Substituted diphenyl sulfides as selective serotonin transporter ligands: Synthesis and in vitro evaluation

Article abstract of DOI:10.1021/jm010939a

A series of diphenyl sulfide derivatives substituted at the 1-, 2′-, and 4′-positions has been synthesized and evaluated for their in vitro affinities at the dopamine, serotonin (SERT), and norepinephrine transporters. The examination of K_i val

Full text of DOI:10.1021/jm010939a

J . Med. Chem. 2002, 45, 1253-1258
1253
Su bstitu ted Dip h en yl Su lfid es a s Selective Ser oton in Tr a n sp or ter Liga n d s:
Syn th esis a n d In Vitr o Eva lu a tion
Patrick Emond,* J ohnny Vercouillie, Robert Innis,† Sylvie Chalon, Sylvie Mavel, Yves Frangin,
Christer Halldin,‡ J ean-Claude Besnard, and Denis Guilloteau
INSERM U316, Laboratoire de Biophysique Me´dicale et Pharmaceutique, 31 Avenue Monge, 37200 Tours, France,
Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland 20892, and Department of Clinical
Neurosciences, Psychiatry Section, Karolinska Hospital, S-171 76 Stockholm, Sweden
Received May 29, 2001
A series of diphenyl sulfide derivatives substituted at the 1-, 2′-, and 4′-positions has been
synthesized and evaluated for their in vitro affinities at the dopamine, serotonin (SERT), and
norepinephrine transporters. The examination of Ki values revealed that most of these
derivatives have high affinity and selectivity for the SERT. Moreover, substitutions at these
positions differently influence the SERT binding: (i) The nature of the substituent linked at
the 1-position critically influences the SERT affinity. (ii) Functions containing heteroatom at
the 2′-position afford compounds with high SERT affinity. (iii) The nature of the substituent
at the 4′-position slightly influences the SERT affinity whereas steric effect markedly decreases
the SERT affinity. From this series, the most SERT selective derivatives (such as 8b, 8c, and
8g) are now evaluated for their potential as positron emission tomography imaging agents
when labeled with carbon-11.
In tr od u ction
The quipazine structure was also found to be a good
framework to design potent SERT ligands. For example,
5-iodo-6-nitroquipazine is highly potent and selective at
SERT in vitro and showed promising properties for in
vivo mapping of SERT in monkey brain.10 However,
human studies with this ligand have not been reported.
More recently, on the basis of a structure described as
a novel antidepressant,11,12 several substituted diphenyl
sulfides have been described as potent and selective
SERT derivatives (Figure 1). These diphenyl sulfide
derivatives (IDAM, ADAM, DAPP, and DASB) have
been labeled with I-125 and C-11 and displayed high
in vitro and in vivo affinities and selectivities for SERT
relative to the dopamine and the norepinephrine trans-
porters (DAT, NET).13-17 Moreover, preliminary studies
with IDAM and ADAM in nonhuman primates18,19 or
with DAPP or DASB in human brains20 showed that
these ligands have promising characteristics for imaging
SERT. On the basis of these results and in order to
extend the knowledge of the SERT binding site require-
ments, we report here the synthesis and in vitro
properties of new diphenyl sulfide derivatives. Informa-
tion from these chemical modulations may be useful in
the design of new radiopharmaceuticals to explore the
SERT in vivo in humans by PET or by SPECT.
The serotoninergic neurotransmission plays an im-
portant role in the central nervous system and involves
the serotonin transporter (SERT), which modulates
synaptic serotonin (5-HT) levels. Recent reviews have
suggested that alteration of SERT function could be
associated with neurological and psychiatric disorders
such as Parkinson’s and Alzheimer’s diseases and
depression.1-4 Moreover, SERT is the site of action of
many existing antidepressant drugs. For these reasons,
in vivo mapping of the SERT in the living human brain
either by positron emission tomography (PET) or by
single photon emission computed tomography (SPECT)
would be of great value to better understand the
physiopathological mechanism of neurodegenerative
and mental illness as well as to assess the quantification
of SERT occupancy in relation to antidepressant drug
treatment. In that aim, the development of highly potent
and selective ligands to explore the SERT by scintigra-
phy has been intensively pursued by many groups.
Several classes of compounds have been screened for
their SERT affinity, such as phenyl nortropane or
quipazine derivatives. In the phenyl nortropane series,
although high in vitro SERT affinity and selectivity
were obtained for EINT,5 RTI-364,6 RTI-330,6 RTI-357,6
or LBT-44,7 the most common limitation has been a
relatively poor signal-to-noise ratio, limiting their use
in vivo for the quantification of the SERT. In contrast
to these nortropane analogues, two new derivatives
named ZIENT and FIPPNT displayed a high specific
binding at the SERT with a low nonspecific accumula-
tion and have been proposed as potential radioligands
for SPECT or PET imaging, respectively, of SERT.8,9
Ch em istr y
All of the compounds tested for their in vitro binding
properties were prepared as described in Schemes 1-3.
Compounds 3a -c and 4a -c (Scheme 1) were prepared
from 2-bromo-5-halogenobenzaldehyde, 2,5-dibromoni-
trobenzene, or 4-bromo-3-nitrotoluene and N,N-di-
methyl or N-methyl-2-thiobenzamide using a previously
described procedure.13,21 The reduction of amide as well
as aldehyde functions of compounds 3a -c and 4a -c
were achieved using the diborane-tetrahydrofuran
(THF) complex to afford 5a -c and 7a -c in 52-85%
* Author to whom correspondence ahould be addressed. Tel: (33)2
47 36 72 42. Fax: (33)2 47 36 72 24. E-mail: emond@univ-tours.fr.
† National Institute of Mental Health.
‡ Karolinska Hospital.
10.1021/jm010939a CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/09/2002

1254 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6
Emond et al.
F igu r e 1. Diphenylsulfide derivatives with high SERT affinity.
Sch em e 1a
Sch em e 3
aromatic A ring and disubstituted by a hydroxymethyl
at the 2′-position and a chlorine at the 4′-position of the
aromatic B ring, has been reported as an inhibitor of
serotonin uptake.12 We have modulated these groups
in order to extend the knowledge of the SERT binding
site requirements, which may be useful for the design
of new radiopharmaceuticals to explore the SERT in
vivo in humans with PET or SPECT imaging. The
affinities for monoamine transporters of the new com-
pounds described here were determined by in vitro
competitive binding assays. [3H] paroxetine, [3H] GBR-
12935, and [3H] nisoxetine were used as transporter
ligands for SERT, DAT, and NET sites, respectively. The
results are expressed as inhibition constants (Ki) and
are summarized in Table 1.
a
Key: (a) NaH/CH3I; (b) FCH2CH2Br/EtOH/Et3N.
Sch em e 2a
The first examination of Table 1 revealed that 3a and
3c are the only derivatives of that series with very low
affinities for the SERT as well as for the DAT and the
NET. These two compounds differ from the other
derivatives by two carbonyl functions (aldehyde and
amide) to which their low affinities could be attributed.
However, Oya et al.22 showed that 7a and the O-
acetylated analogue of compound 5a , which has a
dimethylaminomethyl group at the 1-position, bind with
high affinities to the SERT. Moreover, compounds 5a ,
6a , and 8a that bear an alcohol, ether, or amine function
at the 2′-position also display high SERT affinities. On
the basis of these results, it could be assumed that the
amide function linked at the 1-position of compounds
3a and 3c is responsible for their low SERT affinities
since a large range of functional groups such as ester,
alcohol, ether, nitro, or amino could be introduced at
the 2′-position without affecting the SERT affinity when
a dimethylaminomethyl group is linked at the 1-posi-
tion. The modulation of the dimethylaminomethyl group
at the 1-position, replacing one methyl by a hydrogen
a
Key: (a) (E)Bu3SnHCdCHSnBu3/Pd(PPh3)4; (b) I2/CHCl3.
yields. O-methylation of 5a by methyl iodide and N-
alkylation of 7b by 1-bromo-2-fluoroethane afford 6a
and 7d in 74 and 46% yields, respectively. Scheme 2
described the reduction of the nitro group of 7a -d by
treatment with tin(II) chloride in HCl and MeOH to
obtain 8a -d in 66-80% yields. Compound 8f was
obtained by the coupling reaction of 8a and (E)-1,2-bis-
(tributylstannyl)ethylene under palladium catalysis as
the first step. Compound 8f was finally prepared by
iododestannylation of 8e using iodine in CHCl3 in 65%
yield. The preparation of 5d , 6b, 8g, and 8h follows a
two step sequence in which the bromine atom of 5b, 6a ,
8b, and 8d was exchanged for a tributylstannyl group
and finally for an iodide atom in 21-41% yields for the
two steps (Scheme 3).
Resu lts a n d Discu ssion
403U76 (Figure 1), a diphenyl sulfide substituted by
a dimethylaminomethyl group at the 1-position of the

Diphenyl Sulfides as Serotonin Transporter Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6 1255
Ta ble 1. Ki Values at the SERT, DAT, and NET of Substituted Diphenyl Sulfides
Ki values (nM)
compdsa
R1
R2
CHO
X
SERT
>1000
DAT
NET
>1000
>1000
5.80 ( 1.93
3a
CON(CH3)2
CON(CH3)2
Br
F
Br
F
I
Br
I
>1000
>1000
950 ( 350
339 ( 121
760 ( 214
>1000
172 ( 64
>1000
171 ( 77
171 ( 77
>1000
>1000
818 ( 207
>1000
3c
CHO
695 ( 172
1.92 ( 0.42
7.96 ( 2.43
0.98 ( 0.33
2.75 ( 0.24
2.50 ( 0.26
0.4 ( 0.12
2.23 ( 0.42
1.49 ( 0.28
1.65 ( 0.10
53.3 ( 5.8
1.25 ( 0.01
19.3 ( 1.9
5a 13
5c
CH2N(CH3)2
CH2N(CH3)2
CH2NHCH3
CH2N(CH3)2
CH2N(CH3)2
CH2N(CH3)2
CH2N(CH3)2
CH2NHCH3
CH2N(CH3)2
CH2N(CH3)2
CH2NHCH3
CH2NCH3CH2CH2F
CH2OH
CH2OH
CH2OH
CH2OCH3
CH2OCH3
NH2
NH2
NH2
NH2
NH2
28.4 ( 4.3
12.8 ( 2.3
326 ( 76
212 ( 46
683 ( 143
107 ( 32
107 ( 32
325 ( 108
80.2 ( 23.3
714 ( 184
5d
6a
6b22
ADAM14
8a 22
8b
I
Br
Br
CH3
8c
8f
(E)-CHdCHI
8g31
8h
NH2
NH2
I
I
>1000
a
Other affinity values using different experimental conditions are described in quoted references.
or a fluoroethyl group, has been undertaken. Regarding
the 2′-hydroxymethyl series, compound 5d retains a
high SERT affinity (0.98 nM) when compared to com-
pound 5a ,c (1.92 and 7.96 nM). Similar results were also
obtained in the 2′-amino series, with high SERT affini-
ties for compounds 8a and ADAM (2.23 and 0.40 nM,
respectively) and their corresponding N-desmethylated
analogues 8b and 8g (1.49 and 1.25 nM). However, the
introduction of a fluoroethyl group at the nitrogen (8h )
reduces SERT affinity (19 nM) when compared to
compound 8g or ADAM. Even though the decrease in
SERT affinity could be attributed to the increase of
steric effect brought by the fluoroethyl group, the
reduction of the nitrogen atom basicity by the fluorine
atom could also affect the SERT binding. Regardless of
the causes, these results confirm that the substituent
linked at that part of the molecule critically influences
SERT binding. Subsequent substitutions at the 2′- and
4′-positions have been undertaken on N,N-dimethylami-
nomethyl derivatives.
The N,N-dimethylaminomethyl-4′-bromo or 4′-iodo
derivatives with a hydroxymethyl (5a ), a methoxy-
methyl (6a ,b), or an amino function (8a , ADAM) at the
2′-position displayed high SERT binding affinities rang-
ing from 1.9 to 2.8 nM and low affinities for DAT
ranging from 171 to more than 1000 nM. High SERT
affinities of compounds 5a , 6a ,b, 8a , and ADAM suggest
that the heteroatom link at the 2′-position is critical for
the SERT binding given that Oya et al.22 reported that
the pyridinyl analogue of 8a (in which the 2′-amino-4′-
bromophenyl was replaced with a 4′-bromopyridin-2-yl
group) showed a weak SERT affinity. Furthermore, the
substituent at the 2′-position is implicated in the SERT
selectivity of these compounds, as compound 5a ,d has
a high NET affinity (5.80 and 12.80 nM) whereas
moderate to low NET affinities were obtained for
compounds 8a and 6a (107 and 326 nM).
iodine atom (6b, ADAM, 8g) has weak to no influence
on SERT binding affinity. Moreover, the replacement
of the iodine atom of ADAM by a methyl group (8c)
produced high SERT affinity (1.65 nM). These results
are in agreement with those published earlier describing
that the substitution of the iodine atom of ADAM by a
trifluoromethyl, a chlorine, a methoxy, or a cyano group
affords compounds with nano- to subnanomolar affini-
ties for the SERT.15 On the basis of these results, it
could be assumed that the nature of the substituent
linked at the 4′-position of the molecule has relatively
little effect on SERT binding. However, the steric effect
at that part of the structure seems to greatly influence
the binding potency of such derivatives since compound
8f, with a trans iodovinyl group, displayed a low SERT
affinity (53.4 nM).
In conclusion, chemical modifications of diphenyl
sulfide derivatives at the 1-, 2′-, and 4′-positions have
been realized. Examination of in vitro affinities to
monoamine transporters showed that (i) the substituent
at the 1-position is critical for SERT binding and
significantly influences SERT affinity; (ii) the SERT
binding site tolerates functions containing a heteroatom
(hydroxymethyl, methoxymethyl, amino) at the 2′-
position of diphenyl sulfide and can yield compounds
with high SERT affinities; and (iii) the nature of the
substituent linked at the 4′-position slightly influences
the SERT affinity whereas steric effect markedly de-
creases the SERT affinity.
From this series, the most selective SERT derivatives
such as compounds 6a and 8c,g have been selected for
further biological evaluation. As a first step of these
investigations, compound 8c, also named MADAM, has
been labeled with tritium for more detailed in vitro
characterization and with carbon-11 for PET investiga-
tions. [3H]-MADAM displayed in vitro a Kd value of 59.6
pM with a Bmax of 543 fmol/mg protein (rat cortical
membranes).23 Moreover, preliminary in vivo PET im-
aging in a monkey showed that [11C]-MADAM had a
rapid and high specific accumulation in brain regions
rich in SERT, with a thalamus to cerebellum uptake
ratio of 2.24,25 We are now working on the full in vivo
To evaluate the influence on monoamine transporter
affinity of the substituent linked at the 4′-position, Ki
values of 2′-amino, 2′-hydroxymethyl, or 2′-methoxy-
methyl derivatives were examined. Changing the fluo-
rine atom of compound 5c to a bromine atom (5a ) or
the bromine atom of compounds 6a and 8a ,b to an

1256 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6
Emond et al.
(23), 317 (22), 277 (29), 275 (27), 152 (27), 150 (33), 44 (100),
42 (71). Anal. (C14H13BrN2O2S) C, H, N.
characterization of this compound to evaluate its po-
tential as a PET ligand for SERT imaging in human
subjects.
N,N-Dim eth yl-2-(4′-m eth yl-2′-n itr op h en ylth io)ben zyl-
a m in e (7c). Yield ) 85%; orange oil. 1H NMR: δ 2.23 (s, 6H),
3
2.40 (s, 3H), 3.56 (s, 2H), 6.63 (d, 1H, J ) 8.3 Hz), 7.16 (dd,
Exp er im en ta l Section
3
4
3
4
1H, J ) 8.3 Hz, J ) 2.0 Hz), 7.38 (td, 1H, J ) 7.4 Hz, J )
3
4
Nuclear magnetic resonance (NMR) spectra were recorded
1.5 Hz), 7.50 (td, 1H, J ) 7.4 Hz, J ) 1.5 Hz), 7.56 (dd, 1H,
1
3J ) 7.4 Hz, J ) 1.4 Hz), 7.69 (dd, 1H, J ) 7.4 Hz, J ) 1.4
Hz), 8.08 (d, 1H, 4J ) 2.0 Hz). 13C NMR: δ 20.9, 45.8 (2C),
61.6, 126.3, 128.7, 128.8, 130.6, 130.7, 131.2, 134.9, 135.8,
135.9, 137.4, 144.1, 145.6. MS: m/z ) 302 (M+, 12), 285 (42),
211 (75), 194 (21), 58 (100), 42 (25). Anal. (C16H18N2O2S) C,
H, N.
4
3
4
on a Bru¨ker DPX Advance 200 spectrometer (200 MHz for H,
50.3 MHz for 13C). CDCl3 was used as the solvent; chemical
shifts are expressed in parts per million relative to tetra-
methylsilane as an internal standard. Mass spectra were
obtained on a CG-MS Hewlett-Packard 5989A spectrometer
(electronic impact at 70 eV). The thin-layer chromatographic
analyses were performed using Merck 60F-254 silica gel plates.
Flash chromatography was used for routine purification of
reaction products using silica gel (230-400 mesh). Visualiza-
tion was accomplished under UV or in an iodine chamber. All
chemicals and solvents were of commercial quality and were
purified following standard procedures. Elemental analyses
of new compounds were within (0.4% of theoretical values.
Ch em istr y. Syn th esis of Com p ou n d s 5a -c a n d 7a -c:
Gen er a l P r oced u r e. To a solution of compounds 3a -c and
4a -c (8 mmol) in THF (20 mL) under a nitrogen atmosphere
was added drop by drop diborane-THF (1M, 20 mL) at 0 °C.
The mixture was heated to reflux for 5 h, stirred at room
temperature overnight, and quenched with concentrated HCl
(1 mL). The residue was then dissolved in water (20 mL),
basified with NaOH (to pH 10), and extracted with CHCl3 (3
× 20 mL). After the solvent was evaporated, the crude product
was purified by flash chromatography (EtOAc/petroleum ether/
Et3N: 4/5/1 for N,N-dimethyl derivatives and EtOAc/MeOH/
Et3N: 8/1/1 for N-methyl derivatives).
N,N-Dim et h yl-2-(4′-b r om o-2′-m et h oxym et h ylp h en yl-
th io)ben zyla m in e (6a ). To a solution of compound 5a (290
mg, 0.82 mmol) in 4 mL of dimethylformamide were added at
0 °C NaH (29 mg, 1.21 mmol) and CH3I (156 mg, 1.1 mmol).
The mixture was stirred for 3 h at room temperature, treated
with water (20 mL), and extracted with CHCl3 (3 × 10 mL).
The organic layers were dried and evaporated, and the residue
was purified by flash chromatography (Et2O/Et3N: 9/1) to
1
obtain compound 6a in 74% yield as a yellow oil. H NMR: δ
2.20 (s, 6H), 3.35 (s, 3H), 3.47 (s, 2H), 4.44 (s, 2H), 6.94 (dd,
3
4
3
1H, J ) 7.3 Hz, J ) 1.6 Hz), 6.98 (d, 1H, J ) 8.4 Hz), 7.07
3
4
3
(td, 1H, J ) 7.3 Hz, J ) 1.6 Hz), 7.16 (td, 1H, J ) 7.3 Hz,
4J ) 1.6 Hz), 7.25 (dd, 1H, 3J ) 8.4 Hz, 4J ) 2.2 Hz), 7.34 (dd,
3
4
4
1H, J ) 7.3 Hz, J ) 1.6 Hz), 7.60 (d, 1H, J ) 2.0 Hz). 13C
NMR: δ 45.8 (2C), 59.1, 62.5, 72.0, 122.3, 127.4, 128.4, 130.7,
131.2, 131.4, 131.6, 133.3, 134.5, 135.7, 139.8, 141.9. MS: m/z
) 352 (12), 350 (12), 290 (31), 288 (29), 165 (24), 164 (23), 132
(32), 126 (35), 58 (100), 45 (70), 44 (28), 42 (48). Anal. (C17H20
BrNOS) C, H, N.
-
N,N-Dim et h yl-2-(4′-b r om o-2′-h yd r oxym et h ylp h en yl-
th io)ben zyla m in e (5a ). Yield ) 54%; yellow oil. 1H NMR: δ
2.29 (s, 6H), 3.54 (s, 2H), 4.69 (s, 2H), 6.94-6.98 (m, 1H), 7.06-
N-(2-F lu or oeth yl),N-m eth yl-2-(4′-br om o-2′-n itr op h en -
ylth io)ben zyla m in e (7d ). A solution of compound 7b (354
mg, 1 mmol), EtOH (10 mL), Et3N (140 µL), and 1-bromo-2-
fluoroethane (1.3 mmol) was heated at 70 °C for 16 h. After it
was cooled at room temperature, the solvent was removed, and
the residue was purified by flash chromatography (AcOEt/
Et3N: 9/1) to give compound 7d in 46% yield as an orange oil.
4
7.14 (m, 2H), 7.21-7.26 (m, 2H), 7.36 (dd, 1H, 3J ) 8.3 Hz, J
) 2.0 Hz), 7.50 (d, 1H, 4J ) 2.0 Hz). 13C NMR: δ 45.6 (2C),
62.4, 62.9, 123.1, 127.1, 128.9, 131.1, 131.3, 131.4, 132.3, 133.4,
136.3, 136.4, 138.3, 145.5. MS: m/z ) 353 (M+, 11), 351 (M+,
11), 293 (12), 291 (15), 227 (25), 197 (21), 165 (22), 164 (20),
132 (26), 58 (62), 46 (100), 42 (27). Anal. (C16H18BrNOS) C, H,
N.
1H NMR: δ 2.26 (s, 3H), 2.74 (td, 2H, J ) 27.2 Hz, J ) 5.0
Hz), 3.71 (s, 2H), 4.52 (td, 2H, 2J ) 47.6 Hz, 3J ) 5.0 Hz), 6.60
(d, 1H, 3J ) 8.7 Hz), 7.37-7.46 (m, 2H), 7.51-7.61 (m, 2H),
3
3
N-Met h yl-2-(4′-b r om o-2′-h yd r oxym et h ylp h en ylt h io)-
3
4
7.73 (d, 1H, J ) 6.9 Hz), 8.42 (d, 1H, J ) 2.2 Hz). 13C NMR:
δ 45.8, 57.5 (d, 2J ) 20.1 Hz), 60.2, 82.8 (d, 1J ) 168.1 Hz),
118.0, 128.8, 129.2, 130.0, 130.3, 131.2, 131.4, 136.6, 137.7,
139.0, 144.3, 145.7. MS: m/z ) 383 (12), 381 (12), 277 (25),
1
ben zyla m in e (5b). Yield ) 52%; yellow oil. H NMR: δ 2.36
(s, 3H), 3.01 (s, 1H), 3.75 (s, 2H), 4.50 (s, 2H), 6.97-7.22 (m,
3
4
4
5H), 7.26 (dd, 1H, J ) 8.5 Hz, J ) 2.1 Hz), 7.57 (d, 1H, J )
2.1 Hz). 13C NMR: δ 35.9, 54.0, 61.8, 122.4, 128.2, 128.9, 130.6,
131.0, 131.1, 132.0, 132.5, 133.6, 134.0, 139.8, 144.8. Anal.
(C15H16BrNOS) C, H, N.
275 (25), 243 (32), 90 (46), 44 (76), 42 (100). Anal. (C16H16
BrFN2O2S) C, H, N.
-
Syn th esis of Com p ou n d s 8a -d : Gen er a l P r oced u r e.
To a solution of compound 7a -d (4.11 mmol), concentrated
HCl (15.2 mL) and MeOH (30.5 mL) were added below 10 °C
SnCl2 (3.05 g, 16 mmol). The reaction mixture was stirred at
room temperature overnight, treated with water (75 mL),
basified with NaOH (to pH 10), and extracted with AcOEt (3
× 50 mL). After the solvent was evaporated, the residue was
purified by flash chromatography.
N,N-Dim et h yl-2-(4′-flu or o-2′-h yd r oxym et h ylp h en yl-
th io)ben zyla m in e (5c). Yield ) 55%; orange oil. 1H NMR:
δ 2.35 (s, 6H), 3.58 (s, 2H), 4.59 (s, 2H), 6.91-7.32 (m, 6H),
7.57 (dd, 1H, 3J ) 8.4 Hz, 3J ) 5.7 Hz). 13C NMR: δ 45.5 (2C),
62.2, 62.7, 115.1 (d, 2J ) 21.0 Hz), 115.9 (d, 2J ) 23 Hz), 126.4,
3
127.1, 128.7, 129.6, 131.0, 137.5 (2C), 137.6, 147.3 (d, J ) 7
Hz), 163.7 (d, 1J ) 248.6 Hz). MS: m/z ) 291 (M+, 79), 231
(68), 215 (98), 132 (67), 91 (48), 58 (100), 46 (68), 42 (45). Anal.
(C16H18FNOS) C, H, N.
N,N-Dim eth yl-2-(2′-a m in o-4′-br om op h en ylth io)ben zyl-
a m in e (8a ). Flash chromatography (EtOAc/petroleum ether/
N,N-Dim eth yl-2-(4′-br om o-2′-n itr op h en ylth io)ben zyl-
1
a m in e (7a ). Yield ) 61%; yellow oil. 1H NMR: δ 2.21 (s, 6H),
Et3N: 5/4.5/0.5); yield ) 79%; orange oil. H NMR: δ 2.25 (s,
3
3
6H), 3.53 (s, 2H), 4.68 (s broad, 2H), 6.70-6.81 (m, 2H), 6.85-
6.90 (m, 1H), 7.04-7.10 (m, 2H), 7.18-7.23 (m, 1H), 7.40 (d,
1H, 3J ) 5.7 Hz). 13C NMR: δ 45.7 (2C), 62.9, 114.9, 118.1,
121.3, 125.2, 126.1, 128.5, 128.6, 130.9, 137.0, 137.4, 139.1,
150.7. MS: m/z ) 338 (M+, 9), 336 (M+, 9), 212 (36), 165 (100),
164 (54), 134 (45), 58 (67), 44 (38). Anal. (C15H17BrN2S) C, H,
N.
3.54 (s, 2H), 6.60 (d, 1H, J ) 8.7 Hz), 7.39 (td, 1H, J ) 7.4
4
3
4
Hz, J ) 1.4 Hz), 7.43 (dd, 1H, J ) 8.7 Hz, J ) 2.2 Hz), 7.54
3
4
3
(td, 1H, J ) 7.4 Hz, J ) 1.4 Hz), 7.57 (dd, 1H, J ) 7.4 Hz,
4J ) 1.4 Hz), 7.70 (dd, 1H, J ) 7.4 Hz, J ) 1.4 Hz), 8.40 (d,
1H, 4J ) 2.2 Hz). 13C NMR: δ 45.8 (2C), 61.7, 112.0, 128.8,
129.1, 130.0, 130.3, 131.2, 131.3, 136.6, 137.6, 139.1, 144.4,
145.7. MS: m/z ) 368 (M+, 3), 366 (M+, 3), 277 (19), 275 (18),
58 (100). Anal. (C15H15BrN2O2S) C, H, N.
3
4
N -Me t h yl-2-(2′-a m in o-4′-b r om op h e n ylt h io)b e n zyl-
a m in e (8b). Flash chromatography (EtOAc/MeOH/Et3N: 8/1/
1); yield ) 66%; orange oil. 1H NMR: δ 1.43 (s broad, 1H),
2.44 (s, 3H), 3.94 (s, 2H), 4.46 (s broad, 2H), 6.76-6.84 (m,
3H), 7.03-7.07 (m, 2H), 7.20-7.25 (m, 2H). 13C NMR: δ 36.6,
54.5, 114.0, 118.2, 121.8, 125.3, 126.3, 127.7, 128.4, 129.9,
135.6, 138.1, 138.8, 150.4. MS: m/z ) 324 (M+, 4), 322 (M+,
N -Me t h y l-2-(4′-b r o m o -2′-n it r o p h e n y lt h io )b e n zy l-
a m in e (7b). Yield ) 60%; yellow oil. 1H NMR: δ 1.47 (s broad,
1H), 2.33 (s, 3H), 3.74 (s, 2H), 6.50 (d, 1H, 3J ) 8.7 Hz), 7.27-
7.56 (m, 5H), 8.33 (d, 1H, 4J ) 2.1 Hz). 13C NMR: δ 32.2, 49.3,
119.1, 129.4, 131.3, 131.8, 132.3, 132.5, 135.7, 137.0, 137.5,
138.4, 144.8 145.6. MS: m/z ) 354 (M+, 1), 352 (M+, 1), 319

Diphenyl Sulfides as Serotonin Transporter Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6 1257
3
4), 212 (19), 152 (11), 151 (42), 150 (26), 120 (100), 118 (25),
44 (29). Anal. (C14H15BrN2S) C, H, N.
(s, 6H), 3.45 (s, 3H), 3.57 (s, 2H), 4.54 (s, 2H), 6.91 (d, 1H, J
) 8.2 Hz), 7.09 (dd, 1H, 3J ) 7.5 Hz, 4J ) 1.7 Hz), 7.18 (td,
3
4
3
4
1H, J ) 7.2 Hz, J ) 1.7 Hz), 7.27 (td, 1H, J ) 7.2 Hz, J )
N,N-Dim eth yl-2-(2′-am in o-4′-m eth ylph en ylth io)ben zyl-
a m in e (8c). Flash chromatography (EtOAc/petroleum ether/
3
4
1.7 Hz), 7.46 (dd, 1H, J ) 7.5 Hz, J ) 1.7 Hz), 7.53 (dd, 1H,
3J ) 8.2 Hz, J ) 2.1 Hz), 7.89 (d, 1H, J ) 2.1 Hz). 13C NMR:
δ 45.8 (2C), 59.1, 62.5, 71.2, 93.5, 127.6, 128.4, 130.7, 132.0,
134.3, 134.5, 135.3, 137.2, 137.4, 140.1, 141.6. MS: m/z ) 413
(M+, 8), 290 (31), 398 (22), 336 (21), 209 (59), 165 (29), 164
4
4
1
Et3N: 4.5/5/0.5); yield ) 80%; yellow oil. H NMR: δ 2.34 (s,
6H), 2.36 (s, 3H), 3.62 (s, 2H), 4.44 (s broad, 2H), 6.60-6.65
(m, 2H), 6.91 (dd, 1H, 3J ) 7.3 Hz, 4J ) 1.6 Hz), 7.07-7.16
(m, 2H), 7.27-7.31 (m, 1H), 8.41 (d, 1H, 3J ) 8.3 Hz). 13C
NMR: δ 22.0, 45.8 (2C), 62.8, 112.2, 116.4, 120.0, 125.5, 127.6,
128.4, 130.6, 136.9, 138.0, 138.2, 141.7, 149.7. MS: m/z ) 272
(M+, 24), 165 (100), 164 (57), 150 (48), 134 (44), 132 (32), 58
(57), 44 (40). Anal. (C16H20N2S) C, H, N.
(22), 132 (30), 126 (52, 58 (100), 45 (70), 44 (32). Anal. (C17H20
INOS) C, H, N.
-
N-Met h yl-2-(2-a m in o-4-iod op h en ylt h io)b en zyla m in e
(8g). Yield ) 44%; brown oil; flash chromatography (AcOEt/
MeOH/Et3N: 8/1/1). 1H NMR: δ 1.65 (s broad, 1H), 2.44 (s,
3H), 3.84 (s, 2H), 4.40 (s broad, 2H), 6.77-6.81 (m, 1H), 6.96-
7.10 (m, 5H), 7.20-7.27 (m, 1H). 13C NMR: δ 36.5, 54.5, 97.3,
114.9, 124.2, 126.3, 127.8, 127.9, 128.5, 130.0, 135.5, 138.0,
138.8, 150.3. MS: m/z ) 370 (M+, 6), 212 (19), 152 (10), 151
(40), 150 (25), 120 (100), 118 (22), 44 (26). Anal. (C14H15IN2S)
C, H, N
N-(2-F lu or oeth yl),N-m eth yl-2-(2′-a m in o-4′-br om op h en -
ylth io)ben zyla m in e (8d ). Flash chromatography (EtOAc/
MeOH/Et3N: 5/4.5/0.5); yield ) 57%; brown oil. 1H NMR: δ 2.39
3
3
(s, 3H), 2.90 (td, 2H, J ) 27.4 Hz, J ) 5.0 Hz), 3.53 (s, 2H),
2
3
4.66 (s, 2H), 4.68 (td, 2H, J ) 47.6 Hz, J ) 5.0 Hz), 6.85-
7.01 (m, 3H), 7.12-7.20 (m, 2H), 7.27-7.41 (m, 2H). 13C
2
1
NMR: δ 42.7, 57.5 (d, J ) 20.0 Hz), 61.3, 82.8 (d, J ) 167.6
Hz), 115.0, 118.1, 121.5, 125.1, 126.1, 128.5, 128.6, 130.8,
136.9, 137.2, 139.0, 145.7. MS: m/z ) 370 (M+, 18), 368 (M+,
18), 212 (100), 165 (39), 115 (45), 91 (39). Anal. (C16H18BrFN2S)
C, H, N.
N-(2-F lu or oeth yl),N-m eth yl-2-(2-a m in o-4-iod op h en yl-
th io)ben zyla m in e (8h ). Yield ) 41%; brown oil; flash chro-
matography (AcOEt/MeOH/Et3N: 70/30/5). 1H NMR: δ 2.39
3
3
(s, 3H), 2.89 (td, 2H, J ) 27.5 Hz, J ) 5.0 Hz), 3.76 (s, 2H),
2
3
4.60 (s, 2H), 4.67 (td, 2H, J ) 47.5 Hz, J ) 5.0 Hz), 6.95-
N,N-Dim eth yl-2-(2′-a m in o-4′-(E)-tr i-n -bu tylsta n n ylvi-
n ylp h en ylth io)ben zyla m in e (8e). Under an argon atmo-
sphere, a solution of compound 8a (500 mg, 1.48 mmol), (E)-
1,2-Bis(tri-n-butylstannyl)ethylene (1.43 g, 2.36 mmol), and 60
mg of Pd(PPh3)4 in 6 mL of Et3N was heated at 90 °C for 4 h.
After it was cooled, the solvent was evaporated, and the
residue was purified by flash chromatography (Et2O/petroleum
ether/ Et3N: 50/50/5) to afford compound 7e in 75% yield as a
brown oil. 1H NMR: δ 0.94-1.10 (m, 15H), 1.37-1.51 (m, 6H),
1.46-1.63 (m, 6H), 2.37 (s, 6H), 3.65 (s, 2H), 4.54 (s broad,
2H), 6.75-7.02 (m, 5H), 7.11-7.17 (m, 2H), 7.27-7.35 (m, 1H),
7.00 (m, 1H), 7.05-7.23 (m, 5H), 7.30-7.34 (m, 1H). 13C
2
1
NMR: δ 42.7, 57.5 (d, J ) 19.2 Hz), 61.3, 82.8 (d, J ) 167.6
Hz), 97.2, 115.8, 124.1, 126.1, 127.5, 128.5, 128.6, 130.8, 136.8,
137.2, 139.0, 145.7. MS: m/z ) 416 (M+, 1), 213 (34), 121 (53),
197 (42), 164 (100), 150 (33), 91 (32), 90 (41), 44 (72), 42 (82).
Anal. (C16H18FIN2S) C, H, N.
Tr a n sp or ter Affin ity Assa ys. Radioligand binding assays
for the SERT, DAT, and NET were performed as previously
detailed26,27 by the NIMH Psychoactive Drug Screening Pro-
gram. Screening determinations and inhibitory constants (Ki)
were determined on membrane preparation from cells express-
ing transporters using [3H] paroxetine (KD around 0.15 nM),28
[3H] GBR 12935 (KD around 5 nM),29 and [3H] nisoxetine (KD
around 0.70 nM)30 for SERT, DAT, and NET, respectively, as
reference ligands. For screening purposes, 10 µM of each
compound (dissolved in 10% dimethyl sulfoxide) was incubated
with the appropriate transporter preparation, and percent
inhibition was determined for duplicate determinations, each
performed in duplicate. When >50% inhibition of specific
binding was measured, Ki determinations were then measured
by competition binding assays in which concentrations from
0.1 to 100 000 nM were incubated in duplicate. For each Ki
value, the data represent the mean ( standard deviation of
computer-derived estimates for N ) 4 separate determinations.
3
7.37 (d, 1H, J ) 7.9 Hz). 13C NMR: δ 10.1, 14.2, 27.8, 29.6,
45.7, 62.8, 113.1, 115.1, 116.7, 125.6, 127.9, 128.3, 130.6, 131.3,
137.2, 137.8, 138.0, 141.7, 146.1, 149.5.
N,N-Dim eth yl-2-(2′-a m in o-4′-(E)-iod ovin ylp h en ylth io)-
ben zyla m in e (8f). Compound 8f was obtained from compound
8e (251 mg, 4.4 mmol) by treatment with a solution of iodine
in chloroform (0.1 M) at 0 °C until the color persisted. The
solvent was removed, and the crude product was purified by
flash chromatography (AcOEt/petroleum ether/ Et3N: 50/50/
5) to give compound 8f in 65% yield as an orange oil. 1H
NMR: δ 2.35 (s, 6H), 3.62 (s, 2H), 4.62 (s broad, 2H), 6.63 (d,
4
3
4
1H, J ) 1.8 Hz), 6.71 (dd, 1H, J ) 7.9 Hz, J ) 1.8 Hz), 6.87
(d, 1H, 3J trans)14.9 Hz), 6.94-7.00 (m, 1H), 7.08-7.18 (m, 2H),
3
7.25-7.32 (m, 1H), 7.38 (d, 1H, J trans)14.9 Hz), 7.12 (d, 1H,
3J ) 7.9 Hz). 13C NMR: δ 45.7 (2C), 62.9, 78.2, 112.9, 116.3,
116.4, 126.0, 128.4, 128.5, 130.8, 137.2, 137.5, 138.0, 140.3,
145.1, 149.5. MS: m/z ) 410 (M+, 6), 165 (100), 164 (41), 58
(43), 44 (38). Anal. (C17H19IN2S) C, H, N.
Ack n ow led gm en t. This work was supported by the
Re´gion Centre (France) and INSERM-MFR. We thank
SAVIT (Tours, France) for chemical analyses. Radioli-
gand binding assays were performed by the National
Institute of Mental Health Psychoactive Drug Screening
Program, supported by NO1MH80005, at Case Western
Reserve University’s Biochemistry Department under
the direction of B.L. Roth (supported by KO2MH01366).
Syn t h esis of Com p ou n d s 5d , 6b , a n d 8g,h : Gen er a l
P r oced u r e. Under an argon atmosphere, a solution of com-
pound 5b, 6a , 8b, or 8d (0.77 mmol), Et3N (6 mL), hexabu-
tylditin (2.4 mL), and Pd(PPh3)4 (80 mg) was heated at 100
°C for 24 h. After it was cooled at room temperature. the
solvent was evaporated, and the residue was purified by flash
chromatography. Stannylated derivatives were diluted in
CHCl3 (38 mL) and treated with a solution of iodine in CHCl3
(0.1 M) until the color persisted to afford after purification by
flash chromatography compounds 5d , 6b, and 8g,h .
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