2-(2′-((Dimethylamino)methyl)-4′-(fluoroalkoxy)-phenylthio) benzenamine derivatives as serotonin transporter imaging agents

Article abstract of DOI:10.1021/jm070685e

A novel series of ligands with substitutions at the 5-position on phenyl ring A and at the 4′-position on phenyl ring B of 2-(2′- ((dimethylamino)methyl)-4′-(fluoroalkoxy)phenylthio)benzenamine (4′-2-fluoroethoxy derivatives 28-31 and 4′-3-fluoropropoxy d

Full text of DOI:10.1021/jm070685e

J. Med. Chem. 2007, 50, 6673–6684
6673
2-(2′-((Dimethylamino)methyl)-4′-(fluoroalkoxy)-phenylthio)benzenamine Derivatives as
Serotonin Transporter Imaging Agents
Ajit K. Parhi,† Julie L. Wang,‡ Shunichi Oya,† Seok-Rye Choi,† Mei-Ping Kung,† and Hank F. Kung*,†,‡
Departments of Radiology and Pharmacology, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
ReceiVed June 12, 2007
A novel series of ligands with substitutions at the 5-position on phenyl ring A and at the 4′-position on
phenyl ring B of 2-(2′-((dimethylamino)methyl)-4′-(fluoroalkoxy)phenylthio)benzenamine (4′-2-fluoroethoxy
derivatives 28–31 and 4′-3-fluoropropoxy derivatives 40–42) were prepared and tested as serotonin transporter
(SERT) imaging agents. The new ligands displayed high binding affinities to SERT (Ki ranging from 0.03
to 1.4 nM). The corresponding 18F labeled compounds, which can be prepared readily, showed excellent
brain uptake and retention after iv injection in rats. The hypothalamus region showed high uptake values
between 0.74% and 2.2% dose/g at 120 min after iv injection. Significantly, the hypothalamus to cerebellum
ratios (target to nontarget ratios) at 120 min were 7.8 and 7.7 for [18F]28 and [18F]40, respectively. The
selective uptake and retention in the hypothalamus, which has a high concentration of SERT binding sites,
demonstrated that [18F]28 and [18F]40 are promising positron emission computed tomography imaging agents
for mapping SERT binding sites in the brain.
Introduction
the antidepressant onset of action of SSRIs and that at least
30% of patients are nonresponders. It is believed that SSRIs
directly inhibit serotonin reuptake in the synapse, thus leading
to an increase in serotonin neurotransmission.12 Yet the lag time
and the percentage of nonresponders indicate that there is no
single mechanism that is responsible for depression. There are
many alternative explanations, and new treatment targets have
been suggested to overcome the lack of drug response.3,4,13–15
By estimation of the drug occupancy of SERT binding sites by
the antidepressant used for treatment, in vivo PET or SPECT
imaging studies could assist in the development of more
effective approaches to the treatment of depression.
The association between serotonin and depression has been
well documented. Patients with major depression show distinct
alterations in serotonergic neuronal function.1–3 Selective se-
rotonin reuptake inhibitors (SSRIs) targeting serotonin trans-
porter (SERTa) binding sites in the brain are currently being
prescribed to treat millions of patients with depression.2,4 There
is an urgent need to find a simple method to measure the drug
occupancy (or the lack thereof) of the target sites in the brains
of nonresponders. This could be accomplished by developing
PET and SPECT imaging agents to target SERT in the brain.
These imaging agents could be used to study the interaction of
psychoactive drugs with specific binding sites and therefore to
monitor their effectiveness in occupying the targeted binding
sites in the living human brain. SERT may also play an
important role as a surrogate marker for changes in serotonin
transmission in Parkinson’s disease, drug abuse, and other
mental illnesses. A simple method of imaging SERT would also
further our understanding of these conditions.
The ability to image SERT binding sites could significantly
improve the management of patients on SSRIs. First, PET
imaging techniques could provide a direct measurement of drug
occupancy at the target site. This would enable physicians to
reduce side effects by titrating SSRI dosage to reach >60–70%
occupancy.5–11 A minimum necessary dose could be individually
estimated; personalized medicine can be achieved. Second, it
has been observed that there is a lag time of 2-6 weeks before
There are several types of core structures that have been
employed in developing SERT imaging agents, i.e., nitroquipaz-
ines,16–19 (+)-McN5652,12,20,21 tropanes,22–26 and biphe-
nylthiols.27–36 Because of a higher serotonin transporter binding
selectivity and ease of synthesis, in the past few years a large
number of biphenylthiol derivatives have been prepared and
tested as potential SERT imaging agents.27–33 Several analogues
of biphenylthiol derivatives, such as [123I]ADAM (2), have
shown excellent binding affinity and selectivity and have been
successfully used for SPECT imaging in humans37 (see Chart
1). Comparable PET imaging agents for SERT, based on the
same biphenylthiol core, have also been reported (see Table
1). Wilson’s group developed [11C]DASB(1),27 which has now
become a standard tracer for PET imaging of SERT in
humans.8,10,38–40 Yet the practical challenges of using a 11C
tracer (T1/2 ) 20 min) on a routine basis have limited its
application to major medical centers that possess an on-site
* To whom correspondence should be addressed. Phone: (215) 662-3096.
Fax: (215) 349-5035. E-mail: kunghf@gmail.com.
cyclotron and a radiochemistry team. In contrast, 18F (T1/2
)
†
Department of Radiology.
Department of Pharmacology.
‡
109 min) labeled tracers can be prepared by regional radio-
pharmacies and distributed within any major metropolitan area.
Thus, 18F labeled SERT imaging agents could potentially serve
many more patients. In the past few years, several 18F derivatives
of biphenylthiols have been reported including AFM(4),41
ACF(5),36 and 5-FADAM(3)42,43 (Chart 1). The most promising
candidate is 5-FADAM (3). However, because of radiochemical
limitations, which require a nucleophilic substitution of [18F]flu-
oride on a less activated aromatic ring, the radiochemical yield
aAbbreviations: SPECT, single photon emission computed tomography;
PET, positron emission tomography; FDG, 2-fluoro-2-deoxy-D-glucose;
SERT, serotonin transporter; DAT, dopamine transporter; NET, norepi-
nephrine transporter; (+)-McN5652, (+)-trans-1,2,3,5,6,10-ꢀ-hexahydro-
6-[4-(methylthio)phenyl[pyrrolo[2,1-a]isoquinoline; DASB, 3-amino-4-(2-
dimethylaminomethylphenylsulfanyl)benzonitrile; ADAM, 5-iodo-2′-(2-
((dimethylamino)methyl)phenylthio)benzenamine; 5-FADAM, N,N-dimethyl-
2-(2-amino-4-[18F]fluorophenylthio)benzylamine; AFM, 2-[(2-amino-4-
fluoromethylphenyl)thio]-N,N-dimethylbenzenemethanamine; ACF, 2-[(2-
amino-4-chloro-5-fluorophenyl)thio]-N,N-dimethyl-benzenmethanamine.
10.1021/jm070685e CCC: $37.00
2007 American Chemical Society
Published on Web 12/04/2007

6674 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
Parhi et al.
Chart 1. Chemical Structures and Binding Affinities of
Serotonin Transporter Ligands (1–5)f
new series of biphenylthiols 28-42 were successfully prepared
using Schemes 1–3. The synthesis of fluorinated biphenylthiols
28–31 is illustrated in Scheme 1. Commercially available
2-amino-5-methoxybenzoic acid 6 was readily converted to the
corresponding thiol 7 via diazotization followed by replacement
of the diazonium group by a sulfur atom. The unstable thiol 7
(due to a rapid oxidation of the thiol group) was immediately
coupled with various nitrobenzenes 8–11 to give benzoic acids
12–15 in moderate to good yields (ranging from 55% to 77%
yield). The carboxylic acids were converted to the amides 16–19
by first treating with thionyl chloride to produce the acid
chlorides and the subsequent reaction of acid chlorides with
N,N-dimethylamine. The methoxy group of amides 16–19 were
readily demethylated with BBr3 to produce the corresponding
phenolic compounds 20–23. The free OH groups of phenolic
compounds 20–23 were alkylated with 1-bromo-2-fluoroethane
to provide 2-fluorethoxy compounds 24–27. The simultaneous
reduction of nitro and amide groups yielded the desired
nonradioactive compounds 28–31.
Similarly, three nonradioactive 3-fluorpropoxy compounds
40–42 were synthesized from intermediate phenolic compounds
20–23 (Scheme 2). Alkylation of the free 4′-OH group with
3-bromopropanol yielded compounds 32–34. The amide 34
was directly converted to the fluoride 39 by treatment with
DAST. Alternatively, the amides 32 and 33 were first
transformed into their corresponding mesylates 35 and 36 by
reacting with methanesulfonyl chloride. These mesylates were
further converted to the fluorides 37 and 38 by microwave
irradiation with TBAF. The simultaneous reduction of amide
and nitro groups furnished the desired 3-fluoropropoxy com-
pounds 40–42.
a Wilson et al.10,27 b Choi et al.35,37,47 c Shiue et al.42 d Huang et al.33
e Oya et al.36 f It is important to note that there are at least two different
nomenclatures for the same molecule 3. Depending on the method for
counting the positions on ring A, 5-FADAM (3) could also be named as
4-FADAM.42,43,46,54
Table 1. Binding Affinities of New Biphenylthiols for Monoamine
Transportersa
Ki (nM)
compd
R1
R2
SERT
NET
DAT
28
29
30
31
40
41
42
47
48
49
50
43
44
H
F
Cl
Br
H
F
Br
H
F
H
Br
H
H
O(CH2)2F
O(CH2)2F
O(CH2)2F
O(CH2)2F
O(CH2)3F
O(CH2)3F
O(CH2)3F
O(CH2)2OH
O(CH2)2OH
O(CH2)3OH
O(CH2)3OH
OCH3
0.25 ( 0.02
0.10 ( 0.01
0.03 ( 0.001
0.05 ( 0.01
1.4 ( 0.2
7.5 ( 0.7
37 ( 5
97 ( 3
114 ( 8
12 ( 2
95 ( 9
>1000
11 ( 1
56 ( 5
7 ( 0.2
279 ( 25
14 ( 1
33 ( 3
340 ( 64
>1000
847 ( 73
>1000
299 ( 9
>1000
>1000
351 ( 49
>1000
443 ( 68
>1000
Compounds 43 and 44 were obtained by reduction of both
amide and nitro groups of intermediate compounds 16 and 20
(Scheme 3). Similarly compounds 47 and 48 were synthesized
in two steps from 20 and 21 by alkylation with 2-bromoethanol
followed by reduction. Similarly, reduction of 32 and 34 yielded
the desired compounds 49 and 50. The purity of all nonradioac-
tive compounds used for the bioassay was confirmed from
HPLC analysis using two different systems. All bioassay
involved compounds reported in this paper showed greater than
95% purity in both systems (see Supporting Information).
We have also prepared the O-mesylate derivatives for 18F
radiolabeling. Methanesulfonate precursors 57–60 were prepared
as shown in Scheme 4. The phenolic compounds 20–23 were
alkylated with 2-bromoethanol to give compounds 45–46 and
51–52. Selective reduction of amide group by BH3-THF
followed by an introduction of methanesulfonyl group provided
the desired precursors 57–60. The synthesis of three more
methanesulfonate precursors 64–66 in two similar steps is shown
in Scheme 4.
0.95 ( 0.13
0.15 ( 0.02
1.1 ( 0.04
1.2 ( 0.1
1.3 ( 0.3
0.21 ( 0.02
5 ( 0.4
576 ( 31
659 ( 38
OH
17 ( 2
a In vitro binding assays (n ) 3) were employed to determine inhibition
constants (Ki ( SEM) with membrane preparations of three different groups
of LLC-PK1 cells, each expressing one specific monoamine transporter,
SERT, DAT, or NET.47
of [18F]3 is relatively low (<5%).44 In order to improve the
yield and study the structure–activity relationship of this series
of biphenylthiol derivatives, we evaluated 4′-(2-fluoroethoxy)
and 4′-(3-fluoropropoxy) derivatives with 4′-substitutions on
phenyl ring B. These compounds provide an alternative approach
for introduction of [18F]fluoride via a simple nucleophilic
reaction readily achievable in high yields and in a short time
period. The reaction could be performed in an automated
radiolabeling synthesizer that is commonly used in centralized
radiopharmacies for making [18F]FDG. In this paper, we report
A similar radiolabeling approach, as reported previously, was
used for 2-fluoroethoxy and 3-fluoropropoxy derivatives (Scheme
4). The radiolabeling was accomplished by starting with
mesylate precursors (57–60 or 64–66) reacting with [18F]fluoride
in the presence of Kryptofix 222 and potassium carbonate in
DMSO at 100 °C for 5–10 min. The resulting 18F labeled nitro
intermediates were directly reduced with tin chloride in hydro-
chloric acid/EtOH to provide desired labeled compounds
[18F]28–31 or [18F]40–42 (Scheme 4). The crude product was
purified by HPLC. The procedure took 60–120 min, and the
specific activity at the end of synthesis was 280–1050 mCi/
µmol (n ) 3) (radiochemical purity of >99%, radiochemical
yield of 10–35% decay-corrected). The purified product showed
the preparation and characterization of the first examples of 18
labeled 4′-substituted (ring B substituted) biphenylthiol deriva-
tives targeting SERT for PET imaging.
F
Chemistry
A wealth of information on the synthesis of biphenylthiols
(1–5) has been reported in the past few years.27,28,30–33,45,46 The

Biphenylthiols as SERT Imaging Agents
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6675
Scheme 1. Preparation of 2-Fluoroethoxy Derivativesa
a Reagents and conditions: (a) (1) NaNO2, (2) KS2COEt, (3) HCl; (b) Na/EtOH, (c) (1) SOCl2, (2) (CH3)2NH, CHCl3; (d) 1.0 M BBr3 in DCM, MW, 100
or –78 °C to room temp, 8 h; (e) 1-bromo-2-fluoroethane, DMF, K2CO3, MW; (f) BH3-THF, THF, 4–5 h.
Scheme 2. Preparation of 3-Fluoropropoxy Derivativesa
a Reagents and conditions: (a) 3-bromo-1-propanol, K2CO3, DMF, MW, 15 min; (b) MsCl, TEA, DCM, 1 h; (c) TBAF, THF, MW, 20 min; (d) BH3-THF,
THF, 4-5 h; (e) DAST, DCM, -78 °C to room temp, 1 h.
an HPLC profile consistent with the “cold” carrier (a typical
example of an HPLC profile is shown in Supporting Informa-
tion).
When the O-mesylates were used as the starting material,
the 18F labeling was successfully achieved for [18F]28–31 and
[18F]40–42 in reasonable radiochemical yield and high radio-
chemical purity. The labeling reactions have not been optimized
further; however, it is likely that the two-step one-pot reaction
can be adapted for automation in a higher level (in multi-Ci of
18F) of preparation.
fluoroethoxy or 4′-3-fluoropropoxy substituted derivatives to
SERT were excellent (Ki ) 0.03-0.95 nM) with a rank of
potency of Br g Cl > F (Table 1). Interestingly, an opposite
trend in NET affinity was seen. The binding affinities toward
NET decreased with the size of the halogen atom (F > Cl >
Br). The analogues that were substituted with heavier halogens
(Cl or Br), i.e., 30, 31, and 42, showed the weakest NET
affinities (Ki ) 97, 114, and >1000 nM, respectively). The 5-H
substituted analogues 28 and 40, compared to the 5-halogen
substituted analogues, displayed slightly lower SERT binding
affinities and showed some NET binding (Ki ) 0.25 and 1.4
nM for SERT and 7.5 and 12 nM for NET, respectively). This,
however, is not believed to be a significant impediment toward
their potential as SERT selective radiotracers because it is known
that the concentration of the NET binding sites (Bmax for NET)
is at least 4-fold less than that of SERT in the brain.48,49 Thus,
Biological Studies
In vitro binding assays were carried out using membrane
homogenates prepared from three different LLC-PK1 cell lines,
each overexpressing one of the monoamine transporters. As
expected, the binding affinities of the 5-halogen and 4′-2-

6676 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
Parhi et al.
Scheme 3. Preparation of 4′-Methoxy, 4′-Hydroxy, 4′-(2-Hydroxyethoxy), and 4′-(3-Hydroxypropoxy) Derivativesa
a Reagents and conditions: (a) BH3-THF, THF, 4–5 h; (b) 2-bromo-1-ethanol, K2CO3, DMF, MW, 150 °C, 15 min.
Scheme 4. Preparation of O-Mesylated Precursors and 18F Radiolabelinga
a Reagents and conditions: (a) 2-bromoethanol, K2CO3, DMF, MW; (b) BH3-THF, THF, 1.5 h; (c) methanesulfonyl chloride, TEA, DCM, 1–2 h; (d)
K[18F]F, K222, DMSO; (e) SnCl2.
the new 5-H substituted analogues 28 and 40 will likely be
sufficiently selective for imaging SERT binding sites and will
be further evaluated. It is also apparent that the addition of a
carbon atom to form the 4′-3-fluoropropoxy substituted deriva-
tives results in lower SERT and NET binding affinities compared
to the corresponding 4′-2-fluoroethoxy derivatives. Binding
affinities of these derivatives toward DAT compared to SERT
were much lower (Ki > 300 nM). The results were consistent
with the binding profiles reported for other 5-methyl or
5-halogen substituted biphenylthiol derivatives reported previ-
ously (ring A substituted derivatives).27,31–33,35,36,47 To our
knowledge, this is the first time such a structure–activity

Biphenylthiols as SERT Imaging Agents
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6677
Table 2. Biodistribution of [18F] Labeled SERT Tracers Evaluated in
Rats after an Intravenous Injection: Brain Uptake, Hypothalamus
Uptake, and Hypothalamus to Cerebellum Ratio
Regional brain distribution of [18F]28-31 and [18F]40-42
showed that the hypothalamus, an area containing a high density
of SERT binding sites, had the highest uptake (Table 2). The
hypothalamus to cerebellum ratios displayed a significant
increase from 30 to 120 min, and there was a more pronounced
change for the ring A 5-H substituted compounds [18F]28 and
40. [18F]28 displayed a hypothalamus to cerebellum ratio of
3.79 vs 7.83 at 30 vs 120 min, respectively, while [18F]40
showed a ratio of 3.5 vs 7.67 (Table 2). Although [18F]28 and
40 had lower hypothalamus uptake compared to [18F]29-31,
41, and 42, the hypothalamus to cerebellum ratios of [18F]28
and 40 were higher because of faster washout from the
cerebellum compared to washout from the hypothalamus.
Although [18F]28 and 40 possess slightly lower in vitro binding
affinities than the other compounds in their respective series, it
is not clear why [18F]28 or 40 is able to dissociate more quickly
from the nontarget region. It is known that in vitro experiments
cannot always predict the behavioral kinetics and success of a
tracer. Nevertheless, the favorable in vitro and in vivo kinetic
properties of [18F]28 and 40 make them more desirable
compared to other derivatives in the series as potential SERT
imaging agents. The absolute values of hypothalamus to
cerebellum ratios for [18F]28 and 40 were comparable to those
of [11C]127 and [18F]342 (hypothalamus uptake at 60 min was
0.62 and 0.73 % dose/g and hypothalamus to cerebellum ratio
at 60 min was 8.89 and 5.98, respectively). The absolute
hypothalamus uptake values in the brain were also comparable
to those of the above two tracers.27,42
In order to demonstrate that the uptake in the hypothalamus
region of the brain for this series of 18F labeled derivatives was
indeed due to SERT specific binding, we performed a blocking
study using several of the [18F] labeled compounds including
the most promising ligands, [18F]28 and [18F]40 (data not
shown). Rats were pretreated with 2 mg/kg IDAM, GBR-12909,
or 10 mg/kg nisoxetine iv 5 min prior to the tracer administra-
tion. At 2 h after the tracer injection, uptake in each brain region
was compared between saline-pretreated (control) and drug-
pretreated rats. Only IDAM, a selective SERT ligand, was able
to significantly block the uptake in the hypothalamus region,
an area containing a high density of SERT binding sites. As
expected, the other drugs, nisoxetine, a NET ligand, and GBR-
12909, a DAT ligand, showed no significant inhibition of
selective uptake in the hypothalamus region (data not shown).
The results will be published in the future as part of the full
characterization of these promising SERT imaging agents.
compd
30 min
120 min
Brain Uptake (% Dose/Organ)
28
29
30
31
40
41
42
1.85 ( 0.15
2.23 ( 0.22
1.72 ( 0.35
1.88 ( 0.18
1.23 ( 0.18
1.43 ( 0.06
1.12 ( 0.06
0.63 ( 0.15
2.57 ( 0.18
1.46 ( 0.16
2.16 ( 0.14
0.59 ( 0.10
1.32 ( 0.01
1.15 ( 0.10
Hypothalamus Uptake (% Dose/g)
28
29
30
31
40
41
42
1.62 ( 0.10
1.76 ( 0.16
1.31 ( 0.28
1.19 ( 0.10
1.22 ( 0.16
1.05 ( 0.12
0.85 ( 0.08
0.74 ( 0.18
2.22 ( 0.28
1.19 ( 0.11
1.78 ( 0.24
0.75 ( 0.18
1.09 ( 0.09
1.01 ( 0.21
Hypothalamus to Cerebellum Ratio
28
29
30
31
40
41
42
3.79 ( 0.30
2.78 ( 0.32
2.36 ( 0.68
2.04 ( 0.07
3.50 ( 0.67
2.66 ( 0.56
1.93 ( 0.82
7.83 ( 2.96
4.34 ( 0.60
3.77 ( 0.40
3.70 ( 0.58
7.67 ( 2.60
4.36 ( 0.45
4.17 ( 0.48
relationship has been observed for the biphenylthiol series of
compounds. It also suggests that relative binding affinities
between SERT and NET are highly dependent on the substitu-
tion groups on ring A and ring B. Further exploration of this
structure–activity relationship could enhance the selectivity
between SERT and NET.
To test whether these potential imaging agents could bind to
SERT binding sites in the brain, we measured brain uptake and
regional brain distribution of the [18F] labeled compounds in
rats after an iv injection. The whole-body biodistribution data,
an example of which can be seen in the Supporting Information,
were relatively similar to data of previously reported labeled
biphenylthiols, and the in vivo defluorination for these agents
was relatively low (based on the relatively low bone uptake).
The brain uptake between 30 and 120 min provides information
on the relative brain washout. Biodistribution of all the [18F]
labeled compounds, 28-31 and 40-42, in normal rats showed
that they readily penetrated the intact blood-brain barrier with
initial brain uptakes between 1.12 and 2.23 % dose/organ at 30
min after iv injection (Table 2). We were surprised at the high
brain uptake and persistent retention of [18F]29-31, 41, and
42 at 120 min after injection (Table 2). It is unlikely that this
relatively prolonged retention is caused by any single factor,
but rather it is most likely caused by a combination of factors
such as lipophilicity, affinity, molecular weight, metabolism,
and/or presence of a selective efflux mechanism for the tracer.
Ring A 5-halogen (F, Cl, and Br) substituted derivatives all
displayed high brain uptake but slow brain washout. In contrast,
ring A 5-H substituted compounds, [18F]28 and 40, displayed a
significant washout from the brain (1.85 vs 0.63 % dose/organ
for 28 and 1.23 vs 0.59 % dose/organ for 41 at 30 vs 120 min,
respectively). Such high brain uptake and washout have not been
observed in any other 18F labeled biphenylthiol derivatives
reported in the literature.28,30,33,36,42 Clearly, the 4′-2-fluoroet-
hoxy or 4′-3-fluoropropoxy substitution on phenyl ring B has
led to different in vivo brain kinetics.
Discussion
The biphenylthiol core has several unique advantages for
developing new SERT imaging agents. First, the biphenylthiol
core is relatively easy to prepare. It is also a relatively simple
molecule containing no optical center. Finally, biphenylthiol
derivatives show excellent binding affinities to SERT (in the
nanomolar or subnanomolar range), while their affinities to the
two other monoamine transporters, DAT and NET, are generally
lower. Up to this point, most of the reported structure–activity
studies of biphenylthiols have focused on the 4- or 5- position
of the 2-aminophenyl ring (ring A) (Chart 1). The effects of
adding substitution groups on phenyl ring B have not been fully
explored. We developed the 4′-2-fluoroethoxy or 4′-3-fluoro-
propoxy substituted derivatives in order to provide a simple site
for 18F labeling. We have demonstrated that the substitution
groups described in this paper successfully preserved SERT
binding affinity and the respective derivatives showed selective
SERT binding with favorable in vivo kinetics in the hypothala-

6678 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
Parhi et al.
mus of the rat brain. We were surprised to find that biodistri-
bution was greatly improved, resulting in better SERT local-
ization (higher target to nontarget, i.e., hypothalamus/cerebellum
ratios) and the opportunity to fine-tune the retention time in
the brain. The changes in the in vivo pharmacokinetics were
novel and unexpected. This is the first time that these types of
4′-2-fluoroethoxy or 4′-3-fluoropropoxy substituted biphenylthiol
derivatives have been prepared as PET imaging agents targeting
SERT binding sites.
analogues with similar substitutions would be good potential
candidates for studying serotonin transporters with in vivo PET
imaging.
Experimental Section
I. Chemistry. General Procedure A for the Preparation of
Thiodiarylbenzoic Acid. To a solution of 2-amino-5-methoxy-
benzoic acid (6) (2.5 g, 15 mmol) in 1.6 mL of 50% sodium
hydroxide, water (22 mL) and NaNO2 (1.03 g, 15 mmol) were
slowly added. The resulting mixture was poured into a mixture of
concentrated HCl (5 mL) and 7 g of ice with external cooling with
salt/ice. The mixture was stirred at 0 °C for 1 h and neutralized by
an addition of potassium acetate (∼1–2 g). The mixture was slowly
added with vigorous stirring to a solution of O-ethylxanthic acid,
potassium salt (7 g, 43.7 mmol) in 25 mL of water at 80 °C. The
temperature was maintained at 80 °C during the addition, and
stirring was continued until the evolution of N2 gas had subsided.
After cooling down to room temperature by external cooling by an
ice bath, the mixture was acidified by an addition of concentrated
HCl and extracted by dichloromethane (20 mL × 2) under argon
atmosphere. The organic layer was dried with sodium sulfate under
argon, and the solvent was removed in vacuo. The crude product,
2-mercapto-5-methoxybenzoic acid (7), was quickly dissolved in
20 mL of hot ethanol and added to a mixture of nitrobenene (8–11)
(16.5 mmol) and sodium ethoxide (0.76 g of sodium in 35 mL of
ethanol). The resulting solution was heated to reflux for 2 h. After
the mixture was cooled, the solvent was removed in vacuo and
water was added to the residue. The solution was acidified by an
addition of concentrated HCl and extracted with ethyl acetate. The
combined organic layers were washed with water and dried with
sodium sulfate. The solvent was removed in vacuo. The residue
was purified by silica gel column (ethylacetate/methanol 10%) to
give a yellow solid.
It is important to balance between the brain uptake and
washout out rates for SERT binding sites in the brain and
selectivity between SERT and NET binding sites. It appears
that the 5-H ring A substituted compounds, [18F]28 and 40,
showed the best kinetic properties. Even though these two 5-H
ring A substituted compounds, [18F]28 and 40, displayed
reasonable binding affinities to SERT, they displayed a lower
selectivity between SERT and NET (Ki ) 0.25 and 1.4 nM for
SERT and 7.5 and 12 nM for NET, respectively). We are
currently carrying out additional studies of the in vivo binding
selectivity by using PET imaging studies in rats. Initial data
suggest that the binding in the brain is reversible and the
hypothalamus uptake can be selectively displaced by a challenge
dose of IDAM during imaging studies of SERT binding sites
in the rat brain (data not shown).
Recently, we have reported two other novel ligands with a
4′-substitution (iodo or methoxy group) on the phenyl ring B
of biphenylthiol: 5-chloro-2-(2′-((dimethylamino)methyl)-4′-
iodophenylthio)benzenamine and 2-(2′-((dimethylamino) meth-
yl)-4′-methoxyphenylthio)-5-iodobenzenamine as potential se-
rotonin transporter (SERT) imaging agents.45 These new
iodinated ligands also displayed extremely high binding affinities
to SERT (Ki ) 0.22 ( 0.09 and 0.11 ( 0.04 nM, respectively),
with very low binding affinities to DAT and NET. They showed
good brain uptakes and prolonged retention after iv injection
in rats. Significantly, they also showed excellent uptake and
prolonged retention in the hypothalamus where the SERT
concentration is the highest. The hypothalamus/cerebellum ratios
for the latter 125I labeled agents were 3.97, 5.57, and 5.06 at 1,
2, and 4 h, respectively. Adding the 4′-iodo- group to phenyl
ring B appeared to reduce the rate of clearance from the brain,
and the kinetics favored uptake and retention in the hypothala-
mus. These observations are very consistent with what we have
observed for the 4′-2-fluoroethoxy and 4′-3-fluoropropoxy
derivatives reported in this paper. More recently, an abstract
was presented describing the synthesis and testing of [11C]5-
hydroxymethyl and 4′-bromo derivatives of the same core
structure as SERT imaging agent.50 The results also confirm
our observation that substitution at the 4′-position on the B ring
in general changes the in vivo kinetics of SERT binding in the
brain.
5-Methoxy-2-(2-nitrophenylthio)-benzoic acid (12) was pre-
pared from 8 as a yellow solid in 77% yield according to general
procedure A. 1H NMR (CD3OD) δ 8.16 (dd, J ) 8.0, 1.5 Hz, 1H),
7.53 (d, J ) 8.5 Hz, 1H), 7.45 (d, J ) 2.9 Hz, 1H), 7.43–7.37 (m,
1H), 7.32–7.24 (m, 1H), 7.17 (dd, J ) 8.5, 2.9 Hz, 1H), 6.90 (dd,
J ) 8.0, 1.4 Hz, 1H), 3.90 (s, 3H). HRMS calcd for C14H11NO5SNa
[M+ + Na] 328.0256, obsd 328.0253.
2-(4-Fluoro-2-nitrophenylthio)-5-methoxybenzoic acid (13),
as the crude material, was used for the amidation reaction.
2-(4-Chloro-2-nitrophenylthio)-5-methoxybenzoic acid (14)
was prepared from 10 as a yellow solid in 57% yield according to
1
general procedure A. H NMR (CD3OD) δ 8.17 (d, J ) 1.9 Hz,
1H), 7.57–7.50 (m, 2H), 7.31 (d, J ) 2.0 Hz, 1H), 7.11 (dd, J )
5.9, 2.7 Hz, 1H), 6.79 (d, J ) 8.7 Hz, 1H), 3.90 (s, 3H).
2-(4-Bromo-2-nitrophenylthio)-5-methoxybenzoic acid (15)
was prepared from 11 as a yellow solid in 55% yield according to
1
general procedure A. H NMR (CDCl3) δ 13.4 (s, 1H), 8.39 (s,
1H), 7.81 (d, J ) 8.8 Hz, 1H), 7.59 (d, J ) 8.6 Hz, 1H), 7.44 (d,
J ) 2 Hz, 1H), 7.26 (dd, J ) 8.6, J ) 2 Hz, 1H), 6.86 (d, J ) 8.8
Hz, 1H), 3.91 (s, 3H).
General Procedure B for the Preparation of Amides. A
solution of benzoic acid (12–15) (5.2 mmol) and thionyl chloride
(1.0 mL, 14 mmol) in chloroform (50 mL) was heated to reflux for
2 h. The solvent and excess thionyl chloride were removed in vacuo.
The residue was dissolved in chloroform (20 mL) and added to
the 2 M solution of dimethylamine in tetrahydrofuran (10 mL) at
0 °C. The mixture was stirred at room temperature for 3 h. The
solvent was removed, and the residue was dissolved in ethyl acetate
and washed with water and brine. The organic layer was passed
through a short pad of silica gel, eluting with ethyl acetate to give
the products as yellow oils.
5-Methoxy-2-(2-nitrophenylthio)-N,N-dimethylbenza-
mide (16) was prepared from 12 as a yellow oil in 71% yield
according to general procedure B. 1H NMR (CDCl3) δ 8.18 (dd, J
) 8.2, 1.5 Hz, 1H), 7.5 (d, J ) 8.5 Hz, 1H), 7.41–7.32 (m, 1H),
7.23–7.14 (m, 1H), 7.02–6.93 (m, 3H), 3.88 (s, 3H), 3.02 (s, 3H),
In conclusion, seven novel biphenylthiol derivatives,
[18F]28-31, 40-42, were prepared and tested as serotonin
transporter imaging agents for PET. These new ligands have a
4′-2-fluoroethoxy or 4′-3-fluoropropoxy substitution group on
phenyl ring B that maintains the binding affinity and selectivity.
These substitutions also dramatically changed the kinetics of
in vivo biodistribution and improved the hypothalamus uptake
and retention, a desirable property for a PET imaging agent.
These novel ligands, especially the 5-H ring A substituted
compounds, [18F]28 and 40, showed excellent kinetic properties.
Considering this, we are confident that these ligands and their

Biphenylthiols as SERT Imaging Agents
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6679
2.86 (s, 3H). HRMS calcd for C16H16N2NaO4S [M+ + Na]
355.0728, obsd 355.0738.
Hz, 1H), 7.40–7.32 (m, 1H), 7.20 (m, 1H), 7.04–6.93 (m, 3H), 4.77
(dt, J ) 47.4, 4.0 Hz, 2H), 4.28 (dt, J ) 27.5, 4.0 Hz, 2H), 3.03 (s,
3H), 2.86 (s, 3H). HRMS calcd for C17H18 FN2O4S [M+ + H]
365.0971, obsd 365.0982.
2-(4-Fluoro-2-nitrophenylthio)-5-methoxy-N,N-dimethylben-
zamide (17) was prepared from 13 as a yellow oil in 70% yield
according to general procedure B. 1H NMR (CDCl3) δ 7.90 (dd, J
) 8.5 Hz, 2.7 Hz, 1H), 7.49 (d, J ) 8.5 Hz, 1H), 7.17–7.08 (m,
1H), 7.07–6.90 (m, 3H), 3.88 (s, 3H), 3.03 (s, 3H), 2.86 (s, 3H).
HRMS calcd for C16H15FN2NaO4S [M++ Na] 373.0634, obsd
373.0625.
5-(2-Fluoroethoxy)-2-(4-fluoro-2-nitrophenylthio)-N,N-dim-
ethylbenzamide (25) was prepared from 21 as a yellow oil in 91%
yield according to general procedure D (eluting with ethyl acetate).
1H NMR (CDCl3) δ 7.90 (dd, J ) 8.5, 2.7 Hz, 1H), 7.51 (d, J )
8.5 Hz, 1H), 7.18–6.84 (m, 4H), 4.79 (dt, J ) 47.3, 4.0 Hz, 2H),
4.28 (dt, J ) 27.6, 4.0 Hz, 2H), 3.03 (s, 3H), 2.86 (s, 3H). HRMS
calcd for C17H17F2N2O4S [M+ + H] 383.0877, obsd 383.0858.
2-(4-Chloro-2-nitrophenylthio)-5-(2-fluoroethoxy)-N,N-dim-
ethylbenzamide (26) was prepared from 22 as a yellow oil in 96%
yield according to general procedure D (eluting with methanol/
2-(4-Chloro-2-nitrophenylthio)-5-methoxy-N,N-dimethylben-
zamide (18) was prepared from 14 as a yellow oil in 72% yield
1
according to general procedure B. H NMR (CDCl3) δ 8.17 (d, J
) 2.1 Hz, 1H), 7.49 (d, J ) 8.5 Hz, 1H), 7.32 (m, 1H), 7.03–6.86
(m, 3H), 3.88 (s, 3H), 3.03 (s, 3H), 2.86 (s, 3H). HRMS calcd for
C16H15ClN2NaO4S [M+ + Na] 389.0339, obsd 389.0359.
2-(4-Bromo-2-nitrophenylthio)-5-methoxy-N,N-dimethylben-
zamide (19) was prepared from 15 as a yellow oil in 68% yield
1
dichloromethane mixture). H NMR (CDCl3) δ 8.18 (d, J ) 2.3
Hz, 1H), 7.50 (d, J ) 8.5 Hz, 1H), 7.32 (dd, J ) 8.8, 2.3 Hz, 1H),
7.04 (dd, J ) 8.5, 2.8 Hz, 1H), 6.96 (d, J ) 2.7 Hz, 1H), 6.88 (d,
J ) 8.8 Hz, 1H), 4.79 (dt, J ) 47.5, 4.0 Hz, 2H), 4.29 (dt, J )
27.6, 4.0 Hz, 2H), 3.02 (s, 3H), 2.86 (s, 3H). HRMS calcd for
C17H17ClFN2O4S [M+ + H] 399.0582, obsd 399.0564.
1
according to general procedure B. H NMR (CDCl3) δ 8.31 (d, J
) 2.2 Hz, 1H), 7.39–7.50 (m, 2H), 6.92–7.02 (m, 2H), 6.80 (d, J
) 8.8 Hz, 1H), 3.87 (s, 3H), 3.02 (s, 3H), 2.85 (s, 3H).
General Procedure C for the Deprotection of Methoxy
Group. To a solution of 16–19 (0.78 mmol) in dichloromethane
(3.0 mL) was added 1.0 M solution of BBr3 in dichloromethane
(1.1 mL). The mixture was irradiated with microwaves at 100 °C
for 20 min and washed with water (2 mL). The organic layer was
dried (Na2SO4) and purified by silica gel column, eluting with either
ethyl acetate or methanol/dichloromethane (1/19) to yield a yellow
oil. Alternatively, a solution of amide was added to a 1.0 M solution
of BBr3 in dichloromethane at - 78 °C. The temperature was raised
slowly to room temperature, and the mixture was stirred overnight.
The workup described earlier gave the product as a yellow oil.
5-Hydroxy-2-(2-nitrophenylthio)-N,N-dimethylbanza-
mide (20) was prepared from 16 as a yellow oil in 85% yield
2-(4-Bromo-2-nitrophenylthio)-5-(2-fluoroethoxy)-N,N-dim-
ethylbenzamide (27) was prepared from 23 as a yellow oil in 89%
yield according to general procedure D (eluting with methanol/
1
dichloromethane mixture). H NMR (CDCl3) δ 8.32 (d, J ) 2.1
Hz, 1H), 7.50 (d, J ) 8.6 Hz, 1H), 7.44 (dd, J ) 8.6, 2.1 Hz, 1H),
7.03 (dd, J ) 8.4, 2.6 Hz, 1H), 6.95 (d, J ) 2.6 Hz, 1H), 6.80 (d,
J ) 8.6 Hz, 1H), 4.79 (dt J ) 47.4, 4.05 Hz, 2H), 4.30 (dt J )
27.6, 4.0 Hz, 2H), 3.02 (s, 3H), 2.85 (s, 3H).
General Procedure E for Simultaneous Reduction of Nitro
and Amide Groups. To a solution of 24–27, 37–39, and other
starting materials having both nitro and amide groups (0.1 mmol)
in THF at 0 °C, 1.0 M BH3-THF (10–15 equiv) was added. The
mixture was heated to reflux for 4.5–5 h. After the mixture was
cooled, 0.5 mL of concentrated HCl was cautiously added and
the solvent was removed in vacuo. Water (5 mL) was added to the
residue, and the mixture was heated to reflux for 30 min. To the
mixture 1 N NaOH was added to adjust the pH to basic (pH 10–11),
and it was extracted with ethyl acetate (5 mL × 2). The organic
layer was dried (Na2SO4) and purified by silica gel column (2%
methanol in dichloromethane to 5% methanol in dichloromethane).
2-(2-((Dimethylamino)methyl)-4-(2-fluoroethoxy)phenylthio)-
benzenamine (28) was prepared from 24 as a colorless oil in 63%
1
according to general procedure C (eluting with ethyl acetate). H
NMR (CDCl3) δ 9.01 (s, 1H), 8.19 (dd, J ) 8.2, 1.5 Hz, 1H),
7.48–7.36 (m, 2H), 7.22–7.18 (m, 1H), 6.96–6.91 (m, 2H), 6.85
(dd, J ) 8.4, 2.7 Hz, 1H), 3.06 (s, 3H), 2.90 (s, 3H). HRMS calcd
for C15H15N2O4S [M+ + H] 319.0753, obsd 319.0761.
2-(4-Fluoro-2-nitrophenylthio)-5-hydroxy-N,N-dimethylbanza-
mide (21) was prepared from 17 as a yellow oil in 83% yield
according to general procedure C (eluting with methanol/dichlo-
1
romethane mixture). H NMR (CD3OD) δ 7.97 (dd, J ) 8.5, 2.7
1
Hz, 1H), 7.51 (d, J ) 8.5 Hz, 1H), 7.35–7.26 (m, 1H), 7.06–6.97
(m, 2H), 6.84 (d, J ) 2.6 Hz, 1H), 3.00 (s, 3H), 2.85 (s, 3H). HRMS
calcd for C15H14FN2O4S [M+ + H] 337.0658, obsd 337.0663.
2-(4-Chloro-2-nitrophenylthio)-5-hydroxy-N,N-dimethylbanza-
mide (22) was prepared from 18 as a yellow oil in 80% yield
according to general procedure C (eluting with methanol/dichlo-
yield according to general procedure E. H NMR (CDCl3) δ 7.38
(dd, J ) 7.7, 1.5 Hz, 1H), 7.19–7.11 (m, 1H), 6.96–6.92 (m, 2H),
6.72–6.66 (m, 3H), 4.71 (dt, J ) 47.4, 4.0 Hz, 2H), 4.51 (brs, 2H),
4.17 (dt, J ) 27.8, 4.0 Hz, 2H), 3.57 (s, 2H), 2.30 (s, 6H). HRMS
calcd for C17H22FN2OS [M+ + H] 321.1437, obsd 321.1442. HPLC
>98%.
1
romethane mixture). H NMR (CD3OD) δ 8.21 (d, J ) 2.3 Hz,
2-(2-((Dimethylamino)methyl)-4-(2-fluoroethoxy)phenylthio)-
5-fluoro-benzenamine (29) was prepared from 25 as a colorless
oil in 62% yield according to general procedure E. 1H NMR
(CDCl3) δ 7.45–7.38 (m, 1H), 6.91 (d, J ) 8.6 Hz, 1H), 6.86 (d,
J ) 2.6 Hz, 1H), 6.69 (dd, J ) 8.6, 2.8 Hz, 1H), 6.45–6.36 (m,
2H), 4.85 (brs, 2H), 4.71 (dt, J ) 47.2, 4.1 Hz, 2H), 4.16 (dt, J )
27.7, 4.0 Hz, 2H), 3.53 (s, 2H), 2.30 (s, 6H). HRMS calcd for
C17H21F2N2OS [M+ + H] 339.1343, obsd 339.1342. HPLC >98%.
5-Chloro-2-(2-((dimethylamino)methyl)-4-(2-fluoroethoxy)phe-
nylthio)benzenamine (30) was prepared from 26 as a colorless
oil in 52% yield according to general procedure E. 1H NMR
(CDCl3) δ 7.33 (d, J ) 8.8 Hz, 1H), 6.95 (d, J ) 8.8 Hz, 1H),
6.87(d, J ) 2.8 Hz), 6.73–6.62 (m, 3H), 4.72 (dt, J ) 47.3, 4.1
Hz, 2H), 4.16 (dt, J ) 27.8, 4.0 Hz, 2H), 3.52 (s, 2H), 2.29 (s,
6H). HRMS calcd for C17H21ClFN2OS [M+ + H] 355.1047, obsd
355.1054. HPLC >96%.
5-Bromo-2-(2-((dimethylamino)methyl)-4-(2-fluoroethoxy)phe-
nylthio)benzenamine (31) was prepared from 27 as a colorless
oil in 51% yield according to general procedure E. 1H NMR
(CDCl3) δ 7.23 (d, J ) 8.0 Hz, 1H), 6.65–6.97 (m, 5H), 4.74 (br
s, 2H), 4.73 (dt J ) 47.2, 4.0 Hz, 2H), 4.14 (dt J ) 27.8, 4.0 Hz,
2H), 3.53 (s, 2H), 2.33 (s, 6H). HRMS calcd for C17H20BrFN2OS
[M+] 398.0464, obsd 398.0457. HPLC >98%.
1H), 7.53–7.45 (m, 2H), 7.03–6.94 (m, 2H), 6.85 (d, J ) 2.6 Hz,
1H), 3.00 (s, 3H), 2.86 (s, 3H).
2-(4-Bromo-2-nitrophenylthio)-5-hydroxy-N,N-dimethylben-
zamide (23) was prepared from 19 as a yellow oil in 93% yield
according to general procedure C (eluting with methanol/dichlo-
1
romethane mixture). H NMR (CDCl3/CD3OD 10%) δ 8.23 (d, J
) 2.2 Hz, 1H), 7.38 (dd, J ) 8.4, 2.2 Hz, 1H), 7.28 (d, J ) 8.4
Hz, 1H), 6.83 (dd, J ) 8.4, 2.6 Hz 1H), 6.70–6.75 (m, 2H), 2.91
(s, 3H), 2.77 (s, 3H).
General Procedure D for the Alkylation with 1-Bromo-2-
fluoroethane. To a solution of 20–23 (0.126 mmol) and 1-bromo-
2-fluoroethane (25 mg, 0.197 mmol) in DMF (2 mL) was added
potassium carbonate (400 mg, 2.9 mmol). The mixture was
irradiated with microwaves at 150 °C for 15 min and added to water
(10 mL) and extracted with ethyl acetate (5 mL × 2). The combined
organic layers were dried (Na2SO4) and purified by silica gel column
(ethyl acetate or methanol/dichloromethane, 1/19) to yield yellow
oil.
5-(2-Fluoroethoxy)-2-(2-nitrophenylthio)-N,N-dimethylbenza-
mide (24) was prepared from 20 as a yellow oil in 95% yield
1
according to general procedure D (eluting with ethyl acetate). H
NMR (CDCl3) δ 8.18 (dd, J ) 8.2, 1.5 Hz, 1H), 7.51 (d, J ) 8.5

6680 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
Parhi et al.
2-(2-((Dimethylamino)methyl)-4-(3-fluoropropoxy)phenylthio)-
heated at 100 °C overnight and added to water (50 mL) and
extracted with ethyl acetate (20 mL × 2). The organic layer was
dried (Na2SO4) and purified by silica gel column (ethyl acetate) to
yield a yellow oil. Alternatively, the above mixture irradiated with
microwaves at 150 °C for 15 min followed by the workup described
earlier gave the desired product.
benzenamine (40) was prepared from 37 as a colorless oil in 54%
1
yield according to general procedure E. H NMR (CDCl3) δ 7.38
(dd, J ) 8.0, 1.7 Hz, 1H), 7.19–7.10 (m, 1H), 6.94 (d, J ) 8.6 Hz,
1H), 6.88 (d, J ) 2.7 Hz, 1H), 6.72 (m, 1H), 6.69–6.63 (m, 2H),
4.62 (dt, J ) 47.0, 5.8 Hz, 2H), 4.50 (brs, 2H), 4.05 (t, J ) 6.1 Hz,
2H), 3.54 (s, 2H), 2.30 (s, 6H), 2.13 (dt, J ) 26.0, 5.9 Hz, 2H).
HRMS calcd for C18H24FN2OS [M+ + H] 335.1593, obsd
335.1590. HPLC >99%.
5-(3-Hydroxypropoxy)-2-(2-nitrophenylthio)-N,N-dimethyl-
benzamide (32) was prepared from 20 as a yellow oil in 87% yield
according to general procedure F. 1H NMR (CDCl3) δ 8.18 (dd, J
) 8.2, 1.5 Hz, 1H), 7.49 (d, J ) 8.5 Hz, 1H), 7.40–7.32 (m, 1H),
7.23–7.15 (m, 1H), 7.03–6.93 (m, 3H), 4.19 (t, J ) 6.0 Hz, 2H),
3.88 (m, 2H), 3.02 (s, 3H), 2.86 (s, 3H), 2.08 (m, 2H). HRMS
calcd for C18H21N2O5S [M+ + H] 377.1171, obsd 377.1156.
2-(4-Fluoro-2-nitrophenylthio)-5-(3-hydroxypropoxy)-N,N-
dimethylbenzamide (33) was prepared from 21 as a yellow oil in
2-(2-((Dimethylamino)methyl)-4-(3-fluoropropoxy)phenylthio)-
5-fluorobenzenamine (41) was prepared from 38 as a colorless
oil in 57% yield according to general procedure E. 1H NMR
(CDCl3) δ 7.45–7.37 (m, 1H), 6.91 (d, J ) 8.6 Hz, 1H), 6.82 (d,
J ) 2.7 Hz, 1H), 6.67 (dd, J ) 8.6, 2.7 Hz, 1H), 6.45–6.35 (m,
2H), 4.83 (brs, 2H), 4.62 (dt, J ) 47.0, 5.8 Hz, 2H), 4.04 (t, J )
6.1 Hz, 2H), 3.53 (s, 2H), 2.30 (s, 6H), 2.13 (dt, J ) 26.0, 6.0 Hz,
2H). HRMS calcd for C18H23F2N2OS [M+ + H] 353.1499, obsd
353.1494. HPLC >98%.
1
85% yield according to general procedure F. H NMR (CDCl3) δ
7.90 (dd, J ) 8.4, 2.7 Hz, 1H), 7.49 (d, J ) 8.5 Hz, 1H), 7.13–7.08
(m, 1H), 7.03–6.90 (m, 3H), 4.18 (t, J ) 6.0 Hz, 2H), 3.87 (m,
2H), 3.02 (s, 3H), 2.86 (s, 3H), 2.07 (m, 2H). HRMS calcd for
C18H20FN2O5S [M+ + H] 395.1077, obsd 395.1051.
5-Bromo-2-(2-((dimethylamino)methyl)-4-(3-fluoropropoxy)phe-
nylthio)benzenamine (42) was prepared from 39 as a colorless
oil in 39% yield according to general procedure E. 1H NMR
(CDCl3/CD3OD) δ 7.34 (d, J ) 2.2 Hz, 1H), 7.08 (d, J ) 8.6 Hz,
1H), 6.90–6.79 (m, 3H) 6.72 (dd, J ) 8.6, 1.4 Hz, 1H), 4.55 (dt,
J ) 44, 5.8 Hz 2H), 4.35 (s, 2H), 4,09 (t, J ) 6.1 Hz, 2H), 2.79 (s,
2-(4-Bromo-2-nitrophenylthio)-5-(3-hydroxypropoxy)-N,N-
dimethylbenzamide (34) was prepared from 23 as a yellow oil in
1
70% yield according to general procedure F. H NMR (CDCl3) δ
8.31 (d, J ) 2.2 Hz, 1H), 7.49–7.42 (m, 2H), 7.01–6.93 (m, 2H),
6.80 (d, J ) 8.4 Hz, 1H), 4.21 (t, J ) 5.6 Hz, 2H), 3.87 (dd, J )
5.8, 5.6 Hz, 2H), 3.01 (s, 3H), 2.85 (s, 3H).
6H), 2.19–2.00 (m, 2H). HRMS calcd for C18H23BrFN2OS [M+
H] 413.0698, obsd 413.0705. HPLC >95%.
+
2-(2-((Dimethylamino)methyl)-4-(methoxy)phenylthio)benze-
namine (43) was prepared from 16 as a colorless oil in 61% yield
according to general procedure E. 1H NMR (CDCl3) δ 7.38 (dd, J
) 8.0, 1.7 Hz, 1H), 7.19–7.10 (m, 1H), 6.95 (d, J ) 8.5 Hz, 1H),
6.87 (d, J ) 2.7 Hz, 1H), 6.72–6.64 (m, 3H), 4.53 (brs, 2H), 3.76
(s, 3H), 3.55 (s, 2H), 2.30 (s, 6H). HRMS calcd for C16H21N2OS
[M+ + H] 289.1375, obsd 289.1376. HPLC >98%.
5-(2-Hydroxyethoxy)-2-(2-nitrophenylthio)-N,N-dimethylben-
zamide (45) was prepared from 20 as a yellow oil in 94% yield
according to general procedure F. 1H NMR (CDCl3) δ 8.18 (dd, J
) 8.2, 1.4 Hz, 1H), 7.50 (d, J ) 8.5 Hz, 1H), 7.40–7.32 (m, 1H),
7.19–7.15 (m, 1H), 7.01 (dd, J ) 8.5, 2.8 Hz, 1H), 6.96–6.92 (m,
2H), 4.17–4.10 (m, 2H), 4.03–3.93 (m, 2H), 3.02 (s, 3H), 2.86 (s,
3H). HRMS calcd for C15H19N2O5S [M+ + H] 363.1015, obsd
363.1045.
4-(2-Aminophenylthio)-3-((dimethylamino)methyl)phenol (44)
was prepared from 20 as a colorless oil in 57% yield according to
2-(4-Fluoro-2-nitrophenylthio)-5-(2-hydroxyethoxy)-N,N-dim-
1
general procedure E. H NMR (CDCl3) δ 7.32 (dd, J ) 8.0, 1.6
ethylbenzamide (46) was prepared from 21 as a yellow oil in 93%
1
Hz, 1H), 7.18–7.10 (m, 1H), 6.89 (d, J ) 8.5 Hz, 1H), 6.81 (d, J
) 2.7 Hz, 1H), 6.71 (d, J ) 7.6 Hz, 2H), 6.58 (dd, J ) 8.5, 2.8
Hz, 1H), 4.29 (brs, 2H), 3.58 (s, 2H), 2.32 (s, 6H). HRMS calcd
for C15H19N2OS [M+ + H] 275.1218, obsd 275.1211. HPLC >97%.
2-(4-(2-Aminophenylthio)-3-((dimethylamino)methyl)phenoxy)-
ethanol (47) was prepared from 45 as a colorless oil in 50% yield
according to general procedure E. 1H NMR (CDCl3) δ 7.39 (dd, J
) 8.0, 1.6 Hz, 1H), 7.19–7.11 (m, 1H), 6.96–6.90 (m, 2H),
6.73–6.65 (m, 3H), 4.51 (brs, 2H), 4.06–4.01 (m, 2H), 3.94–3.90
(m, 2H), 3.54 (s, 2H), 2.30 (s, 6H). HRMS calcd for C17H23N2O2S
[M+ + H] 319.1480, obsd 319.1479. HPLC >97%.
yield according to general procedure F. H NMR (CDCl3) δ 7.90
(dd, J ) 8.2, 2.6 Hz, 1H), 7.50 (d, J ) 8.5 Hz, 1H), 7.18–7.08 (m,
1H), 7.05–6.90 (m, 3H), 4.15 (m, 2H), 4.01 (m, 2H), 3.03 (s, 3H),
2.88 (s, 3H). HRMS calcd for C17H18FN2O5S [M+ + H] 381.0920,
obsd 381.0912.
2-(4-Chloro-2-nitrophenylthio)-5-(2-hydroxyethoxy)-N,N-dim-
ethylbenzamide (51) was prepared from 22 as a yellow oil in 89%
1
yield according to general procedure F. H NMR (CDCl3) δ 8.17
(d, J ) 2.1 Hz, 1H), 7.50 (d, J ) 8.5 Hz, 1H), 7.31 (dd, J ) 8.5,
2.2 Hz, 1H), 7.03 (dd, J ) 8.5, 2.7 Hz, 1H), 6.95 (d, J ) 2.4 Hz,
1H), 6.88 (d, J ) 8.8 Hz, 1H), 4.17–4.13 (m, 2H), 4.01–3.99 (m,
2H), 3.02 (s, 3H), 2.86 (s, 3H).
2-(4-(2-Amino-4-fluoro-phenylthio)-3-((dimethylamino)meth-
yl)phenoxy)ethanol (48) was prepared from 46 as a colorless oil
in 47% yield according to general procedure E. 1H NMR (CDCl3)
δ 7.45–7.37 (m, 1H), 6.94–6.87 (m, 2H), 6.69 (dd, J ) 8.5, 2.7
Hz, 1H), 6.44–6.36 (m, 2H), 4.81 (brs, 2H), 4.04 (m, 2H), 3.93
(m, 2H), 3.54 (s, 2H), 2.30 (s, 6H). HRMS calcd for C17H22F2N2O2S
[M+ + H] 337.1386, obsd 337.1401. HPLC >95%.
2-(4-Bromo-2-nitrophenylthio)-5-(2-hydroxyethoxy)-N,N-dim-
ethylbenzamide (52) was prepared from 23 as a yellow oil in 76%
1
yield according to general procedure F. H NMR (CDCl3) δ 8.31
(d, J ) 2.2 Hz, 1H), 7.49 (d, J ) 8.7 Hz, 1H), 7.65 (dd, J ) 8.7,
2.2 Hz, 1H), 7.02 (dd, J ) 8.7, 2.8 Hz, 1H), 6.95 (d, J ) 2.8 Hz,
1H), 8.81 (d, J ) 8.7 Hz, 1H), 4.15 (m, 2H), 3.99 (m, 2H), 3.02 (s,
3H), 2.85 (s, 3H).
3-(4-(2-Aminophenylthio)-3-((dimethylamino)methyl)phenoxy)-
1-propanol (49) was prepared from 32 as a colorless oil in 49%
General Procedure G for Selective Reduction of Amide
Group. To a solution of amides 45–52 and 32–34 (0.18 mmol) in
THF (10 mL) at 0 °C, 1.0 M BH3-THF (5 equiv) was added. The
mixture was heated to reflux for 1.5–2 h. To the mixture, 0.5 mL
of concentrated HCl was cautiously added. The solvent was
removed in vacuo. Water (5 mL) was added to the residue, and the
mixture was heated to reflux for 30 min. To the mixture, 1 N NaOH
was added to adjust the pH to basic (pH 10) and extracted with
ethyl acetate (5 mL × 2). The organic layer was dried (Na2SO4)
and purified by silica gel column (2% methanol in dichloromethane
to 5% methanol in dichloromethane) to provide the product as a
yellow oil.
1
yield according to general procedure E. H NMR (CDCl3) δ 7.37
(dd, J ) 8.0, 1.6 Hz, 1H), 7.19–7.11 (m, 1H), 6.96–6.89 (m, 2H),
6.72–6.60 (m, 3H), 4.52 (brs, 2H), 4.08 (t, J ) 5.9 Hz, 2H), 3.84
(t, J ) 5.9 Hz, 2H), 3.56 (s, 2H), 2.30 (s, 6H), 2.01 (quintet, J )
5.9 Hz, 2H). HPLC >96%.
3-(4-(2-Amino-4-bromophenylthio)-3-((dimethylamino)meth-
yl)phenoxy)propan-1-ol (50) was prepared from 34 as a colorless
oil in 70% yield according to general procedure E. 1H NMR
(CDCl3/CD3OD) δ 7.23 (m, 1H), 6.95 (d, J ) 8.6 Hz, 1H),
6.87–6.66 (m, 4H) 4.8 (br s, 2H), 4.08 (t, J ) 6.0 Hz, 2H), 3.84 (t,
J ) 6.0 Hz, 2H), 3.54 (s, 2H), 2.30 (s, 6H), 2.07–1.95 (m, 2H).
General Procedure F for Alkylation with Bromoethanol
and Bromopropanol. To a solution of 20–23 (0.239 mmol) and
2-bromoethananol or 3-bromopropanol (0.32 mmol) in DMF (10
mL) was added potassiun carbonate (80 mg). The mixture was
2-(3-(Dimethylamino)methyl)-4-(2-nitrophenylthio)phenoxy)-
ethanol (53) was prepared from 45 as a pale-yellow oil in 70%
1
yield according to general procedure G. H NMR (CDCl3) δ 8.25
(dd, J ) 8.0, 1.6 Hz, 1H), 7.49 (d, J ) 8.5 Hz, 1H), 7.34–7.30 (m,

Biphenylthiols as SERT Imaging Agents
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6681
2H), 7.22- 7.14 (m, 1H), 6.90 (dd, J ) 8.5, 2.8 Hz, 1H), 6.66 (dd,
J ) 8.0, 1.4 Hz, 1H), 4.18 (t, J ) 4.0 Hz, 2H), 4.00 (t, J ) 4.0 Hz,
2H), 3.50 (s, 2H), 2.19 (s, 6H). HRMS calcd for C17H21N2O4S [M+
+ H] 349.1222, obsd 349.1215.
2-(3-((Dimethylamino)methyl)-4-(4-fluoro-2-nitrophenylth-
io)phenoxy)ethanol (54) was prepared from 46 as a pale-yellow
oil in 69% yield according to general procedure G. 1H NMR
(CDCl3) δ 7.97 (dd, J ) 8.5, 2.7 Hz, 1H), 7.48 (d, J ) 8.5 Hz,
1H), 7.29 (d, J ) 2.7 Hz, 1H), 7.11–7.02 (m, 1H), 6.91 (dd, J )
8.5, 2.7 Hz, 1H), 6.64 (m, 1H), 4.18 (t, J ) 4.0 Hz, 2H), 4.00 (t,
J ) 4.0 Hz, 2H), 3.48 (s, 2H), 2.18 (s, 6H). HRMS calcd for
C17H20FN2O4S [M+ + H] 367.1128, obsd 367.1121.
2-(4-(4-Chloro-2-nitrophenylthio)-3-((dimethylamino)meth-
yl)phenoxy)ethanol (55) was prepared from 51 as a pale-yellow
oil in 66% yield according to general procedure G. 1H NMR
(CDCl3) δ 8.24 (d, J ) 2.3 Hz, 1H), 7.47 (d, J ) 8.5 Hz, 1H),
7.29 (d, J ) 2.3 Hz, 1H), 7.23 (d, J ) 2.3 Hz, 1H), 6.91 (dd, J )
8.5, 2.8 Hz, 1H), 6.59 (d, J ) 8.8 Hz, 1H), 4.17 (m, 2H), 4.00 (m,
2H), 3.47 (s, 3H), 2.18 (s, 3H). HRMS calcd for C17H20ClN2O4S
[M+ + H] 383.0832, obsd 383.0817.
1H), 7.18–7.09 (m, 1H), 7.01–6.90 (s, 3H), 4.47 (t, J ) 6.0 Hz,
2H), 4.16 (t, J ) 5.8 Hz, 2H), 3.03 (s, 3H), 3.02 (s, 3H), 2.86 (s,
3H), 2.27 (quintet, J ) 6.0 Hz, 2H).
2-(3-((Dimethylamino)methyl)-4-(2-nitrophenylthio)phenoxy)-
ethyl methanesulfonate (57) was prepared from 53 as a yellow
oil in 94% yield according to general procedure H. 1H NMR
(CDCl3) δ 8.25 (dd, J ) 8.0, 1.5 Hz, 1H), 7.50 (d, J ) 8.5 Hz,
1H), 7.35–7.27 (m, 2H), 7.22–7.17 (m, 1H), 6.89 (dd, J ) 8.5, 2.9
Hz, 1H), 6.65 (dd, J ) 8.0, 1.3 Hz, 1H), 4.63–4.59 (m, 2H),
4.36–4.31 (m, 2H), 3.50 (s, 2H), 3.12 (s, 3H), 2.19 (s, 6H).
2-(3-((Dimethylamino)methyl)-4-(4-fluoro-2-nitrophenylth-
io)phenoxy)ethyl methanesulfonate (58) was prepared from 54
as a yellow oil in 93% yield according to general procedure H. 1H
NMR (CDCl3) δ 7.97 (dd, J ) 8.5, 2.7 Hz, 1H), 7.48 (d, J ) 8.5
Hz, 1H), 7.29 (d, J ) 2.7 Hz, 1H), 7.13–7.03 (m, 1H), 6.89 (dd, J
) 8.5, 2.7 Hz, 1H), 6.61 (dd, J ) 9.0 Hz, 5.2 Hz, 1H), 4.60 (t, J
) 4.0 Hz, 2H), 4.33 (t, J ) 4.0 Hz, 2H), 3.47 (s, 2H), 3.12 (s, 3H),
2.17 (s, 6H). HRMS calcd for C18H22FN2O6S2 [M+ + H] 445.0903,
obsd 445.0920.
2-(4-(4-Chloro-2-nitrophenylthio)-3-((dimethylamino)meth-
yl)phenoxy)ethyl methanesulfonate (59) was prepared from 55
as a yellow oil in 93% yield according to general procedure H. 1H
NMR (CDCl3) δ 8.24 (d, J ) 2.2 Hz, 1H), 7.48 (d, J ) 8.5 Hz,
1H), 7.29 (d, J ) 2.3 Hz, 1H), 7.23 (d, J ) 2.3 Hz, 1H), 6.89 (dd,
J ) 8.5, 2.6 Hz, 1H), 6.58 (d, J ) 8.7 Hz, 1H), 4.61 (m, 2H), 4.33
(m, 2H), 3.47 (s, 2H), 3.12 (s, 3H), 2.18 (s, 6H). HRMS calcd for
C18H22ClN2O6S2 [M+ + H] 461.0608, obsd 461.0641.
2-(4-(4-Bromo-2-nitrophenylthio)-3-((dimethylamino)meth-
yl)phenoxy))ethyl methanesulfonate (60) was prepared from 56
as a yellow oil in 70% yield according to general procedure H. 1H
NMR (CDCl3) δ 8.38 (d, J ) 2.2 Hz, 1H), 7.48 (d, J ) 8.5 Hz,
1H), 7.38 (dd, J ) 8.5, 2.2 Hz, 1H), 7.29 (d, J ) 2.8 Hz, 1H), 6.89
(dd, J ) 8.6, 2.8 Hz, 1H), 6.51 (d, J ) 8.6 Hz, 1H), 4.60 (t, J )
4.5 Hz, 2H), 4.35 (t, J ) 4.5 Hz, 2H), 3.48 (s, 2H), 3.11 (s, 3H),
2.18 (s, 6H).
3-(3-((Dimethylamino)methyl)-4-(2-nitrophenylthio)phenoxy)
propyl methanesulfonate (64) was prepared from 61 as a yellow
oil in 90% yield according to general procedure H. 1H NMR
(CDCl3) δ 8.25 (dd, J ) 8.0, 1.5 Hz, 1H), 7.48 (d, J ) 8.5 Hz,
1H), 7.35–7.14 (m, 3H), 6.88 (dd, J ) 8.5, 2.8 Hz, 1H), 6.66 (dd,
J ) 8.0, 1.1 Hz, 1H), 4.48 (t, J ) 6.1 Hz, 2H), 4.18 (t, J ) 5.8 Hz,
2H), 3.49 (s, 2H), 3.03 (s, 3H), 2.27 (quintet, J ) 6.0 Hz, 2H),
2.19 (s, 6H).
2-(4-(4-Bromo-2-nitrophenylthio)-3-((dimethylamino)meth-
yl)phenoxy)ethanol (56) was prepared from 52 as a pale-yellow
oil in 71% yield according to general procedure G. 1H NMR
(CDCl3) δ 8.38 (d, J ) 2.2 Hz, 1H), 7.60 (d, J ) 8.6 Hz, 1H),
7.38 (dd, J ) 8.6, 2.2 Hz, 1H), 7.29 (d, J ) 2.8 Hz, 1H), 6.91 (dd,
J ) 8.8, 2.8 Hz, 1H), 6.52 (d, J ) 8.8 Hz, 1H), 4.17 (t, J ) 4.3
Hz, 2H), 4.00 (t, J ) 4.3 Hz, 2H), 3.47 (s, 2H), 2.23 (s, 6H).
3-(3-(Dimethylamino)methyl)-4-(2-nitrophenylthio)phenox-
y)propanol (61) was prepared from 32 as a pale-yellow oil in 61%
1
yield according to general procedure G. H NMR (CDCl3) δ 8.25
(dd, J ) 8.0, 1.5 Hz, 1H), 7.48 (d, J ) 8.5 Hz, 1H), 7.34–7.29 (m,
2H), 7.22–7.11 (m, 1H), 6.89 (dd, J ) 8.5, 2.8 Hz, 1H), 6.66 (dd,
J ) 8.0, 1.2 Hz, 1H), 4.21 (t, J ) 6.0 Hz, 2H), 3.89 (t, J ) 5.9 Hz,
2H), 3.49 (s, 2H), 2.19 (s, 6H), 2.08 (quintet, J ) 6.0 Hz, 2H).
HRMS calcd for C18H23N2O4S [M+ + H] 363.1379, obsd 363.1406.
3-(3-(Dimethylamino)methyl)-4-(4-flouro-2-nitrophenylth-
io)phenoxy)propanol (62) was prepared from 33 as a pale-yellow
oil in 63% yield according to general procedure G. 1H NMR
(CDCl3) δ 7.97 (dd, J ) 8.4, 2.7 Hz, 1H), 7.47 (d, J ) 8.4 Hz,
1H), 7.27 (m, 1H), 7.12–7.02 (m, 1H), 6.89 (dd, J ) 8.5, 2.8 Hz,
1H), 6.65 (dd, J ) 9.0, 5.2 Hz, 1H), 4.21 (t, J ) 6.0 Hz, 2H), 3.90
(t, J ) 5.9 Hz, 2H), 3.47 (s, 2H), 2.18 (s, 6H), 2.08 (quintet, J )
5.9 Hz, 2H). HRMS calcd for C18H22FN2O4S [M+ + H] 381.1284,
obsd 381.1262.
3-(3-((Dimethylamino)methyl)-4-(4-fluoro-2-nitrophenylthio)
phenoxy)propyl methanesulfonate (65) was prepared from 62 as
3-(4-(4-Bromo-2-nitrophenylthio)-3-((dimethylamino)meth-
yl)phenoxy)propan-1-ol (63) was prepared from 34 as a pale-
yellow oil in 73% yield according to general procedure G. 1H NMR
(CDCl3/CD3OD) δ 8.37 (d, J ) 2.2 Hz, 1H), 7.50 (d, J ) 8.5 Hz,
1H), 7.38 (dd, J ) 8.5, 2.2 Hz, 2H), 7.28 (d, J ) 3.0 Hz, 1H), 6.89
(dd, J ) 8.8, 3.0 Hz, 1H), 6.52 (d, J ) 8.8 Hz, 1H), 4.20 (t, J )
6.0 Hz, 2H), 3.86 (t, J ) 6.0 Hz, 2H), 3.47 (s, 2H), 2.18 (s, 6H),
2.14–2.05 (m, 2H).
1
a yellow oil in 87% yield according to general procedure H. H
NMR (CDCl3) δ 7.97 (dd, J ) 8.4, 2.7 Hz, 1H), 7.47 (d, J ) 8.5
Hz, 1H), 7.27 (m, 1H), 7.12–7.03 (m, 1H), 6.88 (dd, J ) 8.5, 2.7
Hz, 1H), 6.69–6.62 (m, 1H), 4.48 (t, J ) 6.0 Hz, 2H), 4.18 (t, J )
5.8 Hz, 2H), 3.47 (s, 2H), 3.03 (s, 3H), 2.27 (quintet, J ) 5.9 Hz,
2H), 2.18 (s, 6H). HRMS calcd for C19H24FN2O6S2 [M+ + H]
459.1080, obsd 459.1066.
General Procedure H for Mesylation. To a solution of 32–33,
53–56, and 61–63 (0.11 mmol) in dichloromethane (5 mL) and
triethylamine (45 mg, 0.44 mmol) was added methanesulfonyl
chloride (30 mg, 0.26 mmol). The solution was stirred at room
temperature for 2 h and washed with water (2 mL) and brine (2
mL). The organic layer was dried (Na2SO4), and the solvent was
removed in vacuo. Purification by silica gel column (dichlo-
romethane/methanol 19/1) gave the product as yellow oils.
3-(3-(Dimethylcarbamoyl)-4-(2-nitrophenylthio)phenoxy)pro-
pyl methanesulfonate (35) was prepared from 32 as a yellow oil
in 88% yield according to general procedure H. 1H NMR (CDCl3)
δ 8.18 (dd, J ) 8.2, 1.4 Hz, 1H), 7.50 (d, J ) 8.4 Hz, 1H),
7.41–7.32 (m, 1H), 7.23–7.15 (m, 1H), 7.02–6.93 (m, 3H), 4.46 (t,
J ) 6.0 Hz, 2H). 4.16 (t, J ) 5.8 Hz, 2H), 3.04 (s, 3H), 3.02 (s,
3H), 2.86 (s, 3H), 2.28 (quintet, J ) 5.9 Hz, 2H).
3-(4-(4-Bromo-2-nitrophenylthio)-3-((dimethylamino)meth-
yl)phenoxy)propyl methanesulfonate (66) was prepared from 63
as a yellow oil in 85% yield according to general procedure H. 1H
NMR (CDCl3/CD3OD) δ 8.37 (d, J ) 2.2 Hz, 1H), 7.47 (d, J )
8.8 Hz, 1H), 7.39 (dd, J ) 8.8, 2.2 Hz, 2H), 7.28 (br s, 1H), 6.88
(dd, J ) 8.8, 2.8 Hz, 1H), 6.52 (d, J ) 8.8 Hz, 1H), 4.47 (t, J )
6.0 Hz, 2H), 4.17 (t, J ) 6.0 Hz, 2H), 3.56 (s, 2H), 3.00 (s, 3H),
2.32–2.18 (m, 2H), 2.10 (s, 6H).
General Procedure I for Fluorination Reaction. A mixture
of mesylates (0.14 mmol), 1.0 M TBAF in THF (5 eqiuv, 0.7 mL),
and THF (1.3 mL) was irradiated under microwave at 150 °C for
15 min. The solvents were evaporated in vacuo, diluted with 20
mL of dichloromethane, and washed with 2 N HCl. The organic
layer was dried (Na2SO4), and the solvent was removed. The crude
mixture was purified by silica gel chromatography (1/30 methanol/
dichloromethane) to give products as yellow oils.
3-(3-(Dimethylcarbamoyl)-4-(4-fluoro-2-nitrophenylthio)phe-
noxy)propyl methanesulfonate (36) was prepared from 33 as a
yellow oil in 85% yield according to general procedure H. 1H NMR
(CDCl3) δ 7.90 (dd, J ) 8.4, 2.7 Hz, 1H), 7.50 (d, J ) 8.5 Hz,
5-(3-Fluoropropoxy)-2-(2-nitrophenylthio)-N,N-dimethylben-
zamide (37) was prepared from 35 as a pale-yellow oil in 71%
1
yield according to general procedure I. H NMR (CDCl3) δ 8.18

6682 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
Parhi et al.
(dd, J ) 8.2, 1.4 Hz, 1H), 7.50 (d, J ) 8.4 Hz, 1H), 7.40–7.32 (m,
1H), 7.25–7.10 (m, 1H), 7.02–6.93 (m, 3H), 4.66 (dt, J ) 47.0,
5.7 Hz, 2H), 4.17 (t, J ) 6.0 Hz, 2H), 3.02 (s, 3H), 2.86 (s, 3H),
2.21 (dt, J ) 26.2, 5.9 Hz, 2H). HRMS calcd for C18H20FN2O4S2
[M+ + H] 379.1128, obsd 379.1112.
for DAT, and 3.2 µM nisoxetine for NET assays. Incubation was
carried out for 1 h at room temperature, and the bound ligand was
collected on glass fiber filters presoaked with 1% polyethylenimine
(Sigma, St. Louis, MO) and counted in a γ counter (Packard 5000,
Downers Grove, IL). Results of competition experiments were
subjected to nonlinear regression analysis using Microsoft Excel.
Biodistribution in Rats. Three rats per group were used for each
biodistribution study. While under isoflurane anesthesia, 0.2 mL
of sterile water with 1 mg/mL BSA and 10–100 µCi of radioactive
tracer was injected into the femoral vein. The rats were sacrificed
at the time indicated by cervical dislocation while under anesthesia.
Organs of interest were removed and weighed, and the radioactivity
was counted. The percent dose per organ was calculated by
comparing the tissue counts to counts of 1% of the initial dose
(aliquots of the injected material diluted 100 times) measured at
the same time. Samples from different brain regions [cortex (CX),
striatum (ST), hippocampus (HP), cerebellum (CB), and hypothala-
mus (HY)] were dissected, weighed, and counted. The percentage
dose/g of each sample was calculated by comparing sample counts
with the counts of the diluted initial dose as described above. The
ratio of specific binding in each region was obtained by dividing
percentage dose/g of each region by that of the cerebellum [region/
CB]. The cerebellum (CB) was used as a background region because
it contains relatively few serotonin transporters. The standard deviation
for the target to nontarget ratios was calculated by the fol-
2-(4-Fluoro-2-nitrophenylthio)-5-(3-fluoropropoxy)-N,N-dimth-
ylbenzamide (38) was prepared from 36 as a pale-yellow oil in
1
67% yield according to general procedure I. H NMR (CDCl3) δ
7.90 (dd, J ) 8.3, 2.6 Hz, 1H), 7.49 (d, J ) 8.5 Hz, 1H), 7.18–7.08
(m, 1H), 7.02–6.90 (m, 3H), 4.66 (dt, J ) 47.0, 5.7 Hz, 2H), 4.17
(t, J ) 6.0 Hz, 2H), 3.03 (s, 3H), 2.86 (s, 3H), 2.21 (dt, J ) 26.2,
5.9 Hz, 2H). HRMS calcd for C18H19F2N2O4S2 [M+ + H] 397.1034,
obsd 397.1036.
2-(4-Bromo-2-nitrophenylthio)-5-(3-fluoropropoxy)-N,N-dim-
ethylbenzamide (39) was prepared as follows. To a solution of 34
(15 mg, 0.033 mmol) in dichloromethane (1 mL), DAST (10 mg)
was added at -78 °C. The mixture was slowly warmed to room
temperature (1 h). The mixture was directly placed on a preparatory
TLC plate (silica gel) for purification (dichloromethane/ethyl
1
acetate, 1/1). The product was a colorless oil (12 mg, 80%). H
NMR (CDCl3) δ 8.31 (d, J ) 2.2 Hz, 1H), 7.48 (d, J ) 8.6 Hz,
1H), 7.05–6.89 (m, 2H), 6.80 (d, J ) 8.6 Hz, 1H), 4.65 (dt, J )
47.0, 5.7 Hz, 2H), 4,16 (t, J ) 6.0 Hz, 2H), 3.10 (s, 3H), 2.85 (s,
3H), 2.33–2.03 (m, 2H).
II. Radiochemistry. General Procedure for F-18 Radiola-
beling ([18F]28–31, 40–42). [18F]Fluoride was produced by a
cyclotron using the 18O(p,n)18F reaction and passed through a Sep-
Pak Light QMA cartridge as an aqueous solution in [18O]-enriched
water. The cartridge was dried by air flow, and the 18F activity
was eluted with 2 mL of Kryptofix 222 (K222)/K2CO3 solution
(13.2 mg of K222 and 3.0 mg of K2CO3 in CH3CN/H2O, 1.12/
0.18). The solvent was removed at 100 °C under an argon stream.
The residue was azeotropically dried with 1 mL of anhydrous
CH3CN twice at 100 °C under an argon stream. A solution of
mesylate precursor (57–60, 64–66) (2-3 mg) in DMSO (0.3 mL)
was added to the reaction vessel containing the dried 18F activities.
The mixture was heated at 100 °C for 3 min. Water (5 mL) was
added, and the mixture was passed through a preconditioned Waters
OASIS HLB (3 mL) cartridge. The cartridge was washed with water
(10 mL), and labeled compound was eluted with ethanol (2 mL).
To the ethanol solution, 0.5 mL of 2 N HCl and SnCl2 (50 mg)
was added, and the mixture was heated at 80 °C for 4-6 min. Water
(5 mL) was added, and the mixture was passed through precondi-
tioned Waters OASIS HLB (3 mL) cartridge. The cartridge was
washed with water (20 mL), and labeled compound was eluted with
CH3CN (2 mL). The eluted compound was purified by HPLC
[Phenonemex Gemini C-18 semipreparative column (10 mm × 250
mm, 5 µm), CH3CN/ammonium formate buffer (50 mM), 6/4, flow
rate of 4 mL/min, tR ) 6-15 min]. To determine radiochemical
purity (RCP) and specific activity, analytical HPLC was used
[Phenomenex Gemini C18 analytical column (4.6 mm × 250 mm,
5 µm), CH3CN/ammonium formate buffer (10 mM), 8/2, flow rate
of 1 mL/min, tR ) 4.0-6.5 min]. Specific activity was estimated
by comparing the UV peak intensity of purified F-18 labeled
compound with the reference nonradioactive compound of known
concentration.
III. Pharmacology. In Vitro Binding Assays. Membrane
homogenates containing one of the three monoamine transporters
(referred to as LLC-DAT, LLC-NET, and LLC-SERT, which were
expressed in a common parental cell line LLC-PK1) were prepared
and used for the binding assays.51 Competitive binding assays were
performed in a final volume of 0.5 mL. Aliquots of membrane
suspensions (100 µL, corresponding to 30–80 µg of protein) were
mixed with 50 mM Tris-HCl, pH 7.4, 120 mM NaCl, 5 mM KCl,
0.1% bovine serum albumin, radioligand (0.06 nM [125I]N-(3′-
iodopropen-2′-yl)-2ꢀ-carbomethoxy-3ꢀ-(4-chlorophenyl)tropane (DAT
ligand),52 0.09 nM [125I]5-iodo-2-[[2,2-[(dimethylamino)meth-
yl]phenyl]thio]benzyl alcohol (SERT ligand),53 or 0.06 nM [125I]-
iodonisoxetine (NET ligand)49), and 8–10 concentrations
(10-10-10-5M) of competing drugs. Nonspecific binding was
defined with 2.5 µM (+)McN5652 for SERT, 1.9 µM GBR-12909
lowing equation: (mean1/mean2)[(SD1/mean1)2 + (SD2/mean2)2]1/2
.
In vivo competitive binding in the regional uptake of [18F]42
was investigated by pretreating animals with competing drugs (2
mg/kg, each, iv at 5 min prior to injection of a tracer dose of
[18F]42). The competing drugs included GBR-12909, nisoxetine,
and (+)McN5652. Regional brain distributions were determined
at 120 min after [18F]42 injection as described above. The reduction
of regional specific binding in the drug-pretreated rats was compared
to that of control animals that had been pretreated with saline (data
not shown).
Acknowledgment. This work was supported by the National
Institutes of Health (Grant R01-MH068782, H.F.K.). The
authors thank Dr. Carita C. Huang for her editorial assistance.
1
Supporting Information Available: H spectra of some bio-
assay involved compounds, HPLC purity analysis data for all
bioassay involved compounds in two different HPLC systems,
radiochemistry data, and full sets of biodistribution data in normal
mice for [18F]28 and [18F]42. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Owens, M. J. Selectivity of antidepressants: from the monoamine
hypothesis of depression to the SSRI revolution and beyond. J. Clin.
Psychiatry 2004, 4, 5–10.
(2) Baghai, T. C.; Moller, H. J.; Rupprecht, R. Recent progress in
pharmacological and non-pharmacological treatment options of major
depression. Curr. Pharm. Des. 2006, 12, 503–15.
(3) Holtzheimer, P. E.; Nemeroff, C. B. Advances in the treatment of
depression. NeuroRx 2006, 3, 42–56.
(4) Nemeroff, C. B. The burden of severe depression: a review of
diagnostic challenges and treatment alternatives. J. Psychiatr. Res.
2006, 41, 189–206.
(5) Meyer, J. H.; Wilson, A. A.; Ginovart, N.; Goulding, V.; Hussey, D.;
Hood, K.; Houle, S. Occupancy of serotonin transporters by paroxetine
and citalopram during treatment of depression: a [11C]DASB PET
imaging study. Am. J. Psychiatry 2001, 158, 1843–1849.
(6) Ginovart, N.; Wilson, A. A.; Meyer, J. H.; Hussey, D.; Houle, S. [11C]-
DASB, a tool for in vivo measurement of SSRI-induced occupancy
of the serotonin transporter: PET characterization and evaluation in
cats. Synapse 2003, 47, 123–133.
(7) Suhara, T.; Takano, A.; Sudo, Y.; Ichimiya, T.; Inoue, M.; Yasuno,
F.; Ikoma, Y.; Okubo, Y. High levels of serotonin transporter
occupancy with low-dose clomipramine in comparative occupancy
study with fluvoxamine using positron emission tomography. Arch.
Gen. Psychiatr. 2003, 60, 386–391.
(8) Kim, J. S.; Ichise, M.; Sangare, J.; Innis, R. B. PET imaging of
serotonin transporters with [11C]DASB: test-retest reproducibility

Biphenylthiols as SERT Imaging Agents
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6683
using a multilinear reference tissue parametric imaging method.
J. Nucl. Med. 2006, 47, 208–214.
(9) Frankle, W. G.; Narendran, R.; Huang, Y.; Hwang, D. R.; Lombardo,
I.; Cangiano, C.; Gil, R.; Laruelle, M.; Abi-Dargham, A. Serotonin
transporter availability in patients with schizophrenia: a positron
emission tomography imaging study with [11C]DASB. Biol. Psychiatry
2005, 57, 1510–1516.
(10) Parsey, R. V.; Kent, J. M.; Oquendo, M. A.; Richards, M. C.; Pratap,
M.; Cooper, T. B.; Arango, V.; Mann, J. J. Acute occupancy of brain
serotonin transporter by sertraline as measured by [11C]DASB and
positron emission tomography. Biol. Psychiatry 2006, 59, 821–828.
(11) Guilloteau, D.; Chalon, S. PET and SPECT exploration of central
monoaminergic transporters for the development of new drugs and
treatments in brain disorders. Curr. Pharm. Des. 2005, 11, 3237–3245.
(12) Parsey, R. V.; Hastings, R. S.; Oquendo, M. A.; Huang, Y. Y.;
Simpson, N.; Arcement, J.; Huang, Y.; Ogden, R. T.; Van Heertum,
R. L.; Arango, V.; Mann, J. J. Lower serotonin transporter binding
potential in the human brain during major depressive episodes. Am. J.
Psychiatry 2006, 163, 52–58.
(27) Wilson, A. A.; Ginovart, N.; Schmidt, M.; Meyer, J. H.; Threlkeld,
P. G.; Houle, S. Novel radiotracers for imaging the serotonin
transporter by positron emission tomography: synthesis, radiosynthesis,
and in vitro and ex vivo evaluation of 11C-labeled 2-(phenylthio)
araalkylamines. J. Med. Chem. 2000, 43, 3103–3110.
(28) Vercouillie, J.; Mavel, S.; Galineau, L.; Ragusa, T.; Innis, R.; Kassiou,
M.; Chalon, S.; Dolle, F.; Besnard, J. C.; Guilloteau, D.; Emond, P.
Synthesis and in vitro evaluation of novel derivatives of diphenylsulfide
as serotonin transporter ligands. Bioorg. Med. Chem. Lett. 2006, 16,
1297–1300.
(29) Zhang, S.; Zhen, J.; Reith, M. E.; Dutta, A. K. Design, synthesis, and
preliminary SAR study of 3- and 6-side-chain-extended tetrahydro-
pyran analogues of cis- and trans-(6-benzhydryl-tetrahydropyran-3-
yl)-benzylamine. Bioorg. Med. Chem. 2006, 14, 3953-3966.
(30) Zessin, J.; Deuther-Conrad, W.; Kretzschmar, M.; Wust, F.; Pawelke,
B.; Brust, P.; Steinbach, J.; Bergmann, R. [11C]SMe-ADAM, an
imaging agent for the brain serotonin transporter: synthesis, pharma-
cological characterization and microPET studies in rats. Nucl. Med.
Biol. 2006, 33, 53–63.
(31) Jarkas, N.; Votaw, J. R.; Voll, R. J.; Williams, L.; Camp, V. M.;
Owens, M. J.; Purselle, D. C.; Bremner, J. D.; Kilts, C. D.; Nemeroff,
C. B.; Goodman, M. M. Carbon-11 HOMADAM: a novel PET
radiotracer for imaging serotonin transporters. Nucl. Med. Biol. 2005,
32, 211–224.
(32) Jarkas, N.; McConathy, J.; Votaw, J. R.; Voll, R. J.; Malveaux, E.;
Camp, V. M.; Williams, L.; Goodman, R. R.; Kilts, C. D.; Goodman,
M. M. Synthesis and characterization of EADAM: a selective
radioligand for mapping the brain serotonin transporters by positron
emission tomography. Nucl. Med. Biol. 2005, 32, 75–86.
(33) Huang, Y.; Bae, S. A.; Zhu, Z.; Guo, N.; Roth, B. L.; Laruelle, M.
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. J. Med. Chem. 2005,
48, 2559–2570.
(34) Oya, S.; Kung, M. P.; Acton, P. D.; Mu, M.; Hou, C.; Kung, H. A
new single-photon emission computed tomography imaging agent for
serotonin transporters: [123I] IDAM, 5-iodo-2-((2-((dimethylamino)
methyl)phenyl)thio)benzyl alcohol. J. Med. Chem. 1999, 42, 333–335.
(35) Oya, S.; Choi, S. R.; Hou, C.; Mu, M.; Kung, M. P.; Acton, P. D.;
Siciliano, M.; Kung, H. F. 2-((2-((Dimethylamino)methyl)phenyl)thio)-
5-iodophenylamine (ADAM): an improved serotonin transporter
ligand. Nucl. Med. Biol. 2000, 27, 249–254.
(36) Oya, S.; Choi, S. R.; Coenen, H.; Kung, H. F. New PET imaging
agent for the serotonin transporter: [18F]ACF (2-[(2-amino-4-chloro-
5-fluorophenyl)thio]-N,N-dimethyl-benzenmethanamine). J. Med. Chem.
2002, 45, 4716–4723.
(37) Newberg, A. B.; Amsterdam, J. D.; Wintering, N.; Ploessl, K.;
Swanson, R. L.; Shults, J.; Alavi, A. 123I-ADAM binding to serotonin
transporters in patients with major depression and healthy controls: a
preliminary study. J. Nucl. Med. 2005, 46, 973–977.
(38) Cannon, D. M.; Ichise, M.; Fromm, S. J.; Nugent, A. C.; Rollis, D.;
Gandhi, S. K.; Klaver, J. M.; Charney, D. S.; Manji, H. K.; Drevets,
W. C. Serotonin transporter binding in bipolar disorder assessed using
[11C]DASB and positron emission tomography. Biol. Psychiatry 2006,
60, 207–217.
(39) Frankle, W. G.; Slifstein, M.; Gunn, R. N.; Huang, Y.; Hwang, D. R.;
Darr, E. A.; Narendran, R.; Abi-Dargham, A.; Laruelle, M. Estimation
of serotonin transporter parameters with 11C-DASB in healthy
humans: reproducibility and comparison of methods. J. Nucl. Med.
2006, 47, 815–826.
(40) Meyer, J. H.; Houle, S.; Sagrati, S.; Carella, A.; Hussey, D. F.;
Ginovart, N.; Goulding, V.; Kennedy, J.; Wilson, A. A. Brain serotonin
transporter binding potential measured with carbon 11-labeled DASB
positron emission tomography: effects of major depressive episodes
and severity of dysfunctional attitudes. Arch. Gen. Psychiatry 2004,
61, 1271–1279.
(41) Huang, Y.; Narendran, R.; Bischoff, F.; Guo, N.; Zhu, Z.; Bae, S. A.;
Lesage, A. S.; Laruelle, M. A positron emission tomography radio-
ligand for the in vivo labeling of metabotropic glutamate 1 receptor:
(3-ethyl-2-[11C]methyl-6-quinolinyl)(cis-4-methoxycyclohexyl)metha-
none. J. Med. Chem. 2005, 48, 5096–5099.
(42) Shiue, G. G.; Choi, S. R.; Fang, P.; Hou, C.; Acton, P. D.; Cardi, C.;
Saffer, J. R.; Greenberg, J. H.; Karp, J. S.; Kung, H. F.; Shiue, C. Y.
N,N-Dimethyl-2-(2-amino-4-(18)F-fluorophenylthio)-benzylamine (4-
(18)F-ADAM): an improved PET radioligand for serotonin transport-
ers. J. Nucl. Med. 2003, 44, 1890–1897.
(13) Binder, E. B.; Holsboer, F. Pharmacogenomics and antidepressant
drugs. Ann. Med. 2006, 38, 82–94.
(14) Yoshida, K.; Takahashi, H.; Higuchi, H.; Kamata, M.; Ito, K.; Sato,
K.; Naito, S.; Shimizu, T.; Itoh, K.; Inoue, K.; Suzuki, T.; Nemeroff,
C. B. Prediction of antidepressant response to milnacipran by
norepinephrine transporter gene polymorphisms. Am. J. Psychiatry
2004, 161, 1575–1580.
(15) Nemeroff, C. B.; Mayberg, H. S.; Krahl, S. E.; McNamara, J.; Frazer,
A.; Henry, T. R.; George, M. S.; Charney, D. S.; Brannan, S. K. VNS
therapy in treatment-resistant depression: clinical evidence and putative
neurobiological mechanisms. Neuropsychopharmacology 2006, 31,
1345–1355.
(16) Mathis, C. A.; Biegon, A.; Taylor, S. E.; Enas, J. D.; Hanrahan, S. M.
[I-125]5-Iodo-6-nitro-2-piperazinylquinoline: a potent and selective
ligand for the serotonin uptake complex. Eur. J. Pharmacol. 1992,
210, 103–104.
(17) Mathis, C. A.; Taylor, S. E.; Biegon, A.; Enas, J. D. [125I]5-Iodo-6-
nitroquipazine: a potent and selective ligand for the 5-hydroxy-
tryptamine uptake complex I in vitro studies. Brain Res. 1993, 619,
229–235.
(18) Jagust, W. J.; Eberling, J. L.; Biegon, A.; Taylor, S. E.; VanBrocklin,
H. F.; Jordan, S.; Hanrahan, S. M.; Roberts, J. A.; Brennan, K. M.;
Mathis, C. A. Iodine-123–5-iodo-6-nitroquipazine: SPECT radiotracer
to image the serotonin transporter. J. Nucl. Med. 1996, 37, 1207–
1214.
(19) Karramkam, M.; Dolle, F.; Valette, H.; Besret, L.; Bramoulle, Y.;
Hinnen, F.; Vaufrey, F.; Franklin, C.; Bourg, S.; Coulon, C. Synthesis
of a fluorine-18-labelled derivative of 6-nitroquipazine, as a radioligand
for the in vivo serotonin transporter imaging with PET. Bioorg. Med.
Chem. 2002, 10, 2611–2623.
(20) Scheffel, U.; Szabo, Z.; Mathews, W. B.; Finley, P. A.; Dannals, R. F.;
Ravert, H. T.; Szabo, K.; Yuan, J.; Ricaurte, G. A. In vivo detection
of short- and long-term MDMA neurotoxicitysa positron emission
tomography study in the living baboon brain. Synapse 1998, 29, 183–
192.
(21) Parsey, R. V.; Kegeles, L. S.; Hwang, D. R.; Simpson, N.; Abi-
Dargham, A.; Mawlawi, O.; Slifstein, M.; Van Heertum, R. L.; Mann,
J. J.; Laruelle, M. In vivo quantification of brain serotonin transporters
in humans using [11C]McN 5652. J. Nucl. Med. 2000, 41, 1465–1477.
(22) Scheffel, U.; Dannals, R. F.; Cline, E. J.; Ricaurte, G. A.; Carroll,
F. I.; Abraham, P.; Lewin, A. H.; Kuhar, M. J. [123/125I]RTI-55, an in
vivo label for the serotonin transporter. Synapse 1992, 11, 134–139.
(23) Laruelle, M. A.; Giddings, S. S.; Zea-Ponce, Y.; Charney, D. S.;
Neumeyer, J. L.; Baldwin, R. M.; Innis, R. B. Methyl 3beta-(4-
[
125I]iodophenyl)tropane-2beta-carboxylate in vitro binding to dopam-
ine and serotonin transporters under “physiological” conditions.
J. Neurochem. 1994, 62, 978–986.
(24) Bergstrom, K. A.; Halldin, C.; Hall, H.; Lundkvist, C.; Ginovart, N.;
Swahn, C. G.; Farde, L. In vitro and in vivo characterisation of nor-
beta-CIT: a potential radioligand for visualisation of the serotonin
transporter in the brain. Eur. J. Nucl. Med. 1997, 24, 596–601.
(25) Stehouwer, J. S.; Plisson, C.; Jarkas, N.; Zeng, F.; Voll, R. J.; Williams,
L.; Martarello, L.; Votaw, J. R.; Tamagnan, G.; Goodman, M. M.
Synthesis, radiosynthesis, and biological evaluation of carbon-11 and
fluorine-18 (N-fluoroalkyl) labeled 2beta-carbomethoxy-3beta-(4′-(3-
furyl)phenyl)tropanes and -nortropanes: candidate radioligands for in
vivo imaging of the serotonin transporter with positron emission
tomography. J. Med. Chem. 2005, 48, 7080–7083.
(26) Plisson, C.; Jarkas, N.; McConathy, J.; Voll, R. J.; Votaw, J.; Williams,
L.; Howell, L. L.; Kilts, C. D.; Goodman, M. M. Evaluation of carbon-
11-labeled 2beta-carbomethoxy-3beta-[4′-((Z)-2-iodoethenyl)phenyl]-
nortropane as a potential radioligand for imaging the serotonin
transporter by PET. J. Med. Chem. 2006, 49, 942–946.
(43) Huang, Y.; Narendran, R.; Bae, S. A.; Erritzoe, D.; Guo, N.; Zhu, Z.;
Hwang, D. R.; Laruelle, M. A PET imaging agent with fast kinetics:
synthesis and in vivo evaluation of the serotonin transporter ligand
[11C]2-[2-dimethylaminomethylphenylthio)]-5-fluoropheny-
lamine ([11C]AFA). Nucl. Med. Biol. 2004, 31, 727–738.

6684 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
Parhi et al.
(44) Shiue, G. G.; Fang, P.; Shiue, C.-Y. Synthesis of N,N-dimethyl-2-(2-
amino-4-[18F]fluorophenylthio)benzylamine as a serotonin transporter
imaging agent. Appl. Radiat. Isot. 2003, 58, 183–191.
(45) Oya, S.; Choi, S. R.; Kung, M. P.; Kung, H. F. 5-Chloro-2-(2′-
((dimethylamino)methyl)-4′-iodophenylthio)benzenamine: a new se-
rotonin transporter ligand. Nucl. Med. Biol. 2007, 34, 129–139.
(46) Kung, H. F.; Newman, S.; Choi, S. R.; Oya, S.; Hou, C.; Zhuang,
Z. P.; Acton, P. D.; Plossl, K.; Winkler, J.; Kung, M. P. 2-(2-
(Dimethylaminomethyl)phenoxy)-5-iodophenylamine: an improved
serotonin transporter imaging agent. J. Med. Chem. 2004, 47, 5258–
5264.
(47) Choi, S. R.; Hou, C.; Oya, S.; Mu, M.; Kung, M. P.; Siciliano, M.;
Acton, P. D.; Kung, H. F. Selective in vitro and in vivo binding of
[(125)I]ADAM to serotonin transporters in rat brain. Synapse 2000,
38, 403–412.
(50) Jarkas, N.; Voll, R. J.; Williams, L.; Votaw, J. R.; Goodman, M. M.
Synthesis and Evluation of a Serotonin Transporter (SERT) PET
Imaging Agent: 11C-BHOMADAM. In 17th International Symposium
on Radiopharmaceutical Sciences, Aachen, Germany; Elsevier: Am-
sterdam, The Netherlands, 2007; p 208.
(51) Gu, H.; Wall, S. C.; Rudnick, G. Stable expression of biogenic amine
transporters reveals differences in inhibitor sensitivity, kinetics, and
ion dependence. J. Biol. Chem. 1994, 269, 7124–7130.
(52) Kung, M.-P.; Essman, W. D.; Frederick, D.; Meegalla, S.; Goodman,
M.; Mu, M.; Lucki, I.; Kung, H. F. IPT: a novel iodinated ligand for
the CNS dopamine transporter. Synapse 1995, 20, 316–324.
(53) Kung, M. P.; Hou, C.; Oya, S.; Mu, M.; Acton, P. D.; Kung, H. F.
Characterization of [123I]IDAM as a novel single-photon emission
tomography tracer for serotonin transporters. Eur. J. Nucl. Med. 1999,
26, 844–853.
(54) Fang, P.; Shiue, G. G.; Shimazu, T.; Greenberg, J. H.; Shiue, C. Y.
Synthesis and evaluation of N,N-dimethyl-2-(2-amino-5-[18F]fluo-
rophenylthio)benzylamine (5-[18F]-ADAM) as a serotonin transporter
imaging agent. Appl. Radiat. Isot. 2004, 61, 1247–1254.
(48) Kung, M. P.; Kung, H. F. Mass effect of injected dose in small rodent
imaging by SPECT and PET. Nucl. Med. Biol. 2005, 32, 673–678.
(49) Kung, M. P.; Choi, S. R.; Hou, C.; Zhuang, Z. P.; Foulon, C.; Kung,
H. F. Selective binding of 2-[125I]iodo-nisoxetine to norepinephrine
transporters in the brain. Nucl. Med. Biol. 2004, 31, 533–541.
JM070685E