give 86% (1.2 g) of desired compound
1
as a colorless oil. H NMR (CDCl
3
): 1.52 (bs, 8H, homopip
); 2.48-2.51 (m, 2H,
); 7.62-7.64 (d, 2H, arom);
(s, 1H, arom).
2
); 2.40-2.42 (m, 4H, homopip NCH
2
Syn th esis of [125I]N-[2-(1′-p ip er id in yl)eth yl]-4-iod oben -
zen esu lfon a m id e, 6b. An ethanolic solution of N-[2-(1′-
piperidinyl)ethyl]-4-(tri-n-butylstannyl)benzenesulfonamide, 6a
(1.0 mg/mL), was prepared. To 100 µL of this solution was
added Na1 I (1.0-2.0 mCi, 10-15 µL, in 0.1 N NaOH),
followed by the addition of 0.05 N HCl (50-100 µL) to adjust
the pH to between 4.0 and 5.5. A freshly prepared solution
(100 µL) of chloramine-T (1 mg/mL) was added to the above
mixture, and the solutions were incubated at room tempera-
ture for 15 min. After this time 200 µL of sodium metabisulfite
CH
NCH
.71-7.74 (d, 2H, arom).
N-[2-(1′-Hom opiper idin yl)eth yl]-N-m eth yl-4-br om oben -
zen esu lfon a m id e, 9. This compound was prepared from
-bromobenzenesulfonyl chloride (1.3 g, 5.1 mmol) and N-meth-
yl-2-(1′-homopiperidinyl)ethylamine (0.80 g, 5.1 mmol) in 91%
2
); 2.88-2.92 (m, 2H, NCH
2
7
25
4
1
(
1.7 g) yield. H NMR (CDCl
3
): 1.55 (bs, 8H, homopip CH
); 2.79 (s, 3H, NCH ); 3.07-3.11 (s,
); 7.64 (bs, 4H, arom).
N-[2-(1′-Hom op ip er id in yl)eth yl]-N-m eth yl-4-iod oben -
zen esu lfon a m id e, 10. This compound was prepared from
2
);
2
2
.59-2.68 (m, 6H, NCH
2
3
H, NCH
2
(10 mg/mL) was added and incubated for 5 min. Finally, a
saturated solution of sodium bicarbonate (500 µL) was added
to the reaction vial, and the radioactivity was extracted (89-
93%) with chloroform (2 × 1 mL). The organic layer was
separated and evaporated in a stream of air. The residue was
dissolved in MeOH (400 µL) and injected into HPLC fitted with
a reversed phase C18 column (Z module) and eluted with
MeOH/phosphate buffer (80/20; 10 mM, pH ) 7.2). The
retention time at a flow rate of 1.0 mL/min was about 9 min.
The fractions containing the desired compound were pooled
and cospotted on TLC along with authentic “cold” 4-iodo-N-
4
2
-iodobenzenesulfonyl chloride (1.0 g, 3.3 mmol) and N-methyl-
-(1′-homopiperidinyl)ethylamine (0.52 g, 3.3 mmol) in 92%
1
yield (1.3 g). H NMR (CDCl
2
NCH
3
): 1.55 (bs, 8H, homopip CH
); 2.78 (s, 3H, NCH ); 3.06-3.11 (t, 2H,
); 7.47-7.50 (d, 2H, arom); 7.83-7.86 (d, 2H, arom).
2
);
.59-2.68 (6H, NCH
2
3
2
N-[2-(1′-P ip er id in yl)eth yl]-4-m eth oxyben zen esu lfon a -
m id e, 11a . To an ice-cold solution of 1-(2-aminoethyl)-
piperidine (1.28 g, 1.0 mmol) in chloroform (50 mL) and NEt
5 mL) was added 4-iodobenzenesulfonyl chloride (2.06 g, 1.0
3
(
[2-(1′-piperidinyl)ethyl]benzenesulfonamide, and developed in
mmol). The mixture was stirred overnight. The solvent was
evaporated in vacuo, and the residue obtained was suspended
CHCl /MeOH: 90/10. The combined fractions were reduced
3
in volume by evaporation under a stream of nitrogen, and the
residue was suspended in normal saline or phosphate buffer
(pH )7.2) and used for further binding/animal studies. The
yield of HPLC purified 6b was 77%, the radiochemical purity
was >99%.
in CHCl
NaHCO
rated to dryness to give a light yellow oil (2.8 g, 94%). H NMR
CDCl ): 1.36-1.50 (m, 6H, piperidine CH s); 2.22-2.26 (bm,
H, piperidine CH s); 2.27-2.31 (m, 2H, NCH ); 2.88-2.92 (m,
H, CH
3
(40 mL) and washed with saturated solution of
3
. The organic layer was separated, dried, and evapo-
1
(
3
2
4
2
7
2
2
); 3.85 (s, 3H, OMe); 6.94-6.97 (d, 2H, arom); 7.76-
.79 (d, 2H, arom).
P h a r m a cology. σ
1
Recep tor Bin d in g Assa ys. The in
2
vitro σ binding affinity of nonradioactive sulfonamides were
1
3
determined using the σ selective probe [ H](+)-pentazocine
1
N-[2-(1′-P ip er id in yl)eth yl]-3-iod o-4-m eth oxyben zen e-
and guinea pig brain membranes.2 Guinea pig brain mem-
6a
su lfon a m id e, 11. A round-bottom flask was charged with 11a
1.1 g, 3.7 mmol) in CCl (10 mL). A solution of Tl(CF CO
in CF CO H (15 mL) was added to the mixture. Iodine (0.48
branes (300-500 µg of membrane protein) were incubated with
(
4
3
2 3
)
3
3
nM [ H](+)-pentazocine in a total volume of 0.5 mL of 50
3
2
mM Tris-HCl, pH 8.0. Incubations were carried out for 120
min at 25 °C. Nonspecific binding was determined in the
presence of 10 µM haloperidol. Assays were terminated by
dilution with 5 mL of ice cold 10 mM Tris-HCl, pH 8.0, and
vacuum filtered through glass fiber filters using a Brandel cell
harvester (Gaithersburg, MD). Filters were then washed twice
with 5 mL of ice cold 10 mM Tris-HCl, pH 8.0. Filters were
soaked in 0.5% polyethyleneimine for at least 30 min at 25 °C
prior to use. Filters were counted in CytoScint cocktail (ICN,
Costa Mesa, CA) after an overnight extraction of counts.
g, 1.9 mmol) was added, and the reaction contents were heated
at reflux for 2 h. The volatiles were removed in vacuo, the
residue was basified with 10% aqueous NaOH, CHCl (30 mL)
3
was added to the residue, and the mixture was stirred for 15
min. The contents were filtered through a pad of Celite, and
the organic layer was separated, washed with water, dried over
anhydrous Na
solid (1.3 g, 83%). H NMR (CDCl
piperidinyl CH s); 2.17 (bm, 4H, piperidinyl CH
m, 2H, NCH ); 2.89-2.93 (m, 2H, NCH ); 3.93 (s, 3H, OMe);
.83-6.86 (d, 1H, arom); 7.80-7.83 (dd, 1H, arom); 8.22-8.23
d, 1H, arom).
N-[2-(1′-Hom op ip er id in yl)eth yl]-N-m eth yl-4-m eth oxy-
2 4
SO , and evaporated to dryness to give a white
1
3
): 1.37-1.49 (m, 6 H,
2
2
); 2.29-2.33
(
2
2
Membranes were prepared from frozen guinea pig brains
6
(
6a
(
minus cerebella) as previously described.2
σ
2
Recep tor Bin d in g Assa ys. σ
2
receptors were labeled
ben zen esu lfon a m id e, 12a . This compound was prepared by
the same method as 1 using 4-methoxybenzenesulfonyl chlo-
ride (2.0 g, 9.7 mmol) and N-methyl-2-(1′-homopiperidinyl)-
as previously described using rat liver membranes, a rich
3
3
source of σ
2
sites, and [ H]-1,3-di-o-tolylguanidine ([ H]DTG)
2
9
in the presence of 1 µM dextrallorphan to mask σ
1
receptors.
ethylamine (1.44 g, 9.5 mmol) to give 12a as a colorless oil in
Assays were performed in 50 mM Tris-HCl, pH 8.0, for 120
min at 25 °C in a volume of 0.5 mL with 150-200 µg of
membrane protein and 5 nM radioligand. Nonspecific binding
was determined in the presence of 10 µM haloperidol. All
1
9
CH
3
3% yield (2.9 g). H NMR (CDCl
3
): 1.54 (bs, 8H, homopip
); 2.74 (s, 3H, N-CH ); 3.15-
); 3.83 (s, 3H, OMe); 6.93-6.96 (d, 2H,
2
); 2.58-2.65 (m, 6H, NCH
2
3
.19 (m, 3H, NCH
2
arom); 7.68-7.71 (d 2H, arom).
1
other manipulations were as described above for σ receptor
assay. Rat liver membranes were prepared from the livers of
N-[2-(1′-H om op ip er id in yl)et h yl]-N-m et h yl-3-iod o-4-
m eth oxyben zen esu lfon a m id e, 12. A round-bottom flask
male Sprague-Dawley rats as described.29
was charged with 12a (1.0 g, 3.1 mmol) in CF
mL) and CCl (10 mL) and Tl(CF CO (1.3 g, 2.3 mmol,
.75 equiv). The mixture was stirred at room temperature
until all thallium salt dissolved, and then iodine (0.4 g,
.6 mmol, 0.52 eq) was added. The above mixture was
3
CO
2
H (15
Cell Cu ltu r e. B16 melanoma tumor cells were purchased
from ATCC, Rockville, MD, and cultured in serum-supple-
mented RPMI 1640 medium containing 10% heat-inactivated
fetal bovine serum (GIBCO) at 37 °C. The cells were adherent
and split weekly in a 1:5 ratio using trypsin/EDTA (GIBCO).
4
3
2 3
)
0
1

2
450 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
J ohn et al.
The cells were grown in T75 cell culture flasks. When
confluent the cells were detached using trypsin/EDTA (0.025%)
or scraped with a cell scraper in DMEM.
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(
13) Thomas, G. E.; Szucs, M.; Mamone, J . Y.; Bem, W. T.; Rush, M.
D.; J ohnson, F. E.; Coscia, C. J . Sigma and opioid receptors in
human brain tumors. Life Sci. 1990, 46, 1279-1286.
14) Bem, W. T.; Thomas, G. E.; Mamone, J . Y.; Homan, S. M.; Levy,
B. K.; J ohnson, F. E.; Coscia, C. J . Overexpression of sigma
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In Vivo Distr ibu tion . C57 black mice (Charles-River,
Wilmington, MA) weighing 25-32 g were injected with about
1
.0 million B16 murine melanoma cells in the right flank. After
(
about 10 days the tumors were visible, and the animals were
1
25
injected in the tail vein with radiolabeled 4-[ I]iodo-N-[2-(1′-
piperidinyl)ethyl]benzenesulfonamide, 6b, to study the in vivo
tumor imaging potential. The animals were sacrificed at 1,
6
558-6562.
(
15) J ohn, C. S.; Vilner, B. J .; Schwartz, A. M.; Bowen, W. D.
Characterization of sigma receptor binding sites in human
biopsied solid breast tumors. J . Nucl. Med. 1996, 37, 267P
(abstract).
6
, and 24 h post iv injection under ketamine/xylazine anes-
1
9
thesia as previously described.
The organs were excised,
dried on absorbent paper, and placed in preweighed test tubes,
and the radioactivity was assayed in an automatic gamma
counter (Packard, CobraII Autogamma, Meriden, CT). The
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1
60.
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(
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Ack n ow led gm en t. Financial support of this work
from the National Cancer Institute (NIH Grant CA58496)
is gratefully acknowledged. We acknowledge a reviewer
for bringing to our attention the halogenated arylsul-
fonamides in the patent literature. We are grateful to
Noel Whittaker for mass spectral determinations.
(
5
7, 156-161.
(
19) J ohn, C. S.; Bowen, W. D.; Saga, T.; Kinuya, S.; Vilner, B. J .;
Baumgold, J .; Paik, C. H.; Reba, R. C.; Neumann, R. D.; Varma,
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