Fluorinated diaryl sulfides as serotonin transporter ligands: Synthesis, structure-activity relationship study, and in vivo evaluation of fluorine-18-labeled compounds as PET imaging agents

Article abstract of DOI:10.1021/jm0400808

A series of new, fluorine-containing substituted diphenyl sulfides was synthesized to serve as candidate ligands for positron emission tomography (PET) imaging of the serotonin transporter (SERT) and to further probe the structure-activity relationship (S

Full text of DOI:10.1021/jm0400808

J. Med. Chem. 2005, 48, 2559-2570
2559
Fluorinated Diaryl Sulfides as Serotonin Transporter Ligands: Synthesis,
Structure-Activity Relationship Study, and in Vivo Evaluation of
Fluorine-18-Labeled Compounds as PET Imaging Agents
Yiyun Huang,*,†,§ Sung-A Bae,† Zhihong Zhu,† Ningning Guo,† Bryan L. Roth,‡ and Marc Laruelle†,§
Departments of Psychiatry and Radiology, Columbia University College of Physicians and Surgeons,
New York, New York 10032, and Departments of Biochemistry, Psychiatry and Neurosciences,
Case Western Reserve University Medical School, Cleveland, Ohio 44106
Received April 6, 2004
A series of new, fluorine-containing substituted diphenyl sulfides was synthesized to serve as
candidate ligands for positron emission tomography (PET) imaging of the serotonin transporter
(SERT) and to further probe the structure-activity relationship (SAR) of this class of
compounds. Candidate compounds were assayed for their affinities to the monoamine
transporters (SERT, norepinephrine transporter (NET), and dopamine transporter (DAT)) in
competitive binding experiments in vitro using cloned human transporters. From these in vitro
assays, four compounds (7c-f) were chosen for further evaluation. All four compounds have
nanomolar affinity for SERT (Ki 1.46 nM, 1.04 nM,1.83 nM, and 3.58 nM for 7c, 7d, 7e, and
7f, respectively). The F-18-labeled compounds, 16 and 18a-c, were prepared via a two-step
radiosynthesis. Biodistribution studies in rats indicated that the F-18-labeled compounds
localized in brain regions with high concentrations of SERT. Furthermore, competition
experiments demonstrated that the binding of these radioligands in the rat brain was saturable,
specific, and selective to SERT. Specific binding in the rat hypothalamus peaked at 5.6 for
ligand 16 and 4.4 for 18b at 90 min after radioactivity administration. For ligand 18a, this
same ratio was 8.4 at 120 min postinjection, while compound 18c displayed a lower specific
binding ratio of 2.4. In summary, four F-18-labeled ligands were prepared and evaluated as
candidate PET imaging agents for SERT. Among these four ligands, three appear to be
promising radioligands suitable for the labeling of SERT in vivo, with 18a providing a higher
specific binding in vivo than 16 or 18b.
Introduction
The road toward the development of useful radio-
ligands for in vivo imaging of SERT has been long and
difficult. Many compounds have been tried but failed
to show promising imaging properties due to a combina-
tion of deficient selectivity, inappropriate kinetics and/
or inadequate in vivo binding specificity.9 Over the past
decade, efforts in the development of PET and SPECT
imaging agents have been concentrated on three major
classes of compounds: the tropane series, the quipazine
series, and the pyrroloisoquinoline series. From the
tropane series, two SPECT radioligands have reached
human applications: [123I]â-CIT and [123I]nor-â-CIT.
However, these two SPECT ligands are nonselective and
have equal affinities for the dopamine transporter (DAT)
and SERT.10 More recently, Goodman et al. reported the
synthesis and characterization of new tropane deriva-
tives, such as [123I]ZIENT and others, as putative
SPECT or PET imaging agents for SERT.11,12 Yet the
suitability of these new ligands for imaging the SERT
in humans remains to be demonstrated.
In the quipazine series, several I-123-, Br-76-, F-18-,
and C-11-labeled ligands were reported as potential
SPECT or PET imaging agents for SERT.13-16 However,
these agents either displayed relatively low specific
binding signal in vivo or brain uptake kinetics that was
not optimal for the intended imaging purpose. From the
pyrroloisoquinoline series, [11C]McN 5652 (Figure 1)
became the first successful PET radioligand for the
The neurotransmitter serotonin (5-HT) is involved in
the regulation of many brain functions such as mood,
appetite, sleep, pain, and aggressive behavior.1 The
serotonin transporter (SERT), located on the cell bodies
and terminals of the 5-HT neurons, is a marker of 5-HT
innervation.2 Alterations in SERT densities have been
reported in a number of neuropsychiatric conditions,
including major depression, anxiety disorders, schizo-
phrenia, drug abuse, alcoholism, eating disorders, and
Alzheimer’s and Parkinson’s disease.3-7 Many of the
currently available antidepressants are selective sero-
tonin reuptake inhibitors (SSRIs) and are believed to
exert their antidepressant effect through inhibition of
the SERT.8 Thus, in vivo imaging of SERT regional
brain distribution using the noninvasive positron emis-
sion tomography (PET) or Single Photon Emission
Computed Tomography (SPECT) provides an important
tool to study the role of the 5-HT system in the
pathophysiology and treatment of neuropsychiatric
disorders.
* Corresponding author: Yiyun Huang, Ph.D., Department of
Psychiatry, Columbia University College of Physicians and Surgeons,
1051 Riverside Dr., Box #31, New York, NY 10032. Telephone: (212)
543-6629. Fax: (212) 568-6171. E-mail: hh285@columbia.edu.
† Department of Psychiatry, Columbia University College of Physi-
cians and Surgeons.
§ Department of Radiology, Columbia University College of Physi-
cians and Surgeons.
‡ Case Western Reserve University Medical School.
10.1021/jm0400808 CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/11/2005

2560 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Huang et al.
Figure 1. Representative ligands for the serotonin transporter (SERT).
Scheme 1a
a Reagents and conditions: (a) K2CO3, Cu, DMF, 65 °C; (b) 1. SOCl2, 70 °C; 2. Me2NH‚HCl, K2CO3, THF, rt; (c). BH3‚THF, THF, rt; (d)
(MeOCH2CH2)2NSF3, CH2Cl2, rt; (e) SnCl2, HCl, MeOH, rt.
selective imaging of SERT in humans,17,18 but this first
selective SERT radioligand also presented some limita-
tions, such as high nonspecific binding, low specific to
nonspecific binding ratios, and slow brain kinetics.19-22
In the past few years, a new series of selective SERT
ligands have emerged from the substituted diaryl sulfide
class of compounds, based on the prototypical structure
of the serotonin reuptake inhibitor 403U76 (Figure 1).23
labeled ligands still gave low signal-to-noise ratios in
vivo and thus offered no improvement over [11C]McN
5652. In the quipazine series, [18F]5-fluoro-6-nitro-
quipazine was synthesized and shown to lack SERT
binding selectivity in vivo.15 In the substituted diaryl
sulfide series, Oya et al. reported the synthesis and
characterization of one F-18-labeled compound, [18F]-
ACF, while Shiue et al. described the synthesis and
preliminary evaluation of another, [18F]F-ADAM.47-49
In our laboratories we have been interested in the
development of SERT ligands that can be labeled with
either C-11 or F-18 in the same molecule.50 In this paper
we report the synthesis and in vitro pharmacological
characterization of a number of fluorinated diaryl
sulfides with various substitution patterns to further
probe the structure-activity relationship (SAR) of this
class of compounds as selective serotonin transporter
ligands. Based on the results of this SAR study, four
F-18-labeled compounds were prepared and evaluated
in rats to assess their potential as PET radioligands to
image SERT in vivo.
[
123I]IDAM was the first SPECT ligand coming from this
new class, followed by [123I]ADAM.24-29 From this same
class, a large collection of C-11-labeled radioligands has
been synthesized and evaluated as potential PET imag-
ing agents. These included [11C]DASB, [11C]DAPP, [11C]-
MADAM, [11C]DAPA, [11C]AFM, [11C]AFA, and [11C]-
AFE (Figure 1).9,30-40 All these compounds were shown
to be selective serotonin transporter ligands, with
varying specific to nonspecific binding ratios and brain
kinetics in vivo. In nonhuman primates, [11C]DASB and
[11C]AFM were demonstrated to be superior to [11C]McN
5652.9 [11C]DASB has since advanced to imaging ap-
plications in humans.33,34,41,42
In the development of PET imaging agents, radiolig-
ands labeled with the longer-lived isotope F-18 (t1/2 109.8
min vs 20.4 min for C-11) maintain certain advantages,
in that they can be used in longer scanning sessions and
be transported for off-site imaging applications. As a
result, there have been attempts to develop F-18-labeled
PET ligands for SERT. In the pyrroloisoquinoline series,
efforts were made to prepare [18F]fluoromethyl and [18F]-
fluoroethyl McN 5652.43-46 However, these two F-18-
Results and Discussion
Chemistry. The synthesis of various substituted
diaryl sulfides (compounds 7a-f) is depicted in Scheme
1. Halogenated nitrobenzenes (1a-f) were coupled with
thiosalicylic acid (2) to give benzoic acids 3a-f, which
were converted to the amides 4a-f by first reacting with
thionyl chloride to produce the acid chlorides, and
subsequent reaction of the acid chlorides with N,N-

Fluorinated Diaryl Sulfides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7 2561
Scheme 2a
a Reagents and conditions: (a) 1. SOCl2, 70 °C, 3 h; 2. NH3, THF, rt, overnight; (b) BH3‚THF, THF, 70 °C, 2 h then rt, overnight; (c)
SnCl2, HCl, MeOH, rt, overnight; (d) ICH2CH3, Br(CH2)2CH3, Br(CH2)nF, or allyl bromide, K2CO3, MeCN, 80 °C, overnight.
Scheme 3a
a Reagents and conditions: (a) K2CO3, Cu, DMF; (b) 1. SOCl2, 2. Me2NH‚HCl, K2CO3, THF; (c) BH3‚THF, THF; (d) 1. K18F, K-222,
DMSO, 150 °C, 20 min; 2. Cu(OAC)2 or SnCl2, NaBH4, EtOH, 80 °C, 10 min.
Scheme 4a
a Reagents and conditions: (a) 1. SOCl2, 70 °C, 2 h or TsCl, pyridine, CH2Cl2, 50 °C, 12 h; (b) 1. K18F, K-222, MeCN, 80 °C, 15 min; 2.
Cu(OAC)2 or SnCl2, NaBH4, EtOH, 80 °C, 10 min.
dimethylamine hydrochloride. Reduction of the amides
4a-c with borane/THF complex gave compounds 5a-
c. When compounds 4d-f were subjected to the same
reaction conditions, concomitant cleavage of the acetyl
protecting group in 4d or reduction of the ester func-
tionality in 4e-f provided the alcohols 5d-f. Deoxo-
fluorination of compounds 5d-f with bis(2-methoxy-
ethyl)aminosulfur trifluoride led to compounds 6d-f.51
Finally, reduction of the nitro group in compounds 5a-c
and 6d-f with tin(II) chloride under acidic conditions
afforded compounds 7a-f.
gave lower overall yield than Cu(OAc)2. When Cu(OAc)2
was used as the catalyst, an overall radiochemical yield
of ∼11% was achieved.
Precursor preparation and radiosynthesis of 18a-c
are shown in Scheme 4. Alcohols 5d-f were converted
to either the benzyl chloride (17a) or the tosylates (17b-
c), which served as the radiolabeling precursors. In a
manner similar to the preparation of 16, a two-step
radiolabeling sequence provided 18a ([18F]AFM), 18b
([18F]AFE), and 18c ([18F]AFP) in ∼10% or higher
overall radiochemical yield.
Preparation of compounds 11a-e is depicted in
Scheme 2. Starting from compound 3a, amide formation
with ammonia provided compound 8, which underwent
sequential reduction of the amide and nitro groups to
afford the amine 10. Alkylation of compound 10 with
alkyl halides then gave compounds 11a-e.
Synthesis of the radiolabeling precursor 15 and
preparation of the F-18-labeled compound 16 are shown
in Scheme 3. Coupling of 1-chloro-2,4-dinitrobenzene
(12) with thiosalicylic acid (2) gave the benzoic acid 13,
which was converted to the amide 14. Reduction of the
amide afforded the labeling precursor 15. Preparation
of 16 was accomplished in a two-step reaction sequence.
First, displacement of the 4-nitro group with F-18
fluoride produced the radiolabeled intermediate, which
underwent reduction with NaBH4, with either Cu(OAc)2
or SnCl2 as catalyst. Use of SnCl2 as catalyst generally
In Vitro Binding Assays and Structure-Activity
Relationship. The initial patent literature listed the
synthesis of a diverse array of substituted diaryl
sulfides.52-54 However, activity data were limited to a
small number of compounds. These available activity
data indicate that compounds with structure features
exemplified by 403U76, IDAM, and ADAM (Figure 1)
possess the highest SERT binding affinities. As an in
vivo imaging agent, [123I]ADAM displays improved
qualities over [123I]IDAM.25,27 Therefore, our structure-
activity relationship study was focused on the structural
scaffold represented by ADAM, with an amino group at
the 2-position of ring A and an aminomethyl group at
the 2′-position of ring B (Figure 1 and Table 1).
Table 1 lists the in vitro binding data of selected
compounds for human cloned monoamine transporters.
A survey of these structure-activity data brings forth

2562 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Huang et al.
Table 1. In Vitro Binding Data of Selected Compounds for the Monoamine Transporters
Ki (nM)a
compound
R1
R2
R3
R4
SERT
DAT
NET
ADAM
DASB
7a
I
H
H
H
F
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
1.07 ( 0.13
1.12 ( 0.14
1.19 ( 0.11
179.3 ( 36.3
1.46 ( 0.15
0.80 ( 0.03
1.04 ( 0.13
1.83 ( 0.07
3.58 ( 0.28
30.0 ( 4.5
>10 000
1352 ( 748.0
5127 ( 1418
320.4 ( 74.0
7036 ( 3356
141.7 ( 47.4
787.4 ( 231.1
663.8 ( 79.5
946.2 ( 222.5
505.0 ( 73.8
4440 ( 1189
7552 ( 1407
3910 ( 1199
CN
>10 000
>10 000
>10 000
>10 000
CH3
7b
CH3
7c
F
H
H
H
H
H
H
H
H
H
H
H
5d
CH2OH
CH2F
(CH2)2F
(CH2)3F
CH3
3608 ( 926
7d
>10 000
>10 000
>10 000
7e
7f
10
5296 ( 1551
11a
11b
11c
11d
11e
CH3
H
CH2CH3
70.2 ( 5.4
2121 ( 431
4426 ( 1526
3549 ( 680
CH3
H
(CH2)2F
71.3 ( 25.2
2177 ( 205
518 ( 182
CH3
H
(CH2)2CH3
(CH2)3F
>10 000
CH3
H
>10 000
2908 ( 504
4332 (1171
3823 ( 1071
CH3
H
CH2CHdCH2
80.9 ( 14.5
a Inhibition constants (Ki) presented are the mean ( SD of four separate determinations.
several noteworthy points: (1) Substitution at the
4-position of ring A in the diphenyl sulfide structure
produces high affinity compounds (7a, 7c-e). Results
from the present study and others in the literature
indicate that the electronic nature of the substituent in
this position has no effect on the affinity of the com-
pounds for SERT, with groups as diverse as electron-
donating (methoxy group in DAPP, Figure 1, Ki 1.89
nM) to highly electron-withdrawing (e.g. cyano and
fluorine groups in DASB, Ki 1.10 nM, and 7c, Ki 1.46
nM) all giving high affinity ligands for SERT.27,30,31,35,37,55
(2) Alkyl groups from methyl to fluoropropyl are well
tolerated at the 4-position of ring A, although the
affinity for SERT decreases as the chain becomes longer.
The SERT affinity order follows: methyl (7a, Ki 1.19
nM) ∼ fluoromethyl (7d, Ki 1.04 nM) > fluoroethyl (7e,
Ki 1.83 nM) > fluoropropyl (7f, Ki 3.58 nM). (3) The
4-position of ring A appears to accommodate certain
steric bulk. For example, substitution with iodine
produces the high affinity ligand ADAM (Ki 1.07 nM),
and substitution with fluoropropyl group gives 7f (Ki
3.58 nM). However, the ligand’s affinity for SERT
decreases with increasing bulk, as evidenced by the
lower affinity of 7f compared with 7a (Ki 1.19 nM), 7d
(Ki 1.04 nM), and 7e (Ki 1.83 nM). Emond et al. reported
that placement of an iodovinyl group at the 4-position
of ring A resulted in a ligand with only moderate SERT
affinity (Ki 19.3 nM).55 (4) Substituent placed at the
5-position of ring A greatly reduces SERT affinity. For
example, compound 7b displays a SERT Ki (179.3 nM)
more than 100 times higher than that of compound 7a
(1.19 nM), although its selectivity is not much affected.
Oya et al. reported ACF, with a chlorine at the 4-posi-
tion and a fluorine at the 5-position of ring A (Figure
1), to be a high affinity SERT ligand (Ki 0.05 nM for
SERT) as assayed using LLC-PK1 cells overexpressing
SERT and the radioligand [125I]IDAM. However, in vivo
study revealed a low specific binding of [18F]ACF,
probably indicative of a low SERT affinity in vivo.47
Another ligand, [18F]5-fluoro-ADAM, with a fluorine
substituent at the 5-position of ring A and no substitu-
ent at the 4-position, also gave low specific binding in
vivo.56 Taken together, these and other published
results indicate that substitution at the 4-position of
ring A in the diaryl sulfide skeleton is beneficial to the
maintenance of high SERT affinity in vitro and/or high
specific binding in vivo, while substitution at the 5-posi-
tion is detrimental, although the latter observation is
based on a limited number of experimental results and
needs to be confirmed by a larger SAR data set.
Choi et al. have shown that placement of an alkyl, a
substituted alkyl, or an arylcarbonyl group at the
aniline functionality of ring A in ADAM gives rise to
ligands with low SERT affinity.57 Replacement of one
methyl substituent on the N,N-dimethylbenzenemeth-
anamine moiety in ring B with a fluoropropyl group also
results in a compound with lower SERT affinity (Ki 19.3
nM).55 On the other hand, we and others have shown
that monomethylation at the benzenemethanamine
moiety produces compounds with high SERT affin-
ity.37,55,57,58 To further elucidate the structure-activity
relationship at this position, the monosubstituted as
well as unsubstituted benzenemethanamines (com-
pounds 10 and 11a-e) were prepared and assayed.
Placement of an ethyl, fluoroethyl, propyl, fluoropropyl,
or allyl group at this site affords moderate (11a, 11b,
and 11e, with SERT Ki of 70.2, 71.3, and 80.9 nM,
respectively) or low affinity (11c and 11d, Ki 2177 and
518 nM) SERT ligands, indicating a strict steric and/or
electronic requirement at this position. N-Methyl or
N,N-dimethyl substitution at this position appears to
be optimal in retaining high affinity for SERT.
As summarized in Table 1, results from structure-
activity relationship study indicate that compounds
7c-f possess the dual properties of high in vitro binding
affinity for SERT and the possibility for F-18 labeling.
Therefore, they were chosen for radiolabeling with F-18
and the labeled compounds, 16 and 18a-c, were evalu-
ated in biodistribution study in rats for their ability to
bind the SERT in vivo.

Fluorinated Diaryl Sulfides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7 2563
Table 2. Biodistribution of F-18-Labeled Radioligands 16 and 18a-c in Male Sprague-Dawley Rats (%ID/g, mean ( SD)
specific bindinga
(hypothalamus)
time
blood
cerebellum frontal cortex
striatum
16
hippocampus hypothalamus
thalamus
10 min
30 min
60 min
90 min
0.27 ( 0.01 0.38 ( 0.09
0.16 ( 0.01 0.20 ( 0.01
0.08 ( 0.01 0.07 ( 0.01
0.08 ( 0.00 0.04 ( 0.01
0.81 ( 0.26
0.65 ( 0.08
0.28 ( 0.05
0.20 ( 0.02
0.11 ( 0.02
0.65 ( 0.18
0.58 ( 0.05
0.26 ( 0.02
0.19 ( 0.01
0.11 ( 0.02
0.54 ( 0.17
0.48 ( 0.02
0.23 ( 0.04
0.18 ( 0.01
0.10 ( 0.01
0.73 ( 0.26
0.66 ( 0.05
0.38 ( 0.03
0.30 ( 0.06
0.17 ( 0.01
0.72 ( 0.24
0.69 ( 0.03
0.34 ( 0.05
0.23 ( 0.05
0.16 ( 0.02
0.89 ( 0.28
2.23 ( 0.13
4.09 ( 0.19
5.61 ( 0.74
4.92 ( 0.83
120 min 0.07 ( 0.01 0.04 ( 0.00
18a
10 min
30 min
60 min
90 min
0.37 ( 0.04 0.33 ( 0.04
0.18 ( 0.02 0.23 ( 0.03
0.10 ( 0.04 0.13 ( 0.02
0.08 ( 0.03 0.08 ( 0.01
0.82 ( 0.14
0.99 ( 0.20
0.71 ( 0.18
0.52 ( 0.19
0.38 ( 0.09
0.69 ( 0.15
0.83 ( 0.12
0.57 ( 0.12
0.45 ( 0.17
0.42 ( 0.10
0.51 ( 0.07
0.64 ( 0.12
0.45 ( 0.09
0.36 ( 0.12
0.28 ( 0.05
0.70 ( 0.08
0.82 ( 0.16
0.71 ( 0.14
0.58 ( 0.13
0.55 ( 0.08
0.72 ( 0.13
0.88 ( 0.06
0.67 ( 0.15
0.50 ( 0.15
0.56 ( 0.10
0.98 ( 0.22
2.27 ( 0.43
4.56 ( 0.45
5.81 ( 0.96
8.37 ( 0.18
120 min 0.04 ( 0.00 0.07 ( 0.02
18b
10 min
30 min
60 min
90 min
0.25 ( 0.01 0.28 ( 0.02
0.13 ( 0.03 0.13 ( 0.01
0.07 ( 0.02 0.06 ( 0.01
0.04 ( 0.01 0.03 ( 0.01
0.62 ( 0.08
0.32 ( 0.01
0.19 ( 0.04
0.08 ( 0.01
0.06 ( 0.00
0.51 ( 0.05
0.33 ( 0.01
0.21 ( 0.05
0.10 ( 0.02
0.08 ( 0.01
0.38 ( 0.03
0.27 ( 0.04
0.17 ( 0.04
0.09 ( 0.01
0.07 ( 0.00
0.51 ( 0.05
0.41 ( 0.03
0.24 ( 0.04
0.14 ( 0.02
0.10 ( 0.01
0.58 ( 0.08
0.39 ( 0.01
0.27 ( 0.04
0.17 ( 0.02
0.13 ( 0.02
0.96 ( 0.29
2.22 ( 0.45
3.35 ( 0.43
4.36 ( 0.80
4.50 ( 0.90
120 min 0.02 ( 0.01 0.02 ( 0.00
18c
10 min
30 min
60 min
90 min
0.18 ( 0.02 0.31 ( 0.08
0.15 ( 0.07 0.14 ( 0.01
0.14 ( 0.06 0.07 ( 0.00
0.08 ( 0.06 0.03 ( 0.00
0.47 ( 0.15
0.21 ( 0.01
0.12 ( 0.01
0.05 ( 0.01
0.08 ( 0.03
0.41 ( 0.09
0.21 ( 0.02
0.11 ( 0.02
0.08 ( 0.00
0.08 ( 0.01
0.36 ( 0.07
0.19 ( 0.01
0.13 ( 0.01
0.07 ( 0.00
0.08 ( 0.01
0.42 ( 0.09
0.21 ( 0.02
0.13 ( 0.02
0.10 ( 0.00
0.10 ( 0.01
0.44 ( 0.10
0.28 ( 0.01
0.16 ( 0.01
0.10 ( 0.02
0.10 ( 0.01
0.34 ( 0.12
0.57 ( 0.17
0.85 ( 0.27
1.85 ( 0.28
2.40 ( 0.25
120 min 0.04 ( 0.00 0.03 ( 0.00
a Specific binding in the hypothalamus is defined as [(%ID/g in hypothalamus - %ID/g in cerebellum)/%ID/g in cerebellum].
Table 3. Regional Uptake of F-18-Labeled Compounds 16 and 18a-c in Control and Pretreated Ratsa
condition
blood
cerebellum
frontal cortex
striatum
hippocampus
hypothalamus
thalamus
16
control
0.10 ( 0.03
0.07 ( 0.04
0.08 ( 0.00
0.10 ( 0.03
0.09 ( 0.01
0.08 ( 0.00
0.06 ( 0.04
0.06 ( 0.00
0.09 ( 0.01
0.09 ( 0.01
0.34 ( 0.04
0.14 ( 0.02
0.11 ( 0.01
0.36 ( 0.08
0.33 ( 0.06
0.29 ( 0.04
0.12 ( 0.02
0.10 ( 0.01
0.31 ( 0.06
0.28 ( 0.00
0.24 ( 0.03
0.13 ( 0.02
0.11 ( 0.01
0.28 ( 0.04
0.28 ( 0.04
0.36 ( 0.05
0.13 ( 0.01
0.10 ( 0.01
0.48 ( 0.15
0.43 ( 0.03
0.42 ( 0.11
0.15 ( 0.02
0.13 ( 0.02
0.47 ( 0.13
0.36 ( 0.08
7c
citalopram
nisoxetine
GBR12935
18a
control
0.13 ( 0.01
0.11 ( 0.01
0.12 ( 0.03
0.11 ( 0.02
0.11 ( 0.01
0.12 ( 0.02
0.09 ( 0.02
0.08 ( 0.02
0.13 ( 0.02
0.13 ( 0.01
0.76 ( 0.16
0.12 ( 0.04
0.11 ( 0.02
0.72 ( 0.25
0.76 ( 0.16
0.67 ( 0.12
0.14 ( 0.01
0.12 ( 0.04
0.58 ( 0.18
0.70 ( 0.05
0.52 ( 0.11
0.13 ( 0.05
0.13 ( 0.01
0.47 ( 0.07
0.59 ( 0.04
0.72 ( 0.08
0.17 ( 0.02
0.18 ( 0.03
0.73 ( 0.00
0.87 ( 0.03
0.64 ( 0.06
0.17 ( 0.03
0.16 ( 0.03
0.65 ( 0.05
0.74 ( 0.01
7d
citalopram
nisoxetine
GBR12935
18b
control
0.06 ( 0.00
0.06 ( 0.02
0.08 ( 0.02
0.06 ( 0.01
0.06 ( 0.02
0.08 ( 0.00
0.07 ( 0.02
0.06 ( 0.00
0.07 ( 0.01
0.06 ( 0.02
0.16 ( 0.02
0.10 ( 0.00
0.08 ( 0.00
0.19 ( 0.01
0.17 ( 0.06
0.21 ( 0.03
0.11 ( 0.02
0.09 ( 0.01
0.21 ( 0.04
0.20 ( 0.07
0.18 ( 0.01
0.11 ( 0.01
0.09 ( 0.00
0.17 ( 0.00
0.18 ( 0.06
0.30 ( 0.05
0.15 ( 0.04
0.12 ( 0.00
0.33 ( 0.02
0.32 ( 0.09
0.24 ( 0.03
0.14 ( 0.01
0.11 ( 0.01
0.29 ( 0.02
0.25 ( 0.10
7e
citalopram
nisoxetine
GBR12935
18c
control
0.09 ( 0.01
0.07 ( 0.02
0.09 ( 0.02
0.08 ( 0.01
0.09 ( 0.02
0.08 ( 0.02
0.08 ( 0.00
0.08 ( 0.02
0.08 ( 0.02
0.09 ( 0.00
0.16 ( 0.09
0.08 ( 0.00
0.16 ( 0.05
0.13 ( 0.03
0.15 ( 0.00
0.13 ( 0.02
0.08 ( 0.01
0.12 ( 0.02
0.13 ( 0.04
0.17 ( 0.03
0.16 ( 0.04
0.08 ( 0.00
0.11 ( 0.02
0.16 ( 0.04
0.16 ( 0.04
0.16 ( 0.03
0.10 ( 0.00
0.13 ( 0.02
0.15 ( 0.05
0.17 ( 0.04
0.15 ( 0.03
0.10 ( 0.02
0.15 ( 0.02
0.15 ( 0.04
0.18 ( 0.03
7f
citalopram
nisoxetine
GBR12935
a Uptake is expressed as %ID/g. Data presented are mean ( SD for each group (n ) 3 animals per group). Blocking agents (2 mg/kg
each) were given iv 10-15 min before radioligand, and animals sacrificed 60 min after.
In Vivo Evaluation. Tables 2 and 3 list the results
from biodistribution studies in rats. All four labeled
compounds displayed excellent entry into the rat brain
and localization in SERT-rich brain regions such as the
thalamus, hypothalamus, frontal cortex, striatum, and
hippocampus (Table 2). In the brain, compound 18a
displayed the highest specific binding in vivo, with the
specific binding ratio in the hypothalamus reaching 8.4
at 120 min after injection. Compounds 16 and 18b
showed similar brain uptake and specific binding to the
SERT, with 16 giving slightly higher specific binding
ratio in rats (5.6 in the hypothalamus, compared with
4.4 for 18b at 90 min postinjection). On the other hand,
compound 18c displayed lower specific binding in rats,
with ratios of 1.9 and 2.4, respectively, in the hypo-
thalamus at 90 and 120 min postinjection.
To further demonstrate the in vivo binding specificity
and selectivity of these new F-18-labeled compounds,
separate groups of rats were pretreated with the cold
compound, citalopram, nisoxetine, or GBR 12935 (2 mg/
kg each) in saline. The rats were sacrificed 60 min after
administration of the radioligand. Regional brain up-
take, expressed as %ID/g, was determined for each
pretreatment group and compared with the results from
a control group of rats treated with saline (Table 3).
Specific binding, calculated by the formula: specific

2564 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Huang et al.
Table 4. Specific Binding of Compounds 16 and 18a-c in Control and Pretreated Ratsa
condition
frontal cortex
striatum
hippocampus
hypothalamus
thalamus
16
control
3.33 ( 0.33
0.53 ( 0.18
0.64 ( 0.17
2.88 ( 0.92
2.81 ( 0.49
2.79 ( 0.44
0.37 ( 0.10
0.60 ( 0.22
2.45 ( 0.27
2.56 ( 0.45
2.17 ( 0.32
0.55 ( 0.10
0.81 ( 0.13
1.96 ( 0.51
2.21 ( 0.50
4.02 ( 0.37
0.62 ( 0.13
0.65 ( 0.17
3.82 ( 0.96
4.30 ( 0.60
4.07 ( 0.41
0.81 ( 0.15
0.98 ( 0.17
3.53 ( 0.21
4.57 ( 0.81
7c
citalopram
nisoxetine
GBR12935
18a
18b
18c
control
4.89 ( 0.68
0.31 ( 0.21
0.36 ( 0.15
4.02 ( 0.54
3.83 ( 0.02
4.40 ( 0.53
0.53 ( 0.31
0.52 ( 0.15
3.59 ( 0.72
4.37 ( 0.93
3.23 ( 0.41
0.45 ( 0.31
0.67 ( 0.24
2.72 ( 0.03
3.51 ( 0.74
5.05 ( 0.37
0.84 ( 0.27
1.37 ( 0.50
5.24 ( 0.10
5.30 ( 0.39
4.33 ( 0.72
0.85 ( 0.15
1.05 ( 0.12
4.71 ( 0.49
4.38 ( 0.10
7d
citalopram
nisoxetine
GBR12935
control
7e
citalopram
nisoxetine
GBR12935
1.62 ( 0.37
0.48 ( 0.38
0.31 ( 0.03
1.82 ( 0.65
1.98 ( 0.37
2.36 ( 0.27
0.61 ( 0.19
0.50 ( 0.21
2.10 ( 0.59
2.62 ( 0.54
1.88 ( 0.17
0.65 ( 0.26
0.54 ( 0.04
1.63 ( 0.61
2.18 ( 0.32
3.92 ( 0.42
1.21 ( 0.26
1.00 ( 0.10
4.00 ( 1.08
3.85 ( 1.26
3.85 ( 0.35
1.06 ( 0.36
0.89 ( 0.22
3.56 ( 1.36
3.38 ( 0.69
control
7f
citalopram
nisoxetine
GBR12935
0.97 ( 0.77
0.05 ( 0.07
0.84 ( 0.27
0.72 ( 0.19
0.64 ( 0.05
0.65 ( 0.21
0.07 ( 0.04
0.45 ( 0.24
0.58 ( 0.15
0.84 ( 0.35
1.03 ( 0.18
0.03 ( 0.03
0.32 ( 0.04
1.02 ( 0.20
0.77 ( 0.39
1.04 ( 0.04
0.26 ( 0.09
0.66 ( 0.47
0.84 ( 0.26
0.87 ( 0.41
0.89 ( 0.16
0.35 ( 0.32
0.74 ( 0.09
0.88 ( 0.03
0.98 ( 0.38
a Specific binding is defined as [(%ID/g in the region of interest - %ID/g in the cerebellum)/%ID/g in the cerebellum]. Data presented
are mean ( SD for each group (three animals per group).
binding ) [(activity in the region of interest - activity
in the cerebellum)/activity in the cerebellum], was
determined for all SERT-rich regions and listed in Table
4. In rats pretreated with either the cold compound or
the selective serotonin reuptake inhibitor citalopram,
there was a significant reduction in the uptake of the
radioligands in SERT-rich brain regions, while the
uptake in the cerebellum, a region with negligible
SERT, was little affected. As a result, significant reduc-
tions of specific binding were observed in all SERT-
containing regions such as hypothalamus, thalamus,
frontal cortex, striatum, and hippocampus (Tables 3 and
4). For ligand 16 ([18F]AFA or ([18F]F-ADAM), specific
binding was reduced by 63% to 84% in these regions in
the cold compound-treated rats and by 75% to 87% in
the citalopram-treated animals. For ligand 18a ([18F]-
AFM), specific binding decreased by 80% to 94% in the
cold compound-treated group and by 73% to 93% in the
citalopram-treated group. For ligand 18b ([18F]AFE),
specific binding decreased by 64% to 74% in the cold
compound-treated rats and by 71% to 81% in the
citalopram-treated animals (Table 4). As for ligand 18c,
there was a 61 to 97% reduction in specific binding when
the rats were pretreated with the cold compound 7f,
whereas these reductions were generally lower when the
rats were pretreated with citalopram (ranging from 13%
in the cortex to 69% in the hippocampus). On the other
hand, there were no significant changes in either brain
uptake or specific binding in rats pretreated with
nisoxetine, a selective norepinephrine reuptake inhibi-
tor, or GBR 12935, a selective dopamine reuptake
inhibitor (Table 4). In summary, results from these in
vivo competition experiments indicate that the binding
of ligands 16 and 18a-c in the rat brain is not only
specific, but also selective for the SERT. Taken together,
in vitro and in vivo pharmacological studies demon-
strate that all four F-18-labeled compounds are selective
radioligands suitable for the in vivo investigation of
SERT.
Shiue et al. have reported the biodistribution study
of compound 16 (termed [18F]F-ADAM) in rats and
found the specific binding in the hypothalamus reaching
∼11 at 120 min postinjection, while our data indicated
that this ratio was ∼5.49 It is not clear what causes this
discrepancy. We have conducted experiments in rats
and baboons for the C-11-labeled counterparts of com-
pounds 16, 18a, and 18b (termed [11C]AFA, [11C]AFM,
and [11C]AFE).38-40 The results from these studies are
consistent with the data obtained with the F-18-labeled
compounds. For example, at 90 min after tracer injec-
tion, [11C]AFA ([11C]16) displays a specific binding of
5.4 in the hypothalamus vs 5.6 for compound 16.39 In
baboons, [11C]AFA ([11C]16) and [11C]AFE ([11C]18b)
display similar specific binding signals that are lower
than those of [11C]AFM ([11C]18a),38 a result that is
expected from the findings of the present study, which
show that radioligands 16 ([18F]AFA) and 18b ([18F]-
AFE) possess similar specific binding ratios in rats that
are lower than those of 18a ([18F]AFM).
Results from the literature indicate that among the
F-18-labeled PET ligands for SERT, [18F]ACF (Figure
1) displays specific binding similar to that for 18c, but
lower than those of 16, 18a, or 18b.47 For example, at
120 min after tracer injection, specific binding in the
rat hypothalamus is 2.2 for [18F]ACF, 2.4 for 18c, 4.9
for 16, 8.4 for 18a, and 4.5 for 18b (Table 2). The other
F-18-labeled SERT ligand, [18F]fluoromethyl McN 5652,
displays a specific binding of 3.9 in the hypothalamus
at 90 min after ligand injection,59 which is higher than
that from 18c (1.9) or [18F]ACF, but lower than those
from 16 (5.6), 18a (5.8), and 18b (4.4) (Table 2). In PET
imaging study in a piglet, [18F]fluoromethyl McN 5652
displays a slightly faster brain uptake kinetics, but
lower specific binding signals than [11C]McN 5652.46 On
the other hand, PET imaging studies in baboons have
shown that [11C]16 and [11C]18b display specific binding
signals similar to those of [11C]McN 5652, but with a
much faster uptake kinetics, while [11C]18a possesses

Fluorinated Diaryl Sulfides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7 2565
crude product was crystallized from EtOH/H2O to provide the
title compound as a yellowish solid (4.97 g, 86%), mp 189-
191 °C. 1H NMR: δ 8.13 (dd, 1H, J ) 1.6, 7.7 Hz), 7.93 (s,
1H), 7.51 (dd, 1H, J ) 1.6, 7.6 Hz), 7.44 (dt, 1H, J ) 1.2, 7.6
Hz), 7.25-7.35 (m, 2H), 7.13 (d, 1H, J ) 8.1 Hz), 2.47 (s, 3H).
Anal. (C14H11NO4S) C, H, N.
2-[(5-Fluoro-4-methyl-2-nitrophenyl)thio]benzoic Acid
(3b). In an analogous manner the title compound was prepared
from 4-chloro-2-fluoro-5-nitrotoluene (1b) in 61% yield as a
yellowish solid, mp 167-169 °C. 1H NMR: δ 8.16-8.04 (m,
2H), 7.57-7.55 (m, 3H), 6.61(d, 1H, J ) 10.0 Hz), 2.31 (s, 3H).
Anal. (C14H10FNO4S‚0.2H2O) C, H, N.
a slightly faster uptake kinetics and much higher
specific binding signals than [11C]McN 5652.9,38-40 The
equilibrium specific-to-nonspecific binding coefficients
(V3′′), as a quantitative measure of specific binding
signal, are 1.04 for [11C]McN 5652, 1.10 for ([11C]16, 1.07
for [11C]18b, and 2.31 for [11C]18a, respectively, in the
baboon thalamus.38 From these published data it can
be expected that ligands 16, 18a, and 18b will provide
better specific binding signals than either [18F]ACF or
[18F]fluoromethyl McN 5652.
In summary, four fluorinated diaryl sulfides were
identified as selective and potent ligands for the sero-
tonin transporters as a result of the present structure-
activity relationship study. These four ligands were
labeled with the positron-emitting isotope F-18, and the
radiolabeled compounds, 16 and 18a-c, were evaluated
as candidate radioligands for positron emission tomog-
raphy imaging of SERT. Biodistribution studies in rats
demonstrate that ligands 16 and 18a-b display high
brain uptake and high specific binding in vivo, while
ligand 18c shows lower specific binding. Competition
experiments reveal that the F-18-labeled ligands 16 and
18a-c display high SERT binding selectivity and
specificity in vivo. In conclusion, results from these
studies indicate that compounds 16 and 18a-b are
promising PET radioligands for the in vivo imaging of
SERT. The current data also suggest that compound
18a might be a better PET imaging agent than 16 or
18b, as it provides higher specific binding signals in
rats. However, other parameters, such as blood metabo-
lism, brain uptake kinetics, and nonspecific binding of
the radioligands, are also important factors in the
evaluation and selection of PET imaging agents. A
comprehensive PET imaging study in nonhuman pri-
mates, with brain and blood measurements and full
kinetic modeling, is needed to better assess the merits
and suitability of these new F-18 ligands to image the
SERT in vivo.
2-[(4-Fluoro-2-nitrophenyl)thio]benzoic Acid (3c). In
an analogous manner the title compound was prepared from
2-chloro-5-fluoronitrobenzene (1c) in 40% yield as a yellowish
1
solid, mp 167-168 °C. H NMR: δ 8.13 (dd, 1H, J ) 1.2, 7.7
Hz), 7.86 (dd, 1H, J ) 2.3, 8.0 Hz), 7.45-7.58 (m, 2H), 7.30-
7.38 (m, 1H), 7.18-7.25 (m, 2H). Anal. (C13H8FNO4S) C, H,
N.
2-[[4-[(Acetyloxy)methyl]-2-nitrophenyl]thio]benzo-
ic Acid (3d). In an analogous manner the title compound was
prepared from 4-chloro-3-nitrobenzyl acetate (1d) in 39% yield
as a yellowish solid, mp 150-151 °C. 1H NMR: δ 8.16 (d, 1H,
J ) 1.1 Hz), 8.12 (dd, 1H, J ) 1.1, 7.2 Hz), 7.60-7.38 (m, 4H),
7.08 (d, 1H, J ) 8.3 Hz), 5.15 (s, 2H), 2.15 (s, 3H). Anal. (C16H13-
NO6S) C, H, N.
4-[(2-Carboxyphenyl)thio]-3-nitrobenzeneacetic Acid
r-Methyl Ester (3e). In an analogous manner the title
compound was prepared from methyl 4-bromo-3-nitrophenyl-
acetate (1e) in 56% yield as a yellowish solid, mp 135-136
1
°C. H NMR: δ 8.12-8.04 (m, 2H), 7.54-7.45 (m, 2H), 7.42
(d, 1H, J ) 7.7 Hz), 7.34 (d, 1H, J ) 8.3 Hz), 7.06 (d, 1H, J )
8.3 Hz), 3.72 (s, 3H), 3.67 (s, 2H). Anal. (C16H13NO6S) C, H,
N.
4-[(2-Carboxyphenyl)thio]-3-nitrobenzenepropanoic
Acid r-Methyl Ester (3f). In an analogous manner the title
compound was prepared from methyl 3-(4-chloro-3-nitrophen-
yl)propanoate (1f) in 46% yield as a yellowish solid, mp 155-
157 °C. 1H NMR: δ 8.09 (dd, 1H, J ) 1.6, 7.7 Hz), 7.85 (d, 1H,
J ) 1.7 Hz), 7.50 (dt, 1H, J ) 1.6, 7.6 Hz), 7.44 (dt, 1H,
J ) 1.6, 7.6 Hz), 7.35 (dd, 1H, J ) 1.0, 7.7 Hz), 7.29 (dd, 1H,
J ) 1.8, 8.4 Hz), 6.87 (d, 1H, J ) 8.4 Hz), 3.66 (s, 3H), 2.94 (t,
2H, J ) 7.6), 2.61 (t, 2H, J ) 7.6). Anal. (C17H15NO6S) C, H,
N.
2-[(2,4-Dinitrophenyl)thio]benzoic Acid (13). In an
analogous manner the title compound was prepared from
bromo-2,4-dinitrobenzene (12) in 20% yield as a yellow solid,
Experimental Section
General. All reagents were purchased from commercial
suppliers and used without further purification unless other-
wise stated. When reactions were worked up by extraction with
dichloromethane (CH2Cl2), chloroform (CHCl3), ethyl acetate
(EtOAc), or ethyl ether (Et2O), organic solutions were dried
with anhydrous MgSO4 and concentrated with a rotary
evaporator under reduced pressure. Reactions requiring an-
hydrous conditions were carried out in oven-dried glassware
under an inert atmosphere of nitrogen. Anhydrous Et2O and
THF were prepared by distilling over Na/benzophenone.
Melting points were determined on a Thomas-Hoover Unimelt
apparatus and are uncorrected. Column chromatography was
performed using silica gel 60, 230-400 mesh (Aldrich). Unless
otherwise noted, 1H NMR spectra were recorded on a Bruker
DRX400 spectrometer at 400 MHz, with CDCl3 as solvent and
tetramethylsilane (TMS) as the internal standard (0 ppm).
Mass spectra were run on a JMS-110HX spectrometer. El-
emental analyses were performed at Midwest Microlab, In-
dianapolis, IN.
2-[(4-Methyl-2-nitrophenyl)thio]benzoic Acid (3a). A
mixture of 4-bromo-3-nitrotoluene (1a, 4.54 g, 21 mmol),
thiosalicylic acid (2, 3.1 g, 20 mmol), Cu powder (365 mg, 5.74
mmol), and K2CO3 (6.4 g, 46.4 mmol) in DMF (50 mL) was
heated at 65 °C overnight, cooled to room temperature, and
poured to ice-water. The mixture was filtered through a layer
of Celite. The filtrate was made acidic with 6 N HCl and
extracted with CH2Cl2 (70 mL × 3). The combined organic
layers were washed with H2O, dried, and concentrated. The
1
mp 179-181 °C. H NMR: δ 9.07 (d, 1H, J ) 2.4 Hz), 8.18-
8.08 (m, 2H), 7.76-7.64 (m, 3H), 6.97 (d, 1H, J ) 9.0 Hz). Anal.
(C13H8N2O6S) C, H, N.
2-[(4-Methyl-2-nitrophenyl)thio]-N,N-dimethylbenza-
mide (4a). A solution of compound 3a (2.0 g, 6.9 mmol) in
thionyl chloride (20 mL) was heated at 70 °C for 3 h, cooled to
room temperature, and the excess thionyl chloride removed
in vacuo. The residue was redissolved in THF (25 mL), and to
this solution were added N,N-dimethylamine hydrochloride
(1.2 g, 13.8 mmol) and K2CO3 (1.9 g, 13.8 mmol). The reaction
mixture was stirred overnight at room temperature, diluted
with H2O, and extracted with CH2Cl2 (60 mL × 4). The
combined organic layers were washed with H2O, dried, and
concentrated. Column chromatography of the crude product
on silica gel and elution with EtOAc/hexane (60:40) afforded
the title compound (2.04 g, 93%) as a yellow solid, mp 105-
1
106 °C. H NMR: δ 8.02 (d, 1H, J ) 1.5 Hz), 7.40-7.63 (m,
4H), 7.21 (dd, 1H, J ) 1.5, 8.3 Hz), 6.88 (d, 1H, J ) 8.3 Hz),
3.08 (s, 3H), 2.88 (s, 3H), 2.36 (s, 3H). Anal. (C16H16N2O3S) C,
H, N.
2-[(5-Fluoro-4-methyl-2-nitrophenyl)thio]-N,N-dimeth-
ylbenzamide (4b). In an analogous manner the title com-
pound was prepared from compound 3b in 85% yield as a
yellow solid, mp 140-141 °C. 1H NMR: δ 8.13 (d, 1H, J ) 7.1
Hz), 7.67-7.57 (m, 2H, J ) 7.6 Hz), 7.51 (d, 1H, J ) 7.5 Hz),
7.47 (d, 1H, J ) 7.6 Hz), 6.53 (d, 1H, J ) 10.3 Hz), 3.07 (s,
3H), 2.87 (s, 3H), 2.27 (s, 3H). Anal. (C16H15FN2O3S) C, H, N.

2566 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Huang et al.
2-[(4-Fluoro-2-nitrophenyl)thio]-N,N-dimethylbenza-
mide (4c). In an analogous manner the title compound was
prepared from compound 3c in 93% yield as a yellowish solid,
mp 56-57 °C. 1H NMR: δ 7.90 (dd, 1H, J ) 2.8, 8.3 Hz), 7.65-
7.55 (m, 2H), 7.49 (dt, 1H, J ) 1.5, 7.6 Hz), 7.43 (dd, 1H, J )
1.2, 7.6 Hz), 7.15 (ddd, 1H, J ) 2.8, 7.2, 9.1 Hz), 6.96 (dd, 1H,
J ) 5.2, 9.1 Hz), 3.08 (s, 3H), 2.88 (s, 3H). Anal. (C15H13-
FN2O3S) C, H, N.
2-[(4-Fluoro-2-nitrophenyl)thio]-N,N-dimethylbenzen-
emethanamine (5c). In an analogous manner the title
compound was prepared from compound 4c in 58% yield as
yellowish thick oil. 1H NMR: δ 7.98 (dd, 1H, J ) 2.8, 8.4 Hz),
7.67 (d, 1H, J ) 7.7 Hz), 7.56 (d, 1H, J ) 7.6 Hz), 7.52 (t, 1H,
J ) 7.6 Hz), 7.47 (t, 1H, J ) 7.6 Hz), 7.1 (ddd, 1H, J ) 2.8,
7.2, 9.1 Hz), 6.72 (dd, 1H, J ) 5.2, 9.1 Hz), 3.55 (s, 2H), 2.20
(s, 6H). Anal. (C15H15FN2O2S) C, H, N.
2-[[4-[(Acetyloxy)methyl]-2-nitrophenyl]thio]-N,N-di-
methylbenzamide (4d). In an analogous manner the title
compound was prepared from compound 3d in 58% yield as a
yellow solid, mp 117-118 °C. 1H NMR: δ 8.22 (d, 1H, J ) 0.9
Hz), 7.63-7.42 (m, 4H), 7.37 (dd, 1H, J ) 1.5, 8.4 Hz), 6.95 (d,
1H, J ) 8.4 Hz), 5.09 (s, 2H), 3.07 (s, 3H), 2.88 (s, 3H), 2.12 (s,
3H). Anal. (C18H18N2O5S) C, H, N.
4-[[2-[(Dimethylamino)methyl]phenyl]thio]-3-nitro-
benzenemethanol (5d). In an analogous manner the title
compound was prepared from compound 4d in 67% yield as
yellowish thick oil, which solidified upon standing, mp 91-93
1
°C. H NMR: δ 8.22 (d, 1H, J ) 1.1 Hz), 7.64 (d, 1H, J ) 8.1
Hz), 7.58-7.43 (m, 2H), 7.38-7.25 (m, 2H), 6.67 (d, 1H, J )
8.4 Hz), 4.69 (s, 2H), 3.54 (s, 2H), 2.19 (s, 6H). Anal.
(C16H18N2O3S) C, H, N.
4-[[2-[(Dimethylamino)carbonyl]phenyl]thio]-3-nitro-
benzeneacetic Acid Methyl Ester (4e). In an analogous
manner the title compound was prepared from compound 3e
4-[[2-[(Dimethylamino)methyl]phenyl]thio]-3-nitroben-
zeneethanol (5e). In an analogous manner the title compound
was prepared from compound 4e in 80% yield as yellowish
thick oil. 1H NMR: δ 8.12 (d, 1H, J ) 1.7 Hz), 7.66 (d, 1H,
J ) 7.6 Hz), 7.54 (d, 1H, J ) 7.7 Hz), 7.48 (dt, 1H, J ) 1.0, 7.5
Hz), 7.33 (dt, 1H, J ) 1.1, 7.6 Hz), 7.20 (dd, 1H, J ) 1.9, 8.3
Hz), 6.62 (d, 1H, J ) 8.3 Hz), 3.87 (t, 2H, J ) 6.4 Hz), 3.55 (s,
2H), 2.87 (t, 2H, J ) 6.4 Hz), 2.20 (s, 6H). Anal. (C17H20N2O3S)
C, H, N.
4-[[2-[(Dimethylamino)methyl]phenyl]thio)-3-nitroben-
zenepropanol (5f). In an analogous manner the title com-
pound was prepared from compound 4f in 60% yield as
yellowish thick oil. 1H NMR: δ 8.07 (d, 1H, J ) 1.7 Hz), 7.66
(d, 1H, J ) 7.7 Hz), 7.53 (dd, 1H, J ) 0.9, 7.7 Hz), 7.48 (dt,
1H, J ) 1.1, 7.6 Hz), 7.33 (dt, 1H, J ) 1.1, 7.5 Hz), 7.15 (dd,
1H, J ) 1.6, 8.4 Hz), 6.62 (d, 1H, J ) 8.4 Hz), 3.66 (t, 2H, J )
6.3 Hz), 3.54 (s, 2H), 2.73 (t, 2H, J ) 7.6 Hz), 2.20 (s, 6H),
1.92-1.82 (m, 2H). Anal. (C18H22N2O3S) C, H, N.
2-[(4-Methyl-2-nitrophenyl)thio]benzenemethana-
mine (9). In an analogous manner the title compound was
prepared from compound 8 in 85% yield. Recrystallization in
CH2Cl2/hexane afforded an analytical sample as a yellowish
solid, mp 94-96 °C. 1H NMR: δ 8.06 (d, 1H, J ) 0.9 Hz), 7.61-
7.47 (m, 3H), 7.35 (dt, 1H, J ) 1.4, 7.5 Hz), 7.14 (m, 1H), 6.59
(d, 1H, J ) 8.3 Hz), 3.91 (br s, 2H), 2.36 (s, 3H). Anal.
(C14H14N2O2S) C, H, N.
2-[(2,4-Dinitrophenyl)thio]-N,N-dimethylbenzenemeth-
anamine (15). In an analogous manner the title compound
was prepared from compound 14 in 52% yield as a yellowish
solid, mp 128-129 °C [lit.48 mp 122-124 °C]. 1H NMR: δ 9.11
(d, 1H, J ) 2.5 Hz), 8.08 (dd, 1H, J ) 2.5, 9.1 Hz), 7.69-7.38
(m, 4H), 6.82 (d, 1H, J ) 9.1 Hz), 3.50 (s, 2H), 2.15 (s, 6H).
1
in 53% yield as a yellowish solid, mp 124-125 °C. H NMR:
δ 8.12 (d, 1H, J ) 2.0 Hz), 7.58 (dd, 1H, J ) 1.2, 7.6 Hz), 7.55
(dd, 1H, J ) 1.5, 7.6 Hz), 7.48 (dd, 1H, J ) 1.5, 7.6 Hz), 7.42
(dd, 1H, J ) 1.5, 7.6 Hz), 7.29 (dd, 1H, J ) 2.0, 8.4 Hz), 6.89
(d, 1H, J ) 8.4 Hz), 3.69 (s, 3H), 3.62 (s, 2H), 3.05 (s, 3H),
2.85 (s, 3H). Anal. (C18H18N2O5S) C, H, N.
4-[[2-[(Dimethylamino)carbonyl]phenyl]thio]-3-nitro-
benzenepropanoic Acid Methyl Ester (4f). In an analogous
manner the title compound was prepared from compound 3f
in 60% yield as yellow oil. 1H NMR: δ 8.03 (d, 1H, J ) 1.6
Hz), 7.56 (d, 1H, J ) 7.8 Hz), 7.53 (d, 1H, J ) 7.8 Hz), 7.46
(dt, 1H, J ) 1.4, 7.6 Hz), 7.42 (d, 1H, J ) 7.6 Hz), 7.21 (dd,
1H, J ) 1.6, 8.4 Hz), 6.86 (d, 1H, J ) 8.4 Hz), 3.67 (s, 3H),
3.04 (s, 3H), 2.94 (t, 2H, J ) 7.6 Hz), 2.85 (s, 3H), 2.61 (t, 2H,
J ) 7.6 Hz). Anal. (C19H20N2O5S‚0.2H2O) C, H, N.
2-[(4-Methyl-2-nitrophenyl)thio]benzamide (8). In an
analogous manner the title compound was prepared from
compound 3a and ammonia in 89% yield. Recrystallization in
CH2Cl2/hexane afforded an analytical sample as a yellow solid,
mp 143-144 °C. 1H NMR: δ 8.02 (m, 1H), 7.92 (m, 1H), 7.64-
7.48 (m, 3H), 7.20 (m, 1H), 6.78 (d, 1H, J ) 8.3 Hz), 6.61 (br
s, 1H), 5.62 (br s, 1H), 2.37 (s, 3H). Anal. (C14H12N2O3S) C, H,
N.
2-[(2,4-Dinitrophenyl)thio]-N,N-dimethylbenzamide
(14). In an analogous manner the title compound was prepared
from compound 13 and N,N-dimethylamine hydrochloride in
85% yield as a yellow solid, mp 144-145 °C [lit.48 mp 147-
1
149 °C]. H NMR: δ 9.06 (d, 1H, J ) 2.4 Hz), 8.18-8.10 (dd,
1H, J ) 2.4, 9.1 Hz), 7.66-7.44 (m, 4H), 7.06 (d, 1H, J ) 9.1
Hz), 3.03 (s, 3H), 2.87 (s, 3H).
N,N-Dimethyl-2-[(4-methyl-2-nitrophenyl)thio]benzene-
methanamine (5a). To a solution of compound 4a (1.3 g, 4.2
mmol) in THF (10 mL), cooled at 0 °C, was introduced the BH3‚
THF complex (10 mL, 1 M solution in THF, 10.0 mmol) via a
syringe. The solution was heated at 70 °C for 2 h and then
stirred overnight at room temperature. The reaction mixture
was cooled to 0 °C and concentrated HCl added. The solvent
was removed. The aqueous phase was diluted with H2O (20
mL), heated to reflux for 20 min, and, after cooling to room
temperature, adjusted to pH 8 with 10% NaHCO3. The mixture
was extracted with CH2Cl2 (30 mL × 4). The combined organic
layers were dried and concentrated. Column chromatography
on silica gel and elution with EtOAc/hexane (60:40) afforded
the title compound (1.05 g, 83%) as a yellow solid, mp 109-
111 °C. 1H NMR: δ 8.09 (d, 1H, J ) 1.5 Hz), 7.78 (dd, 1H,
J ) 1.5, 7.6 Hz), 7.65 (dd, 1H, J ) 1.5, 7.6 Hz), 7.58 (dt, 1H,
J ) 1.5, 7.6 Hz), 7.51 (dt, 1H, J ) 1.5, 7.6 Hz), 7.17 (dd, 1H,
J ) 1.5, 8.3 Hz), 6.44 (d, 1H, J ) 8.3 Hz), 4.24 (s, 2H), 2.65 (s,
6H), 2.40 (s, 3H). Anal. (C16H18N2O2S) C, H, N.
2-[[4-(Fluoromethyl)-2-nitrophenyl]thio]-N,N-dimeth-
ylbenzenemethanamine (6d). To a solution of compound 5d
(228 mg, 0.72 mmol) in CH2Cl2 (10 mL) was added [bis(2-
methoxyethyl)amino]sulfur trifluoride (0.15 mL, 0.80 mmol)
at 0 °C. The solution was stirred for 2 h at room temperature.
The reaction mixture was then diluted with CH2Cl2 (30 mL)
and washed with 10% NaHCO3 (25 mL × 3). The aqueous
phase was combined and back extracted once with CH2Cl2. The
organic layers were washed with H2O, dried, and concentrated.
The crude product was purified by column chromatography
on silica gel (MeOH/CH2Cl2, 5:95) to provide the title compound
1
as yellowish thick oil (76 mg, 33%). H NMR: δ 8.25 (s, 1H),
7.65 (d, 1H, J ) 7.7 Hz), 7.55 (d, 1H, J ) 7.7 Hz), 7.50 (dt, 1H,
J ) 1.3, 7.6 Hz), 7.35 (dt, 1H, J ) 1.3, 7.6 Hz), 7.30 (d, 1H,
J ) 8.4 Hz), 6.72 (d, 1H, J ) 8.4 Hz), 5.36 (d, 2H, J ) 47.3
Hz), 3.53 (s, 2H), 2.19 (s, 6H). Anal. (C16H17FN2O2S) C, H, N.
2-[[4-(2-Fluoroethyl)-2-nitrophenyl]thio]-N,N-dimeth-
ylbenzenemethanamine (6e). In an analogous manner the
title compound was obtained from compound 5e in 52% yield
as yellowish oil. 1H NMR: δ 8.12 (d, 1H, J ) 1.7 Hz), 7.66 (d,
1H, J ) 7.7 Hz), 7.52 (d, 1H, J ) 7.5 Hz), 7.48 (t, 1H, J ) 7.6
Hz), 7.33 (t, 1H, J ) 7.5 Hz), 7.18 (dd, 1H, J ) 1.8, 8.4 Hz),
6.63 (d, 1H, J ) 8.4 Hz), 4.63 (td, 2H, J ) 6.0, 46.9 Hz), 3.55
(s, 2H), 3.00 (td, 2H, J ) 6.0, 25.7 Hz), 2.20 (s, 6H). Anal.
(C17H19FN2O2S) C, H, N.
2-[(5-Fluoro-4-methyl-2-nitrophenyl)thio]-N,N-dimeth-
ylbenzenemethanamine (5b). In an analogous manner the
title compound was prepared from compound 4b in 78% yield
1
as a yellowish solid, mp 59-60 °C. H NMR: δ 8.19 (d, 1H,
J ) 7.1 Hz), 7.68 (d, 1H, J ) 7.6 Hz), 7.58-7.51 (m, 2H), 7.38
(dt, 1H, J ) 1.3, 7.5 Hz), 6.28 (d, 1H, J ) 10.6 Hz), 3.55 (s,
2H), 2.28 (s, 3H), 2.22 (s, 6H). Anal. (C16H17FN2O2S) C, H, N.

Fluorinated Diaryl Sulfides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7 2567
2-[[4-(3-Fluoropropyl)-2-nitrophenyl]thio]-N,N-dimeth-
ylbenzenemethanamine (6f). In an analogous manner the
title compound was obtained from compound 5f in 88% yield
as yellowish oil. 1H NMR: δ 8.07 (d, 1H, J ) 1.8 Hz), 7.64 (d,
1H, J ) 7.7 Hz), 7.53 (d, 1H, J ) 7.7 Hz), 7.49 (t, 1H, J ) 7.6
Hz), 7.33 (t. 1H. J ) 7.6 Hz), 7.16 (dd, 1H, J ) 1.8, 8.4 Hz),
6.63 (d, 1H, J ) 8.4 Hz), 4.44 (td, 2H, J ) 5.8, 47.1 Hz), 3.54
(s, 2H), 2.77 (t, 2H, J ) 7.8 Hz), 2.19 (s, 6H), 2.06-1.93 (m,
2H). Anal. (C18H21FN2O2S) C, H, N.
6.65-6.57 (m, 2H), 4.02 (s, 2H), 2.30 (s, 3H). An analytical
sample was prepared by reaction with tartaric acid in acetone
to give a colorless solid, mp 203-205 °C. Anal. (C14H16N2S‚
C4H6O6) C, H, N.
2-[(2-Amino-4-methylphenyl)thio]-N-ethylbenzenemeth-
anamine (11a). A mixture of amine 10 (100 mg, 0.25 mmol),
1-iodoethane (51.4 mg, 0.33 mmol), and K2CO3 (138.2 mg, 1.0
mmol) in anhydrous CH3CN (20 mL) was refluxed overnight.
The reaction mixture was concentrated, mixed with H2O (30
mL), and extracted with Et2O (20 mL × 4). The combined
organic layers were washed with saturated NaCl solution,
dried, and concentrated to give compound 11a (30.4 mg, 45%)
as colorless oil. 1H NMR: δ 7.35-7.28 (m, 2H), 7.14-7.03 (m,
2H), 6.85-6.78 (m, 1H), 6.64-6.56 (m, 2H), 4.30 (br s, 2H),
3.96 (s, 2H), 2.75 (q, 2H, J ) 7.1 Hz), 2.30 (s, 3H), 1.17 (t, 3H,
J ) 7.1 Hz). An analytical sample was prepared by reaction
with tartaric acid in acetone to afford a colorless solid, mp
162-164 °C. Anal. (C16H20N2S‚C4H6O6) C, H, N.
2-[(2-Amino-4-methylphenyl)thio]-N,N-dimethylben-
zenemethanamine (7a). To a solution of compound 5a (100
mg, 0.33 mmol) in MeOH (4 mL) was added concentrated HCl
(2 mL). The suspension was cooled to 0 °C, SnCl2 (378 mg,
1.98 mmol) was added, and the reaction mixture stirred
overnight at room temperature. The mixture was then diluted
with H2O (10 mL) and extracted with EtOAc (10 mL × 2). The
organic layers were discarded. The aqueous layer was adjusted
to pH 10 with 1 N NaOH and extracted with EtOAc (15 mL ×
4). The combined organic layers were washed with H2O, dried,
and concentrated to give compound 7a (66.2 mg, 73%) as
2-[(2-Amino-4-methylphenyl)thio]-N-(2-fluoroethyl)-
benzenemethanamine (11b). In an analogous manner com-
pound 11b was prepared from compound 10 and 1-bromo-2-
1
colorless oil. H NMR: δ 7.43 (d, 1H, J ) 7.7 Hz), 7.22-7.32
1
(m, 1H), 7.05-7.15 (m, 2H), 6.88 (m, 1H), 6.55-6.65 (m, 2H),
4.42 (br s, 2H), 3.62 (s, 2H), 2.38 (s, 6H), 2.32 (s, 3H).
2-[(2-Amino-4-fluoro-5-methylphenyl)thio]-N,N-dimeth-
ylbenzenemethanamine (7b). In an analogous manner
compound 7b was prepared from compound 5b in 88% yield
fluoroethane in 60% yield as colorless oil. H NMR: δ 7.35-
7.27 (m, 2H), 7.14-7.05 (m, 2H), 6.83 (m, 1H), 6.62-6.57 (m,
2H), 4.59 (td, 2H, J ) 4.8, 47.5 Hz), 4.02 (s, 2H), 2.99 (td, 2H,
J ) 4.8, 28.0 Hz), 2.30 (s, 3H). An analytical sample was
prepared by reaction with tartaric acid in acetone to give a
colorless solid, mp 99-101 °C. Anal. (C16H19FN2S‚C4H6-
O6•0.5H2O) C, H, N.
1
as colorless oil. H NMR: δ 8.20 (d, 1H, J ) 7.1 Hz), 7.87 (d,
1H, J ) 7.7 Hz), 7.63-7.57 (m, 2H), 7.43 (t, 1H, J ) 7.6 Hz),
6.21 (d, 1H, J ) 10.4 Hz), 4.11 (br s, 2H), 3.75 (s, 2H), 2.34 (s,
6H), 2.28 (s, 3H). An analytical sample was prepared by
reaction with tartaric acid in acetone to give a colorless solid,
mp 192-193 °C. Anal. (C16H19FN2S‚C4H6O6‚H2O) C, H, N.
2-[(2-Amino-4-fluorophenyl)thio]-N,N-dimethylben-
zenemethanamine (7c). In an analogous manner compound
7c was prepared from compound 5c in 74% yield as colorless
oil. 1H NMR: δ 7.48 (m, 1H), 7.23 (m, 1H), 7.07-7.18 (m, 2H),
6.90 (m, 1H), 6.40-6.53 (m, 2H), 4.80 (br s, 2H), 3.60 (s, 2H),
2.32 (s, 6H). An analytical sample was prepared by reaction
with tartaric acid in acetone to give a colorless solid, mp 158-
159 °C. Anal. (C15H17FN2S‚C4H6O6) C, H, N.
2-[(2-Amino-4-methylphenyl)thio]-N-propylbenzene-
methanamine (11c). In an analogous manner compound 11c
was prepared from compound 10 and 1-bromopropane in 51%
yield as colorless oil. 1H NMR: δ 7.33-7.27 (m, 2H), 7.12-
7.03 (m, 2H), 6.84-6.78 (m, 1H), 6.63-6.55 (m, 2H), 4.29 (br
s, 2H), 3.95 (s, 2H), 2.66 (t, 2H, J ) 7.2 Hz), 2.30 (s, 3H), 1.64-
1.50 (m, 2H), 0.95 (t, 3H, J ) 7.4 Hz). Anal. (C17H22N2S) C, H,
N.
2-[(2-Amino-4-methylphenyl)thio]-N-(3-fluoropropyl)-
benzenemethanamine (11d). In an analogous manner com-
pound 11d was prepared from compound 10 and 1-bromo-3-
fluoropropane in 80% yield as colorless oil. 1H NMR: δ 7.33-
7.25 (m, 2H), 7.14-7.03 (m, 2H), 6.82 (m, 1H), 6.65-6.55 (m,
2H), 4.59 (td, 2H, J ) 5.9, 47.3 Hz), 4.28 (br s, 2H), 3.95 (s,
2H), 2.83 (t, 2H, J ) 6.9 Hz), 2.30 (s, 3H), 2.00-1.85 (m, 2H).
Anal. (C17H21FN2S) C, H, N.
2-[(2-Amino-4-fluoromethylphenyl)thio]-N,N-dimeth-
ylbenzenemethanamine (7d). In an analogous manner
compound 7d was prepared from compound 6d in 54% yield
1
as colorless oil. H NMR: δ 7.51 (d, 1H, J ) 7.8 Hz), 7.30-
7.24 (m, 1H), 7.16-7.07 (m, 2H), 6.95-6.90 (m, 1H), 6.77 (s,
1H), 6.74 (d, 1H, J ) 7.8 Hz), 5.32 (d, 2H, J ) 47.6 Hz), 4.76
(br s, 2H), 3.69 (s, 2H), 2.32 (s, 6H). An analytical sample was
prepared by reaction with tartaric acid in acetone to give a
colorless solid, mp 142-143 °C. Anal. (C16H19FN2S‚C4H6O6) C,
H, N.
2-[[2-Amino-4-(2-fluoroethyl)phenyl]thio]-N,N-dimeth-
ylbenzenemethanamine (7e). In an analogous manner
compound 7e was obtained from compound 6e in 77% yield
as colorless oil, which solidified over time to give a colorless
solid, mp 54-56 °C. 1H NMR: δ 7.42 (d, 1H, J ) 7.6 Hz), 7.28-
7.20 (m, 1H), 7.13-7.05 (m, 2H), 6.92-6.87 (m, 1H), 6.65-
6.57 (m, 2H), 4.62 (dt, 2H, J ) 6.6, 47.1 Hz), 4.50 (br s, 2H),
3.57 (s, 2H), 2.95 (td, 2H, J ) 6.6, 23.3 Hz), 2.31 (s, 6H). Anal.
(C17H21FN2S) C, H, N.
N-Allyl-2-[(2-amino-4-methylphenyl)thio]-benzenemeth-
anamine (11e). In an analogous manner compound 11e was
prepared from compound 10 and allyl bromide in 79% yield
as colorless oil. 1H NMR: δ 7.35-7.27 (m, 2H), 7.14-7.03 (m,
2H), 6.86-6.78 (m, 1H), 6.64-6.56 (m, 2H), 5.97 (tdd, 1H,
J ) 6.0, 10.3, 17.2 Hz), 5.23 (dd, 1H, J ) 1.6, 17.2 Hz), 5.13
(dd, 1H, J ) 1.4, 10.3 Hz), 4.30 (br s, 2H), 3.96 (s, 2H), 3.34
(td, 2H, J ) 1.4, 6.0 Hz), 2.31 (s, 3H). Anal. (C17H20N2S‚0.2H2O)
C, H, N.
2-[[4-(Chloromethyl)-2-nitrophenyl]thio]-N,N-dimeth-
ylbenzenemethanamine (17a). To a solution of compound
5d (10 mg, 0.031 mmol) in anhydrous CHCl3 (5 mL) were
added Et3N (5 µL, 0.031 mmol) and SOCl2 (300 µL). The
reaction mixture was heated at reflux for 2 h, cooled to room
temperature, and washed with H2O. The aqueous phase was
removed. The organic layer was neutralized with 10% aqueous
NaHCO3 and extracted with CH2Cl2 (3 × 5 mL). The combined
organic layers were washed with H2O, dried, and concentrated
to give compound 17a (7.0 mg, 66%) as yellowish thick oil. 1H
NMR: δ 8.28 (d, 1H, J ) 2.0 Hz), 7.80-7.30 (m, 5H), 6.68 (d,
1H, J ) 8.4 Hz), 4.56 (s, 2H), 3.20 (s, 2H), 2.19 (s, 6H).
HRMS: calcld for C16H18ClN2O2S (MH+): m/z 337.0772;
found: 337.0763.
2-[[2-Amino-4-(3-fluoropropyl)phenyl]thio]-N,N-dimeth-
ylbenzenemethanamine (7f). In an analogous manner
compound 7f was obtained from compound 6f in 79% yield as
1
colorless oil. H NMR: δ 7.39 (d, 1H, J ) 8.3 Hz), 7.27-7.20
(m, 1H), 7.13-7.05 (m, 2H), 6.90-6.82 (m, 1H), 6.63-6.55 (m,
2H), 4.47 (td, 2H, J ) 5.9, 47.2 Hz), 4.45 (br s, 2H), 3.57 (s,
2H), 2.68 (t, 2H, J ) 7.5 Hz), 2.29 (s, 6H), 2.06-1.92 (m, 2H).
An analytical sample was prepared by reaction with tartaric
acid in acetone to give a colorless solid (hygroscopic). Anal.
(C18H23FN2S‚C4H6O6) C, H, N.
4-[[2-[(Dimethylamino)methyl]phenyl]thio]-3-nitroben-
zeneethanol 4-Methylbenezenesulfonate (17b). To a solu-
tion of compound 5e (17 mg, 0.051 mmol) in CH2Cl2 (2 mL)
were added toluenesulfonyl chloride (11 mg, 0.056 mmol) and
pyridine (5.4 µL, 0.067 mmol). The reaction mixture was
refluxed overnight, cooled to room temperature, and washed
with 10% aqueous Na2CO3. The organic layer was separated,
2-[(2-Amino-4-methylphenyl)thio]benzenemethana-
mine (10). In an analogous manner compound 10 was
prepared from compound 9 in 77% yield as colorless oil. 1H
NMR: δ 7.34-7.26 (m, 2H), 7.11 (dt, 1H, J ) 1.4, 7.4 Hz),
7.06 (dt, 1H, J ) 1.6, 7.6 Hz), 6.79 (dd, 1H, J ) 1.4, 7.6 Hz),

2568 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Huang et al.
dried, and concentrated. The crude product was purified by
silica gel column (MeOH/CH2Cl2 2:98) to provide compound
17b (13 mg, 60%) as yellowish oil. 1H NMR: δ 7.89 (d, 1H,
J ) 1.8 Hz), 7.67 (m, 1H), 7.64 (d, 2H, J ) 8.3 Hz), 7.57-7.47
(m, 2H), 7.35 (m, 1H), 7.28 (d, 2H, J ) 8.3 Hz), 7.10 (dd, 1H,
J ) 1.8, 8.4 Hz), 6.59 (d, 1H, J ) 8.4 Hz), 4.22 (t, 2H, J ) 6.4
Hz), 3.55 (s, 2H), 2.94 (t, 2H, J ) 6.4 Hz), 2.44 (s, 3H), 2.21 (s,
6H). HRMS: calcld for C24H27N2O5S2 (MH+): m/z 487.1356;
found: 487.1362.
4-[[2-[(Dimethylamino)methyl]phenyl]thio]-3-nitroben-
zenepropanol 4-Methylbenzenesulfonate (17c). In an
analogous manner compound 17c was prepared from com-
pound 5f in 59% yield as yellowish oil. 1H NMR: δ 7.95 (d,
1H, J ) 1.7 Hz), 7.77 (d, 2H, J ) 8.3 Hz), 7.67 (d, 1H, J ) 7.5
Hz), 7.57-7.44 (m, 2H), 7.39-7.30 (m, 3H), 7.05 (dd, 1H, J )
1.7, 8.3 Hz), 6.58 (d, 1H, J ) 8.3 Hz), 4.02 (t, 2H, J ) 6.0 Hz),
3.56 (s, 2H), 2.68 (t, 2H, J ) 7.7 Hz), 2.44 (s, 3H), 2.14 (s, 6H),
1.95 (m, 2H). HRMS: calcld for C25H29N2O5S2 (MH+): m/z
501.1512; found: 501.1516.
Radiochemistry. Instruments used for radiochemistry are
as follows: a semipreparative HPLC system including a
Waters 515 HPLC pump, a Rheodyne 7010 injector with a
2 mL loop, a Phenomenex Prodigy C18 ODS Prep column
(10 µm, 10 × 250 mm), an Alltech Model 450 UV detector, a
custom-made gamma detector, and a PC running LookOut
HPLC data acquisition software; an analytical HPLC system
consisting of a Waters 515 HPLC pump, a Rheodyne 7125
injector, a Phenomenex Prodigy C18 ODS-3 column (5 µm,
4.6 × 250 mm), a Waters PDA 996 detector, a Flow Cell
gamma detector (Bioscan) and a PC with the Empower
software used for system control.
Anhydrous [18F]fluoride was prepared from aqueous [18F]-
NaF produced via the (p, n) nuclear reaction of [18O]H2O in a
RDS-112 cyclotron. Aqueous [18F]NaF was mixed with K2CO3
and Kryptofix 222 in a 5 mL reaction vial. Water was removed
by repeated addition of anhydrous MeCN and azeotropic
evaporation of the resulting mixture to bring the [18F]fluoride
to complete dryness and ready for use in fluorination reaction.
Irradiation of the target with a beam current of 30 µA for 60
min typically produces about 1000 mCi of [18F]fluoride.
2-[(2-Amino-4-[18F]fluorophenyl)thio]-N,N-dimethyl-
benzenemethanamine (16, [18F]AFA). The precursor 15 (3
mg) in DMSO (1 mL) was added to the reaction vial containing
anhydrous [18F]fluoride. The mixture was heated at 150 °C
for 20 min, cooled, and then diluted with H2O (50 mL). The
resulting aqueous solution was passed through a C18 SepPak
and the SepPak rinsed with 25% aqueous MeOH (20 mL). The
crude product, eluted off the SepPak with EtOH (1.5 mL), was
then heated at 80 °C for 10 min with a combination of SnCl2
(2 mg) or Cu(OAc)2 (2 mg) with NaBH4 (4 mg, added in two
portions, 5 min apart). The reaction mixture was diluted with
H2O (50 mL). The aqueous solution was passed through a
second C18 SepPak and the SepPak rinsed with 10% aqueous
EtOH (10 mL), followed by H2O (10 mL). The crude product,
eluted off the SepPak with EtOH (1 mL), was then purified
by preparative HPLC (mobile phase: 25% MeCN/75% 0.1 M
ammonium formate, flow rate: 8 mL/min). The product
fraction, eluted off the column at ∼30 min, was collected,
diluted with H2O (100 mL), and passed through a third C18
SepPak. The SepPak was washed with 0.01 N HCl (10 mL)
and H2O (10 mL). The final product 16 was eluted off the
SepPak with EtOH (1 mL) and formulated by dilution of the
EtOH solution with sterile normal saline (9 mL) and filtration
of the solution through a sterile membrane filter (0.22 µm).
Radiochemical purity of the final product was >98%. Radio-
chemical yield was 10.8%. Identity of the labeled compound
16 was confirmed by coinjection of the product in saline with
the cold standard (7c) onto the analytical HPLC (mobile
phase: 35% MeCN/65% 0.1 M ammonium formate; flow rate:
2 mL/min; retention time for product: 8.5 min). The radiola-
beled product and the cold compound (7c) coeluted from the
column, and only one single UV peak was detected.
2-[[2-Amino-4-([18F]fluoromethyl)phenyl]thio]-N,N-di-
methylbenzenemethanamine (18a, [18F]AFM). The radio-
labeling precursor 17a (2 mg) was dissolved in MeCN (1 mL)
and reacted with anhydrous [18F]fluoride at 80 °C for 15 min
to effect F-18 fluorination. Subsequent workup and reaction
procedures are similar to those for the synthesis of compound
16. Radiochemical purity of the final product 18a was >98%.
Radiochemical yield was 9.8%. The radiolabeled compound
(18a) and the cold standard (7d) coeluted on the analytical
HPLC (mobile phase: 35% MeCN/65% 0.1 M ammonium
formate; flow rate: 2 mL/min; retention time for product: 7.6
min).
2-[[2-Amino-4-(2-[18F]fluoroethyl)phenyl]thio]-N,N-di-
methylbenzenemethanamine (18b, [18F]AFE). In analogy
to the preparation of 18a, compound 18b was prepared from
the radiolabeling precursor (17b) in >99% radiochemical
purity and 14.2% radiochemical yield. The radiolabeled product
18b and the cold standard 7e coeluted on the analytical HPLC
(mobile phase: 35% MeCN/65% 0.1 M ammonium formate;
flow rate: 2 mL/min; retention time for product: 8.2 min).
2-[[2-Amino-4-(3-[18F]fluoropropyl)phenyl]thio]-N,N-
dimethylbenzenemethanamine (18c, [18F]AFP). In anal-
ogy to the preparation of 18a, compound 18c was prepared
from the radiolabeling precursor (17c) in >98% radiochemical
purity and 15.5% radiochemical yield. The labeled product 18c
and the cold standard 7f coeluted on HPLC (mobile phase:
40% MeCN/60% 0.1 M ammonium formate; flow rate: 2 mL/
min; retention time for product: 7.6 min).
In Vitro Binding Assays. Candidate compounds were
assayed for their affinities to the monoamine transporters
(SERT, NET and DAT) in competitive binding experiments in
vitro using cloned human receptors (hSERT, hNET, and
hDAT) expressed on HEK-293 cells and the radioligands [3H]-
paroxetine (SERT), [3H]nisoxetine (NET), and [3H]GBR12935
(DAT), in accordance with the published procedures.37
Biodistribution Studies in Rats. Experiments in rodents
were carried out according to protocols approved by the
Institutional Animal Care and Use Committee (IACUC) of
New York State Psychiatric Institute and Columbia Univer-
sity. Specifically, the F-18-labeled compound in saline (∼20
µCi for each rat at the time of injection) was injected into
groups of male Sprague-Dawley rats (three animals for each
group) via the tail vein and the rats were sacrificed by
decapitation, following anesthesia with CO2, at 10, 30, 60, 90,
and 120 min after radioactivity injection. The brain regions
(cerebellum, hippocampus, striatum, frontal cortex, thalamus,
and hypothalamus), along with sample of blood, were removed,
weighed, and counted in a Packard Cobra II gamma counter.
A section of the tail, where the injection took place, was cut
and counted for residual activity. This residual activity was
then used to correct the individual injected dose by subtraction
from the total radioactivity injected for each rat. The percent
injected dose (%ID) of the decay- and tail-corrected activity in
the brain regions and blood were calculated based upon F-18
standards prepared from the injection solution, and the %ID/g
were calculated using the tissue weights. In another set of
experiments, three groups of rats (three animals per group)
were treated with citalopram (selective serotonin re-uptake
inhibitor), nisoxetine (selective norepinephrine reuptake in-
hibitor), GBR12935 (selective dopamine reuptake inhibitor),
or the cold compound (16, or 18a-c) (2 mg/kg each, iv) 10-15
min before the radiotracer injection. In a control group, rats
(n ) 3) were injected with saline. Each group of rats was
sacrificed 60 min after the injection of the radioactivity. Blood
sample and brain tissues were taken, counted, and weighed,
and %ID/g was calculated as described above. The average
%ID/g in the control group was then compared with that from
each of the treatment groups.
Acknowledgment. Supported by NIMH and
NIDA (R21 MH66624-01 to Y.H., KO2MH01366 and
NO1MH32004 to B.L.R. for the NIMH Psychoactive
Drug Screening Program) and the Lieber Center for
Schizophrenia Research at Columbia University.

Fluorinated Diaryl Sulfides
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Supporting Information Available: Elemental analysis
of new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
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