New fluoro-diphenylchalcogen derivatives to explore the serotonin transporter by PET

Article abstract of DOI:10.1016/j.bmcl.2007.02.082

A series of fluorinated diphenylchalcogen derivatives, possessing a sulfur or an oxygen bridge, has been prepared with the aim to get a suitable radiotracer to image the SERT in vivo using positron emission tomography (PET). The compounds were synthesized

Full text of DOI:10.1016/j.bmcl.2007.02.082

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4991–4995
New fluoro-diphenylchalcogen derivatives to explore the
serotonin transporter by PET
Johnny Vercouillie,a,* Winnie Deuther-Conrad,a Matthias Scheunemann,a
Patrick Emond,b,c Steffen Fischer,a Uta Funke,a Jo¨rg Steinbach,a
Denis Guilloteaub,c and Peter Brusta
aInstitut fu¨r Interdisziplina¨re Isotopenforschung, Permoserstr. 15, 04318 Leipzig, Germany
bUniversite´ Franc¸ois-Rabelais de Tours, 37200 Tours, France
ˆ
INSERM U619, 37044 Tours Cdx 09, CHRU, Hopital Bretonneau, 37044 Tours, France
c
Received 1 February 2007; revised 27 February 2007; accepted 27 February 2007
Available online 7 March 2007
Abstract—A series of fluorinated diphenylchalcogen derivatives, possessing a sulfur or an oxygen bridge, has been prepared with the
aim to get a suitable radiotracer to image the SERT in vivo using positron emission tomography (PET). The compounds were
synthesized and assayed toward the serotonin (SERT), dopamine (DAT), and norepinephrine (NET) transporters. Among the
developed series, five compounds display a high SERT affinity (Ki: 0.27–2.91 nM range) and can be labeled either with carbon-
11 or fluorine-18.
Ó 2007 Elsevier Ltd. All rights reserved.
The serotonin transporter (SERT), a pre-synaptic re-up-
O
N
N
NO2
NO2
take system responsible for the clearance of the neuro-
transmitter serotonin after its release into the synaptic
cleft, plays a key role in serotonergic signaling as it reg-
ulates the extracellular serotonin concentration.1 Altera-
tions of SERT densities have been reported in various
psychiatric and neurological disorders.1 Neuroimaging
with SERT radiotracers is expected to provide informa-
tion in diagnostics and therapy, in particular to evaluate
properties of new drugs.1
Y
Y
a
R
W
R
W
1a
2a
3a
4a
1b
2b
3b
4b
R = Me Y = OW=F
R = Me Y = OW=F
F
Me
Cl
O
S
S
Cl
F
F
F
Me
Cl
O
S
S
Cl
F
F
Scheme 1. Reagents and conditions: (a) THF, addition of BH3–THF
(1 M in THF) at 0 °C, followed by 5 h at reflux and overnight at rt.
During the last two decades, different classes of com-
pounds were investigated for their suitability for the
development of SERT radiotracers, for example, tro-
pane, pyridine, and pyrroloisoquinoline derivatives.1,2
Even though some of them have been proved to be use-
ful for human studies, for example, the tropane deriva-
tives
pyrroloisoquinoline derivative [11C]McN5652,6 all of
them display certain limitations (Scheme 1).
potent inhibitors of serotonin re-uptake.8 A radioiodin-
ated diphenylsulfide, 5-iodo-2-((2-((dimethylamino)
methyl)phenyl)thio) benzyl alcohol (IDAM), has been
anticipated to be a promising SPECT tracer for SERT
imaging.9 Based on this class of compounds, new
SPECT agents called ODAM and ADAM were devel-
oped.10,11 The interest in these compounds is based on
their high SERT affinity (within the nanomolar range)
and selectivity versus the dopamine transporter (DAT)
and the norepinephrine transporter (NET). Among the
[ [
123I]b-CIT or 123I]nor b-CIT,3–5 and the
Diphenylsulfide derivatives, initially proposed and
synthesized as potential antidepressants,7 are highly
three
mentioned
diphenylsulfide
compounds,
[
123I]ADAM appears to be the most suitable SPECT tra-
cer,12 due to its higher in vitro SERT affinity and selec-
tivity in comparison to IDAM and ODAM. These better
properties were attributed to the presence of the amino
Keywords: SERT; PET; Diphenylsulfides; Affinity; Selectivity.
*
Corresponding author. E-mail: vercouillie@univ-tours.fr
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.02.082

4992
J. Vercouillie et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4991–4995
group in ortho-position to the bridging atom for
ADAM, which is substituted by a hydroxymethyl group
in IDAM and ODAM.13 Concerning the in vivo SPECT
studies [123I]ADAM displays an excellent uptake and a
better target versus non-target contrast compared to
the two other developed radioligands. However, critical
assessment of the kinetics and metabolism of
on the affinity and selectivity for the SERT.13 Thus, at
this position fluoro groups were introduced to obtain
[18F]AFA, [18F]AFM, [18F]AFE, and [18F]AFP (fluorine
linked either directly on the aryl, or via methyl-, ethyl-,
and propyl-spacers, respectively; see Fig. 1). In vitro, all
compounds display SERT affinity and specificity versus
DAT similar to ADAM, but a lower selectivity toward
the NET (Ki = 141 nM for AFA, for other derivatives
between 500 and 1000 nM).20 The potency of [18F]AFP
is reduced in vivo due to a low signal-to-noise ratio
while [18F]AFM displays the highest blood–brain pene-
tration and specific binding (hypothalamus-to-cerebel-
lum ratio: 6 at 60 min pi).20 However, in vivo
defluorination of [18F]AFM may occur. Two other fluo-
rinated analogs of ADAM, 5-[18F]ADAM and
[18F]ACF, were synthesized and evaluated in vivo.
5-[18F]ADAM displays a low brain uptake and signifi-
cant defluorination,29 while [18F]ACF exhibits a good
brain penetration but a moderate signal-to-noise ratio
(hypothalamus-to-cerebellum ratio: ꢀ3 at 60 min pi).
So far, all fluorinated tracers developed for in vivo
PET investigation of the SERT present critical limita-
tions such as in vivo defluorination, low brain uptake,
or a non-negligible NET affinity resulting in in vivo
properties inferior to those of [11C]DASB.
[
123I]ADAM, as well as acquisition protocols, is
warranted.1
Regarding PET, there is still a need for alternative
radiotracers to assess SERT densities in the human
brain. We have recently prepared and evaluated
11
in vivo a C-labeled analog of ADAM.14 It displays a
slow kinetics which is incompatible with the short
half-life of 11C (ꢀ20 min). Based on the ADAM lead
structure, numerous 11C tracers were developed such
as MADAM, DASB, SMe-ADAM, DAPA, EADAM,
or AFM (Fig. 1).15–19 In vitro, comparable properties
concerning SERT affinity and selectivity were detected,
but the in vivo evaluation of these tracers in non-human
primates revealed that [11C]DASB and [11C]AFM are
superior tracers compared to the others.20,21 Although
in vivo evaluation demonstrated that [11C]DASB is a
suitable tracer to image the SERT in humans,22–24 there
is still a potential for improvement such as reduction of
non-specific binding and introduction of 18F-label (half-
life ꢀ110 min) into the molecule to allow longer scan-
ning protocols, radiotracer distribution within the satel-
lite concept, and higher resolution due to the lower
positron energy.1
Herein we report the synthesis and in vitro evaluation of
new diphenylsulfides and oxo analogs which can lead to
ligands with high SERT affinity and selectivity.30,31 To
avoid in vivo defluorination of the radiotracers, the fluo-
rine atom was linked directly to the aryl ring. For the
better understanding of the molecular basis of the
SERT–ligand interaction, the bridge atom was modified
and the fluorine was introduced either at the aryl bear-
ing the amino group (ring B, position 40) or at the aryl
bearing the dimethylaminomethyl group (ring A, posi-
tion 5, Fig. 1). Moreover, these derivatives offer the pos-
sibility to be labeled either with 11C or 18F. While a
standard 11C methylation of a monomethylamine pre-
cursor is obvious, a 18F fluorination in ring A is sup-
posed to be possible via a nucleophilic substitution
applying an electron deficient precursor followed by a
reduction.29
Accordingly, several 18F tracers based on the structures
11
of C radioligands, such as McN-derivatives25,26 and
diphenylsulfides, were prepared. First, the S-fluorom-
ethyl and the S-fluoroethyl derivatives of McN5652 dis-
play SERT affinities similar to the parent ligand
in vitro,25,26 and have been evaluated in vivo to deter-
mine their potency to image the SERT. The S-fluoroeth-
yl derivative presents a lower blood–brain penetration
compared to [11C]McN5652 and a low signal-to-noise
ratio. The S-fluoromethyl derivative presents a higher
potential than its fluoroethyl analog. Nevertheless, none
of these tracers offer an improvement over
[11C]McN5652 for the in vivo PET imaging of the SERT
except for the longer half-life.27,28
Compounds 1a–4a were obtained by nucleophilic aro-
matic substitution in yields of 60–92%, using 1-halo-2-
nitrobenzenes (Br or Cl), 2-hydroxy (or 2-mercapto)-
N,N-dimethylbenzamides and potassium carbonate in
DMF. The reduction of the amide function to afford
1b–4b was performed using diborane–THF complex
(1 M) as reductive agent. The synthesis of the cyano
analogs, 5b and 6b, is depicted in Scheme 2.
Second, attempts have been made to develop fluoro-
diphenylsulfide analogs based on the ADAM structure.
It appears that the nature of the group on position 40 in
ring B of diphenylsulfides (see Fig. 1) has limited impact
N
1
N
N
NH2
NH2
NH2
2'
2
1' S
S
S
B
A
R4'
Cl
N
N
F
F
R =
F
: AFA
NO2
Cl HY
NO2
Y
R = CH2F : AFM
R = (CH2)2F : AFE
R = (CH2)3F : AFP
ACF
5-FluoroADAM
a
+
NC
F
NC
F
Y = O or S
Y = O (5b) or S (6b)
Figure 1. Potent fluorinated tracers developed to image the SERT by
PET.
Scheme 2. Reagents and conditions: (a) DMSO, KOH, 160 °C, 8 h.

J. Vercouillie et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4991–4995
4993
In contrast to 1b–4b, compounds 5b and 6b could not be
prepared from benzamides due to the presence of the cy-
ano group and its incompatibility with reducing agents
such as borane–THF complex. Based on similar cou-
pling reaction for the preparation of diphenyl ether
derivatives,31 we synthesized 5b and 6b by nucleophilic
aromatic substitution of 2-[(dimethylamino)methyl]-4-
fluorophenol or 2-[(dimethylamino)methyl]-4-fluoro-
benzenethiol with 4-chloro-3-nitrobenzonitrile using
potassium hydroxide in DMSO (yield >50%).
Table 1 shows that the compounds display a reasonable
to high SERT affinity and selectivity. Among the tested
compounds, three diphenylsulfide derivatives display
subnanomolar affinities (Ki values 3c: 0.27, 4c: 0.35,
and 6c: 0.28 nM), whereas the oxo-compounds present
higher Ki values (1c: 7.01, 2c: 2.06, 5c: 2.91, and
7c:13.4 nM).
Although nitrobenzenes and nitroanilines have geno-
toxic properties,32 we have not performed the Ames
test32 with our compounds because for most genotoxic
carcinogenic drugs the cancer life-time risk is
<0.0001% if <1.5 lg/d is applied (P. Kasper, unpub-
lished). Three aspects are discussed concerning the struc-
tural modifications and their impact on the SERT ligand
affinity and selectivity: (i) the effect of the nature of the
substituent in position 40 (R in ring B, Scheme 3), (ii) the
bridge atom linking the phenyl rings, and (iii) the intro-
duction of a halogen at position 5 in ring A.
Two different methods were employed for the reduction
of the nitro group of derivatives 1b–6b (Scheme 3). For
compounds 1b–4b we used MeOH, hydrogen, and palla-
dium/charcoal as catalyst. Under these conditions 1b,
3b, and 4b led to 1c, 3c, and 4c, respectively, in high
yields (88–92%). However, with that method, concomi-
tant to the reduction of the nitro group of 2b, a hydrode-
chlorination was observed which led to derivative 7c.
Finally, compound 2c was prepared from 2b using tin
(II) chloride under HCl–MeOH conditions.
The nature of the substituent at position 40 does not af-
fect the SERT affinity since the KiSERT values of 3c, 4c,
and 6c, as well as 1c and 5c, are in the same range.
Therefore, in the sulfide and oxo series, it seems that
the nature of the group in position 40 does not signifi-
cantly affect the SERT–ligand interaction which is in
accordance with the literature.13,31 Second, by compar-
ing the sulfur- and the respective oxo-bridged com-
pounds (1c–3c, and 5c–6c), the SERT affinities of the
oxo-bridged compounds are generally lower. The same
observation was made in the comparison of IDAM/
ODAM and ADAM/OADAM (KiSERT: 0.097 nM for
IDAM, 0.12 nM for ODAM, 0.013 nM for ADAM,
and 0.37 nM for OADAM).31 By contrast, MADAM
displays a slightly lower affinity than its oxo analog
The same method was also employed for the prepara-
tion of 5c and 6c using their correspondent precursors
5b and 6b to avoid the cyano group reduction.
Compounds 1c–7c were tested to evaluate their affinity
and selectivity for the SERT. [3H]WIN 35,428 for
DAT, [3H]nisoxetine for NET, and [3H]paroxetine for
SERT, and rat cortical and striatal homogenates were
used to determine the affinities for the different
transporters.
N
N
NO2
NH2
OMADAM (KiSERT
: 1.65 nM for MADAM and
Y
Y
a or b
0.53 nM for OMADAM).30 It appears that both oxygen
and sulfur bridges can lead to ligands with high SERT
affinity and selectivity. Although the atom bridge linking
the two phenyl rings seems to play a major role in the
SERT–ligand interaction,30 it does not directly interact
with the transporter. The bridge atom may induce a dif-
ferent conformation of the two phenyl groups and there-
by of the amino and dimethylaminomethyl groups,
which could be essential in the SERT–ligand interac-
tion.13 In the oxo and diphenylsulfides series, the cyano
B
A
R
W
R
W
1b-6b
1c R =Me Y = OW=
F
2c
3c
4c
5c
6c
7c
F
O
S
S
O
S
O
Cl
F
Me
Cl
i
F
CN
CN
F
F
F
H
Scheme 3. Reagents and conditions: (a) Pd/C, H2, 5 h; (b) MeOH,
HCl, SnCl2, 0 °C to rt overnight. (i) Using palladium on charcoal with
H2 2c was not observed, dehydrochlorination occurred, concomitant
to the reduction of the nitro group and afforded 7c.
Table 1. Binding affinities of potential SERT–ligands (see Scheme 3) to the three biogenic amine transporters SERT, DAT, and NET isolated from
rat brain
Compound
Ki in nM
DATb
SERTb
NETb
518 (429;607)
1c
2c
7.01 (4.82;9.20)
2.06c (1.84;2.28)
0.27 (0.21;0.32)
0.35 (0.21;0.49)
2.91 (1.69;3.47)
0.28c (0.22;0.34)
13.4 (6.26;20.5)
0.62 (0.62;0.62)
2790 (2330;3260)
2530 (1800;3250)
3650 (5520;1780)
1840 (1420;2270)
68,300 (4400;88,100)
14,100a
2740 (1770;3700)
1040 (641;1430)
919 (487;1350)
5550 (1140;9970)
17,900a
3c
4c
5c
6c
7c
MADAM
4360 (4300;4410)
4160a
1083 (686;1480)
Not determined
Ki values are means of two experiments, each realized in triplicate.
a n = 1 (in triplicate).
b Radioligands: [3H]paroxetine (SERT), [3H]WIN35,428 (DAT), and [3H]nisoxetine (NET).
c Radioligand: [3H]citalopram (SERT).

4994
J. Vercouillie et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4991–4995
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derivatives 5c and 6c possess low affinities for the DAT
and NET compared to the other ligands (Table 1). For
compounds 5c and 6c, KiDAT values of 68.3 and
14.1 lM, and KiNET values of 5.55 and 17.9 lM, respec-
tively, were determined. For the other derivatives, Ki
values were in the range between 0.52 and 4.36 lM for
both DAT and NET. Therefore, although the nature
of the group in position 4 does not significantly affect
the SERT affinity it influences the selectivity of the li-
gand. In a series of ADAM analogs with different
groups in position 40 such as a cyano (DASB), a chlo-
rine, a methoxy (DAPP), and a trifluoro methyl group,
developed by Wilson et al.,33 the derivatives display sim-
ilar affinity for DAT and NET (between 1.4 and 2.7 lM
for the DAT and 1.2 and 2.0 lM for the NET), except
the chlorine derivative with higher and non-negligible
affinity for both transporters (KiDAT = 115 nM and
KiNET = 230 nM). Comprehensive SAR studies are
needed to draw a profound conclusion whether the cya-
no group in position 40 (Scheme 3) affects the SERT
selectivity of the compounds. Third, the introduction
of a halogen in position 5 (ring A, Scheme 3) does not
affect the SERT affinity of the ligands. Even if the elec-
tronic density has been modified, with the introduction
of a chlorine or fluorine atom, all the compounds 1c–
6c display high affinity for the SERT, which is compara-
ble to MADAM. Moreover, the introduction of an hal-
ogen at this position does not affect the SERT selectivity
as shown by Ki values for DAT and NET higher than
500 nM. It appears that the introduction of a halogen
at this position does not affect the SERT affinity and
selectivity, and therefore this part of the molecule pre-
sumably does not play a critical role in the SERT–ligand
interaction. It can be hypothesized, that at least small
groups can be introduced at position 5 without signifi-
cantly modifying SERT affinity and selectivity. This will
allow chemical modifications which might result in im-
proved SERT tracer properties.
In conclusion, we have synthesized a new series of fluo-
rinated diphenylchalcogen derivatives with sub- to low
nanomolar SERT affinity combined with low affinity to-
ward the DAT and NET.
19. Huang, Y.; Hwang, D. R.; Bae, S. A.; Sudo, Y.; Guo, N.;
Zhu, Z.; Narendran, R.; Laruelle, M. Nucl. Med. Biol.
2004, 31, 543.
Acknowledgment
20. Huang, Y.; Bae, S. A.; Zhu, Z.; Guo, N.; Roth, B. L.;
Laruelle, M. J. Med. Chem. 2005, 48, 2559.
21. Zhu, Z.; Guo, N.; Narendran, R.; Erritzoe, D.; Ekelund,
J.; Hwang, D. R.; Bae, S. A.; Laruelle, M.; Huang, Y.
Nucl. Med. Biol. 2004, 31, 983.
22. Ginovart, N.; Wilson, A. A.; Meyer, J. H.; Hussey,
D.; Houle, S. J. Cereb. Blood Flow Metab. 2001, 21,
1342.
23. Huang, Y.; Hwang, D. R.; Narendran, R.; Sudo, Y.;
Chatterjee, R.; Bae, S. A.; Mawlawi, O.; Kegeles, L. S.;
Wilson, A. A.; Kung, H. F.; Laruelle, M. J. Cereb. Blood
Flow Metab. 2002, 22, 1377.
This work has been supported in part by a grant of the
Sa¨chsisches Ministerium fur Wissenschaft und Kunst.
¨
Supplementary data
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.bmcl.
2007.02.082.
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