Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET

Article abstract of DOI:10.1016/j.bmc.2009.03.021

Radiolabelled piperidine derivatives such as [¹¹C]MDL 100907 and [¹⁸F]altanserin have played an important role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine MDL 100907 derivatives, possible to label with ¹⁸F-fluorine, were synthesized to improve molecular imaging properties of [¹¹C]MDL 100907. Their in vitro affinities to a broad spectrum of neuroreceptors and their lipophilicities were determined and compared to the clinically used reference compounds MDL 100907 and altanserin. The novel compounds MA-1 (53) and (R)-MH.MZ (56) show K_i-values in the nanomolar range towards the 5-HT_2A receptor and insignificant binding to other 5-HT receptor subtypes or receptors. Interestingly, compounds MA-1 (53), MH.MZ (55) and (R)-MH.MZ (56) provide a receptor selectivity profile similar to MDL 100907. These compounds could possibly be preferable antagonistic ¹⁸F-tracers for visualization of the 5-HT_2A receptor status. Medium affine compounds (VK-1 (32), (51), (52), (54)) were synthesized and have K_i values between 30 and 120 nM. All promising compounds show log P values between 2 and 3, that is, within the range of those for the established radiotracers altanserin and MDL 100907. The novel compounds MA-1 (53) and (R)-MH.MZ (56) thus appear to be promising high affine and selective tracers of ¹⁸F-labelled analogues for 5-HT_2A imaging with PET.

Full text of DOI:10.1016/j.bmc.2009.03.021

Bioorganic & Medicinal Chemistry 17 (2009) 2989–3002
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and in vitro affinities of various MDL 100907 derivatives as potential
18F-radioligands for 5-HT2A receptor imaging with PET
a
a
b
a
Matthias M. Herth a, , Vasko Kramer , Markus Piel , Mikael Palner , Patrick J. Riss ,
*
Gitte M. Knudsen b, Frank Rösch a
a Institute of Nuclear Chemistry Johannes Gutenberg-University Mainz, Fritz-Strassmann-Weg 2, 55128 Mainz, Germany
b Center for Integrated Molecular Brain Imaging and University of Copenhagen, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark
a r t i c l e i n f o
a b s t r a c t
Radiolabelled piperidine derivatives such as [11C]MDL 100907 and [18F]altanserin have played an impor-
tant role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine
MDL 100907 derivatives, possible to label with 18F-fluorine, were synthesized to improve molecular
imaging properties of [11C]MDL 100907. Their in vitro affinities to a broad spectrum of neuroreceptors
and their lipophilicities were determined and compared to the clinically used reference compounds
MDL 100907 and altanserin. The novel compounds MA-1 (53) and (R)-MH.MZ (56) show Ki-values in
the nanomolar range towards the 5-HT2A receptor and insignificant binding to other 5-HT receptor sub-
types or receptors. Interestingly, compounds MA-1 (53), MH.MZ (55) and (R)-MH.MZ (56) provide a
receptor selectivity profile similar to MDL 100907. These compounds could possibly be preferable antag-
onistic 18F-tracers for visualization of the 5-HT2A receptor status. Medium affine compounds (VK-1 (32),
(51), (52), (54)) were synthesized and have Ki values between 30 and 120 nM. All promising compounds
show logP values between 2 and 3, that is, within the range of those for the established radiotracers
altanserin and MDL 100907. The novel compounds MA-1 (53) and (R)-MH.MZ (56) thus appear to be
promising high affine and selective tracers of 18F-labelled analogues for 5-HT2A imaging with PET.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 1 November 2008
Revised 6 March 2009
Accepted 11 March 2009
Available online 14 March 2009
Keywords:
MH.MZ
5-HT2A
MDL 100907
PET
18F-fluorine
1. Introduction
ment of appropriate therapies. Positron emission tomography
(PET) is an appropriate tool to measure in vivo directly, non-inva-
Serotonin (5-hydroxytryptamine, 5-HT), its transporter and
various receptors are of central interest in the field of medicinal
chemistry.1–3 Seven major families of transmembrane receptors
(5-HT1–7) and one transporter (SERT) are known to control 5-HT
function by three different structures (transporters, ligand-gated
ion channels and G-protein-coupled receptors).4 The role of 5-
HT2A receptors in the regulation of a number of processes of the
central nervous system (CNS) such as mood, appetite, sexual
behaviour, learning and memory and their dysfunctions such as
psychosis, depression and anxiety has been well documented.5,6
In particular, the 5-HT2A receptors have been implicated in the
beneficial effects of some antidepressants as well as antipsychot-
ics.7 All clinically approved atypical antipsychotic drugs are also
potent 5-HT2A receptor antagonists.8,9 Moreover, many hallucino-
gens including LSD function as agonists at 5-HT2A receptors.7
Consequently, in vivo studies of 5-HT2A receptor availability
would significantly advance the understanding of the biological
principles of mentioned disorders and contribute to the develop-
sively and repetitively the relevant pharmacologic parameters of
ligand–neuroreceptor interactions.
Supposed adequate radiolabeled neurotransmitter analogues are
available for the molecular imaging of the 5-HT2A receptor. To date,
in vivo studies have been performed with several 5-HT2A selective
antagonists. Of these tracers, [11C]MDL 100907 (a) and [18F]altanser-
in (b) represent the radioligands of choice for in vivo 5-HT2A PET
imaging because of their high affinity and selectivity for the 5-
HT2A receptor. In addition to their high binding affinities to the 5-
HT2A receptor (altanserin: Ki = 0.13 nM; MDL 100907 Ki = 0.36 nM)
their binding affinities are more than 30-fold lower for other rele-
vant receptors such as 5-HT1A, 5-HT2C, a
1, D1 and D2 (Table 1).10–14
In in vitro and in in vivo experiments, both tracers revealed high
affinity, selectivity and a good ratio of specific to non-specific
Table 1
Affinities (Ki (nM)) of altanserin and MDL 10090710–14
5-HT1A
5-HT2A
5-HT2c
D2
a1
Altanserin
(R)-MDL 100907
1570
>10,000
0.13
0.36
40
107
62
2250
4.55
128
* Corresponding author. Tel.: +49 6131 39 25849; fax: +49 6131 39 24692.
E-mail address: herthm@uni-mainz.de (M.M. Herth).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.03.021

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M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
Figure 1. Structures of [11C]MDL 100907 (a), [18F]altanserin (b) and [18F]MH.MZ (c).
binding for 5-HT2A receptors.15,16 However, Table 1 indicates that
the selectivity of [11C]MDL 100907 for the 5-HT2A receptor is
slightly higher than that of [18F]altanserin.15 Tracer affinity and
selectivity are of crucial importance for uptake kinetics in brain,
and tracers with very high affinity and selectivity give new insights
into the role of the status of the serotonergic system and antipsy-
chotic drug action. For example, Mintun et al. measured in vivo
with [18F]altanserin a decreased hippocampel 5-HT2A receptor
binding in major depressive patients.17
Heinrich et al.22 described an optimization of the structure and
the discovery of a selective 5-HT2A antagonist, but no attempts
have been made to optimize these MDL 100907 analogues for
in vivo PET imaging.
Herein, we report the syntheses of new MDL 100907 analogues
to enlighten structure–activity relationships. In addition, some
new derivatives may be considered as potential 18F-radioligands
for 5-HT2A receptor PET imaging.
Concerning molecular imaging, the advantage of [18F]altanserin
(b) over [11C]MDL 100907 (a) is the possibility to perform equilib-
rium scans lasting several hours and to transport the tracer to
other facilities based on the 110 min half-life of 18F-fluorine.
A drawback of [18F]altanserin is its rapid and extensive metab-
olism. Four metabolites are formed in humans that cross the blood-
brain-barrier,13 whereas metabolites of [11C]MDL 100907 do not
enter the brain to any larger extent.18
The aim of this study was to synthesize a ligand combining the
reported better selectivity and in vivo stability of MDL 100907 as
compared to those of altanserin and the superior isotopic proper-
ties of an 18F-label as compared to those of a 11C-label.
2. Results and discussion
2.1. Chemistry
Organic synthesis of MDL 100907 has been described in the liter-
atureby Huanget al.16 and Ullrichand Ice.23 Bothmethodsdepended
upontheformationof aWeinrebamide, asa keyintermediate,which
is then reacted with ortho-lithiated veratrole derivatives to afford
the ketone matrix of the MDL 100907 lead structure.
Huang et al.16 synthesized the racemic phenolic precursor mol-
ecule first, and subsequently separated the isomers by chiral deriv-
atization with (S)-(+)-a-methoxyphenyl-acetic acid and flash
chromatography. Whereas Ullrich and Ice23 performed the optical
resolution earlier, in particular before adding the p-fluoropheneth-
yl substituent to the piperidine moiety. This strategy also allows
introducing a variety of N-substituents.
Recently, we have reported the synthesis, first in vitro, ex vivo
and in vivo evaluations of an 18F-analogue of MDL 100907,
[
18F]MH.MZ (c) (Fig. 1).
The promising results obtained in ex vivo and in vivo experi-
ments19,20 encouraged us to study structure–activity relationships
of MDL 100907 analogues in more detail aiming at even improving
affinity and selectivity of new compounds. Unfortunately, no
detailed structure–activity relationship has been reported yet for
this class of compound. A rudimental pharmacophore model has
been published by Andersen et al.21 It describes the binding of var-
ious arylpiperidines at 5-HT2 receptors. The model requires two
aryl substituents, separated by distance a and located distances b
and c from an amine moiety (Fig. 2). Distances suggested by Ander-
son et al. for a, b and c are 5.1, 7.5 and 8.1 Å, respectively.
We decided to follow a similar synthesis route, but in contrast
to Ullrich and Ice23 the ketone bodies (7) and (8) were isolated
(Scheme 1). Those compounds permit structure–affinity studies
of the ketone group versus the racemic or enantioselective
aliphatic secondary alcohol.
In addition, deprotection of the phenolic hydroxyl group is per-
formed earlier to get versatile access to fluoroethylated reference
compounds.
According to the literature,23 ethylisonipecotate (1) was t-boc-
protected and afterwards transformed to the corresponding Wein-
reb amide (3). Regioselective ortho-lithiated veratrole derivatives
(5/6) were reacted with the mentioned amide (3) to afford the ma-
trix ketone body (7/8). Either deprotection of the TBDPS-group
with NH4F followed by fluoroalkylation was performed or direct
deprotection of the piperidine moiety with TFA ensued by reduc-
tion with NaBH4 to the racemic alcohol was carried out. Com-
pounds (9)–(12) were prepared in this way (Scheme 1).
The racemic alcohol could be separated by means of salt forma-
tion with (+)- and (À)-mandelic acid (Scheme 2) as reported by
Ullrich and Ice.23
Figure 2. A general pharmacophore model to account for the binding of 5-HT2
antagonists.21

M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
2991
Scheme 1. Synthesis of MDL 100907 key intermediates.
Longer chain lengths lead to a higher
a
1 and D2 affinity as reported
by Schmidt et al.,24 that is, n > 2 were not considered.
Commercially unavailable (2-bromoethyl)-4-fluorobenzene
(36) and (1-bromomethyl)-4-fluorobenzene (35) were obtained
by treatment of 4-fluorophenethyl alcohol (34) or (4-fluorophenyl)
methanol (33) with PBr3 (Scheme 4). The latter resulted in a heavy
lachrymatory substance.
To determine the influence of a carbonyl group between the
piperidine and the phenyl moiety, preparation of the three com-
pounds (39)–(41) were tried via N-alkylation (Scheme 5).
In contrast to (39), both ketone derivatives (40)–(41) were syn-
thetically not accessible. Even Finkelstein-conditions, variation of
solvent and temperature could not alter the synthetic behaviour.
Modified reaction characteristics could possibly be due to the elec-
tronic withdrawing carbonyl group and could therefore lead to sty-
rene derivatives. These reactive by-products could interact with
themselves or other reactants thus forming a broad spectrum of
compounds. However, protection of the carbonyl moiety by form-
ing 2-(bromomethyl)-2-(4-fluorophenyl)-1,3-dioxolane (37), and
thus reducing the electronic withdrawing effect, could not
overcome the problem. N-Alkylation to (3-(2-fluoroethoxy)-2-
methoxyphenyl)(1-((2-(4-fluorophenyl)ethyl)-1,3-dioxolan-2-yl)
methyl)piperidin-4-yl)methanol (38) was not accessible probably
due to steric effects.
Scheme 2. Optical resolution of (10) and (11).
The diastereomeric salts were isolated and recrystallized twice
from methanol. Aqueous work up afforded the enantiomers in high
purity, as determined via optical resolution (Table 2).
Enantiomeric excess (ee) of compounds (13)–(16) was not
examined via chiral HPLC. Instead, enantioselective reference com-
pounds and precursors were tested on (ee) via chiral HPLC later on.
In addition, N-alkylation of piperidine derivatives was per-
formed in DMF in yields of 60–90% and provided compounds
(17)–(32) that enable structure–activity studies of the p-substitu-
ent of the aromatic ring and of the chain length [(–CH2–)n with
n = 1,2] between the piperidine and phenyl moiety (Scheme 3).
Table 2
Deprotection of the phenolic hydroxy moiety with NH4F or with
K2CO3 overnight leads to high yields of >75%. Precursors (42)–(49)
were prepared in such a way. In addition, reference compounds
(50)–(56) were synthesized by fluoroalkylation with 1,2-bromoflu-
oroethane (Scheme 6).
Alternatively, MH.MZ (55) and (54) could be prepared by reduc-
tion of their carbonyl derivatives with NaBH4. Similarly, compound
(57) could also be obtained via that reaction route (Scheme 7).
Optical resolution of (13)–(16)
Compd#
[a]
D
This work
Ref. 23
(13)
(14)
(15)
(16)
+46.86 (c 0.1, MeOH)
À53.34 (c 0.1, MeOH)
À6.32 (c 0.13; MeOH)
+7.04 (c 0.12, MeOH)
+45.5 (c 0.1, MeOH)
À46.8 (c 0.1, MeOH)
À7.1 (c 0.1, MeOH)
+6.6 (c 0.1, MeOH)

2992
M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
(7)
(17)/(18)/(19)/(20)
(21)/(22)/(23)
(10)
(11)
R2
O
R2
O
(24)/(25)/(26)/(27)/(28)
O
R1
R3
O
R1
HN
(14)
(16)
(12)
N
(29)
n
(30)
(31)/(32)
cmpd#
R1
R2
cmpd#
R1
R2
R3
n
7
TBDPS
TBDPS
Me
= O
- OH
- OH
OH
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
TBDPS
Me
= O
= O
- CH3
- NO2
2
2
2
2
2
2
2
1
2
2
2
2
2
2
2
2
10
11
14
16
12
= O
- OCH3
- F
TBDPS
Me
= O
OH
- OH
- OH
- OH
- OH
- OH
- OH
- OH
- OH
OH
- NO2
- OCH3
- F
-[CH2]2F
- OH
- F
Me
- NO2
- OCH3
- CH3
- F
Me
Me
Me
TBDPS
Me
- F
OH
-F
-[CH2]2F
-[CH2]2F
- OH
- OH
-H
32
(VK-1)
-NO2
Scheme 3. N-Alkylation of piperidine derivatives (general reaction conditions: alkylating agent, DMF, NaHCO3, 85 °C, 90 min).
Scheme 4. Synthesis of bromo-alkyl-4-fluorobenzenes.
Finally, an amine MDL 100907 derivative (58) was synthesized
by reduction of the NO2-compound (32) in a microwave oven (CEM
LabMate) (Scheme 8).
Enantiomeric excess of (R)-MH.MZ (56) and (R)-MDL 100907
(30) was determined by chiral HPLC analysis (Fig. 3). Purities of
ee >98% were detected.
Scheme 5. Synthesis to carbonyl derivatives of MDL 100907 via N-alkylation.

M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
2993
(17)
(18)
(19)
(20)
(42)
(43)
(44)
(45)
(42)
(43)
(44)
(45)
(50)
(51)
(52)
(53)
O
O
O
R
OTBDPS
R
OH
R
O
NaHCO3, BrCH2CH2F,
DMF
F
NH4F
(21)
(22)
(23)
(46)
(46)
(47)
(48)
(32)
(54)
(55)
(47)
(48)
(29)
(49)
(49)
(56)
cmpd#
R
R1
R2
cmpd#
R
R1
R2
42
43
44
45
46
47
48
= O
= O
= O
= O
-OH
-OH
-OH
-CH3
-NO2
50
51
= O
= O
= O
= O
-OH
-OH
-OH
-CH3
-NO2
-OCH3
-F
-OCH3
-F
52
R1
R1
53 [MA-1]
32 [VK-1]
54
N
N
-NO2
-OCH3
-F
-NO2
-OCH3
-F
R2
R2
55 [MH.MZ]
56
[(R)-
49
OH
-F
OH
-F
MH.MZ]
Scheme 6. Deprotection and fluoroalkylation of various MDL 100907 derivatives.
Scheme 7. Reduction of carbonyl-compounds to their corresponding alcohol derivatives.
Scheme 8. Synthesis of (58) by reduction of (32) in a microwave oven.

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M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
expected. Influence of p-substitution of the aryl moiety was
examined and showed the expected ascending tendency –NO2 < –
OMe < –F < –H < –Me.
In conclusion, almost all reference compounds besides (39),
(50) and (57) demonstrated favourable lipophilicity and therefore
should have good in vivo properties. In comparison, relevant label-
ling precursors, which could be possibly formed via metabolism of
the parent, should penetrate the BBB less because of their reduced
logP values.
2.3. Receptor characterization
2.3.1. Affinity towards the 5-HT2A receptor
5-HT2A receptor affinity was determined by a radioligand com-
petition binding assay with GF-62 cells, a clonal cell line expressing
high amounts (5–7 pmol/mg) of the 5-HT2A receptor. The test tubes
contained [3H]MDL (0.2 nM) and seven different concentrations of
Figure 3. Chiral HPLC analyses of (R)-MH.MZ: The black line represents the racemat
(MH.MZ); in contrast, the grey line shows the enantioselective pure compound (R)-
MH.MZ.
the test compounds (1
lM–1 pM) in a total of 1 mL assay buffer.
Ketanserin (1 M) was added to determine non-specific binding.
l
Binding affinities of the tested compounds are shown in Table 4.
The tested compounds had affinities to the 5-HT2A receptor in
the nanomolar range, except (24) and (39). Both compounds are
varied between the piperidine and phenyl ring. Shortening the
chain length from n = 2 to n = 1 leads to a total loss of affinity
towards the 5-HT2A receptor and is therefore in accordance with
the receptor model suggested by Andersen et al.21 It describes
the ideal distance between the phenyl moieties to be 8.1 Å. Intro-
ducing an amide between the piperidine and phenyl ring reduced
the affinity by a factor of 2000. This is probably due to the lower
basic characteristic properties of the resulting compound than
the original tertiary amine structure.
Moreover, replacing the 3-methoxy- by a fluoroethoxy group
slightly reduces the 5-HT2A affinity but the remaining compound
is still within the nanomolar range of the parent, for example,
(28)–(55), (30)–(56) and (27)–(57). However, 3-hydroxy deriva-
tives (48)–(55) had a better affinity. In contrast, introducing a
methoxy- or a nitro-moiety to the phenethyl group resulted in a
reduced affinity by a factor of ꢀ20 for methoxy- and by a factor
of ꢀ40 for nitro-derivatives, for example, (28)–(25)–(26) or (53)–
(52)–(51). One exception to the mentioned results was found by
analyzing compounds (32) and (54). Indeed, replacing the fluorine
atom of MH.MZ (55) by a nitro- or a methoxy group leads to a
decreased affinity, but only by factor ꢀ3 for the nitro- and by factor
ꢀ7 for the methoxy compound. Interestingly, reduction of affinity
appears not so harsh and vice versa in that case compared with
(28)–(25)–(26) and (53)–(52)–(51). Therefore, we speculate that
(32) and (54) could fit differently in the binding pocket. Neverthe-
less, all compounds of these series show medium affinity towards
the 5-HT2A receptor. Besides, replacing the p-substituent of the
phenethyl moiety by a methyl group, an amine or a single proton
2.2. Lipophilicities
The lipophilicities of promising compounds were determined
using the HPLC method according to Krass et al.25 Soerensen buffer
was used as eluent and logP values were calculated from retention
times of the respective substances. The calculated logP values are
displayed in Table 3.
All new fluoroethylated reference compounds besides (39), (50)
and (57) examined showed logP values between 2 and 3, ranging
within those found for already established radiotracers such as
altanserin and MDL 100907 (Table 3). Rowley et al. pointed out
that a logP between 2 and 3 presents the ideal interval for small
molecules for penetrating the blood-brain-barrier (BBB).26 This fact
gives rise to the assumption that the new compounds may have
similarly good properties for molecular imaging.
As expected, logP values of precursors (46) and (48) are reduced
by 0.4 compared to their corresponding reference compounds VK-1
(32) and MH.MZ (55) probably resulting in less BBB penetrating
ligands, which are formed by the metabolic cleavage of the ether.
For compound (48), MDL 105725, this behaviour has already been
observed.18 Comparison of ketone- versus hydroxyl moieties
shows a 0.3 higher lipophilicity for carbonyl compounds, see, for
example, (53)–(55). MDL 100907 (28), MH.MZ (55) and MDL
105725 (48) indicate the expected descending order of lipophilic-
ity. However, logP values of MDL 100907 (28) and MH.MZ (55) dif-
fer not much and therefore, similar lipophilicities should be
Table 3
Lipophilicities/logP values of altanserin, MDL 100907 and new MDL 100907
derivativesa
Reference compounds
Precursors
Cmpd#
Name
Compd#
—
LogP
LogP
Table 4
Affinities of tested ligands towards the 5-HT2A receptora
Altanserin
2.15
2.98
2.98
2.80
2.80
3.08
2.37
3.40
3.64
2.72
2.71
3.02
1.57
2.92
(48)
(46)
2.27
1.90
(R)-MDL 100907
MDL 100907
MH.MZ
(30)
(28)
(55)
(56)
(53)
(32)
(57)
(50)
(54)
(51)
(52)
(39)
(31)
Name
Compd#
Ki (nM)
Compd#
Ki (nM)
Altanserin
(R)-MDL 100907
MDL 100907
MH.MZ
(R)-MH.MZ
MA-1
—
0.72 0.19
0.38 0.05
2.10 0.13
9.02 2.11
0.72 0.21
3.23 0.18
26.0 6.70
>1000
(31)
(39)
(45)
(48)
(49)
(50)
(51)
(52)
(54)
(57)
(58)
1.63 5.50
1987 360
1.34 0.48
1.24 0.23
0.25 0.06
4.56 0.73
138 20.0
153 93.0
59 54.0
(R)-MH.MZ
MA-1
VK-1
(30)
(28)
(55)
(56)
(53)
(32)
(24)
(25)
(26)
(27)
VK-1
90.0 71.0
55 12.0
0.31 0.06
1.83 0.43
2.06 0.96
a
a
LogP values are based on the means of three experiments.
Ki values in nM SEM are based on the means of four experiments.

M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
2995
Table 6
leads to a slightly increased affinity, for example, (28)–(27) and
(55)–(58)–(57). This may probably be due to the slightly different
space required. Changing the racemic secondary hydroxy group to
a ketone group [(28)–(53); (57)–(50)] showed no dramatic effects
but as expected, the enantioselective pure product (56) showed
increased affinity than the carbonyl (53) and racemic compounds
(28).
Affinities to a broad spectrum of neuroreceptors and transporters of MDL 100907
derivatives
Kia (nM)
MA-1 (53)
(R)-MH.MZ (56)
MH.MZ (55)
(50)
(57)
D1
D2
D4
1410
3828
174
3828
2686
442
899
>10,000
544
1930
>10,000
923
1759
>10,000
2708
D5
Beta3
H1
H2
H3
Sigma 2
Alpha 1A
Alpha 1B
Alpha 2A
Alpha 2C
DAT
7398
>10,000
944
1757
>10,000
86
146
550
863
333
7419
>10,000
509
2428
>10,000
923
n.d.
>10,000
374
3178
>10,000
n.d.
n.d.
>10,000
665
827
9033
228
n.d.
n.d.
n.d.
154
n.d.
>10,000
439
1156
>10,000
676
2.3.2. Selectivity of promising ligands
Promising 5-HT2A affinity compounds (32) and (50)–(57) were
assayed for their selectivity for other 5-HT receptor subtypes (Ta-
ble 5).
Besides a medium affinity of MH.MZ (55) towards the 5-HT7
(Ki = 116 14 nM), and the 5-HT2C receptor (Ki = 71 10 nM), all
335
500
n.d.
325
n.d.
>10,000
>10,000
143
>10,000
2646
other tested receptors showed affinities in the
lM range. Thus,
>10,000
n.d.
>10,000
2207
>10,000
>10,000
148
>10,000
3516
>10,000
MH.MZ (55) (5-HT2A: Ki = 9.02 2.11 nM) is a selective ligand for
the 5-HT2A receptor. Furthermore, the enantioselective derivative
(R)-MH.MZ (56) even showed a better selectivity profile, whereas
MA-1 (53) showed a good affinity towards the 5-HT2A receptor
(Ki = 3.23 0.18 nM) and a medium affinity towards the 5-HT2C
receptor (Ki = 128 14 nM). Moreover, the introduced carbonyl
group within MA-1 (53) leads to a slightly affine compound of
the 5-HT1A receptor (Ki = 1681 97 nM) compared to its structural
related hydroxyl group derivatives MH.MZ (55) and (R)-MH.MZ
(56). But still MA-1 (53) is a selective 5-HT2A ligand. All other
tested compounds (32), (50), (51), (52), (54) and (57) showed a
similar behaviour regarding the 5-HT2A selectivity.
Moreover, high 5-HT2A affinity compounds (50), (53), (56) and
(57) were also assayed for a broad spectrum of receptors and
monoamine transporters in competitive binding experiments
in vitro using cloned human receptors or transporters (Table 6).
Interestingly, new compounds, (50), (53), (56) and (57), have no
affinity to Beta1-3, H4, M1-M5, DOR, KOR receptors. Minor affinity
towards the other tested receptors and transporters (D1-D5, H1-
H2, DAT, SERT, MOR, sigma 2, alpha 1A-2B) is summarized in Table
6.
>10,000
3087
>10,000
n.d
1009
2009
SERT
MOR
>10,000
a
Ki values in nM are based on the means of four experiments; n.d. (not
determined).
(56) and (27)–(57). The 3-hydroxy derivatives (48)–(55) had a bet-
ter affinity. In contrast, introducing a methoxy or a nitro moiety to
the phenethyl group results in a reduction of affinity to medium
affine compounds (Ki ꢀ 1
lM). Besides, replacing the p-substituent
of the phenethyl moiety by a methyl group, an amine or a single
proton slightly increases the affinity, for example, (28)–(27) and
(55)–(58)–(57). This could be due to the slightly different space
required. Changing the racemic secondary hydroxyl group to a
ketone group [(28)–(53); (57)–(50)] causes no dramatic effects
but as expected, the enantioselective pure product (56) enhances
the affinity than the carbonyl (53) and the racemic compound
(28). Furthermore, 5-HT2A affine compounds (Tables 5 and 6) were
tested for selectivity. All tested ligands thereby showed a reason-
able receptor profile and determined them as 5-HT2A selective
compounds.
3. Conclusion
Except for (39), (50) and (57), all our fluoroethylated com-
pounds had logP values between 2 and 3, that is, within the range
of those of already established radiotracers such as altanserin and
MDL 100907.
The novel compounds MA-1 (53) and (R)-MH.MZ (56) seem to
be promising high affinity compounds for 18F-PET-tracer due to
their Ki-values in the nanomolar range of 1–10 towards the 5-
HT2A receptor and their insignificant binding to other 5-HT recep-
tor subtypes or receptors. Interestingly, compounds MA-1 (53),
MH.MZ (55) and (R)-MH.MZ (56) showed a receptor selectivity
profile similar to MDL 100907, which is slightly improved
A series of novel MDL 100907 derivatives containing a fluorine
atom were synthesized and evaluated for their in vitro behaviour.
Structure–activity relationships (SARs) studies suggested that the
tested compounds had affinities to the 5-HT2A receptor in the
nanomolar range except (24) and (39), which are varied between
the piperidine and phenyl ring. This is in accordance with the
rudimental pharmacophore model that has been published by
Andersen et al.21 Replacing the 3-methoxy by a fluoroethoxy group
slightly reduces the 5-HT2A affinity but still the affinity is within
the nanomolar range of the parent, for example, (28)–(55), (30)–
Table 5
Ligand affinities to 5-HT receptors
Kia (nM)
MA-1 (53)
(R)-MH.MZ (56)
MH.MZ (55)
(50)
(57)
(51)
VK-1 (32)
(52)
(54)
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT2A
5-HT2B
5-HT2C
5-HT3
1681 97
2174 336
713 124
>10,000
3.23 0.18
960 113
128 14
>10,000
>10,000
>10,000
1883 158
3359 676
n.d.
>10,000
1723 239
>10,000
1835 259
>10,000
118 20.0
1052 111
>10,000
>10,000
>10,000
>10,000
6241 847
>10,000
>10,000
991 135
>10,000
1436 196
>10,000
153 93.0
1972 181
9417 2798
>10,000
>10,000
>10,000
>10,000
>10,000
59 54
2751 289
>10,000
>10,000
>10,000
>10,000
>10,000
884 106
1062 186
>10,000
0.72 0.21
320 27
1846 426
706 109
>10,000
9.02 2.11
299 27
71 10
>10,000
>10,000
3890 1921
116 14
4886 1081
1440 253
>10,000
1.83 0.43
466 51
508 70
>10,000
>10,000
>10,000
498 77
3418 512
>10,000
26.0 6.70
1844 183
>10,000
>10,000
>10,000
>10,000
5170 642
>10,000
4.56 0.73
559 58
497 72
>10,000
1684 287
>10,000
53
7
>10,000
5-HT5A
5-HT6
5-HT7
1584 270
>10,000
210 38
6814 982
3842 623
59 11
>10,000
>10,000
2862 430
731 117
a
Ki values in nM SEM are based on the means of four experiments; n.d. (not determined).

2996
M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
compared to that of altanserin. Therefore, the mentioned
compounds could possibly be preferable antagonistic 18F-tracers
for visualization of the 5-HT2A status. Medium affine compounds
(VK-1 (32), (51), (52) and (54)) have Ki values of 30–120 nM which
are in the range of endogenous serotonin (according to PDSP).
Challenging experiments with those compounds to measure
changes in the endogenous serotonin level could be possible and
allow a deeper insight in the serotonin system.
for 2 h. After cooling to À50 °C, 4-(N-methoxy-N-methyl-carboxa-
mido)-1-piperidinecarboxylic acid t-butyl ester (3) (153 mmol)
was added dropwise to the stirred solution, followed by warming
to room temperature and stirring for 2 h. Saturated aqueous NH4Cl
was added; the layers were separated and the aqueous layer was
extracted 3Â with ether. The combined organic extracts were
washed with brine, dried (Na2SO4), filtered and evaporated to
afford the crude product. Chromatography of the residue gave
the pure product.
In extension to the in vitro data discussed concerning the SAR of
the new fluorine containing MDL 100907 derivatives, 18F-fluoroe-
thylation and small
l
PET studies are planned to exam the in vivo
4.2.3.1. 4-(2-Methoxy-3-(t-butyldiphenylsilyloxy)-benzoyl)-1-
piperidinecarboxylic acid t-butyl ester (7). 21 g (5) (58 mmol),
n-BuLi (120 mmol), 15.9 g (3) (58 mmol) and 150 mL dry THF
yielded 14.8 g of (7) (25.8 mmol; 44%). Rf 0.43 (silica gel, 5:1 PE/
EtOAc). 1H NMR: (300 MHz, CDCl3) d [ppm] = 7.702 (dd, 4H);
7.421–7.322 (m, 6H); 6.832 (t, 1H); 6.685 (t, 1H); 6.617 (dd, 1H);
4.053 (d, 2H); 3.901 (s, 3H); 3.176 (tt, 1H); 2.827 (dt, 2H); 1.764
(dd, 2H); 1.527 (dd, 2H); 1.444 (s, 9H); 1.113 (s, 9H) MS (FD) m/z
(% rel Int.): 573.4 (100.0 [M]+); 574.4 (44.8 [M+1]+); 575.4 (14.2
[M+2]+).
characteristics of the potential 5-HT2A ligands. In particular, a com-
parison of [18F]MH.MZ to [18F]altanserin and other 18F-labelled
MDL 100907 derivatives should be done.
4. Experimental
4.1. General
4.1.1. Chemicals, flash chromatographies and TLC
Chemicals were purchased from ABX, Acros, Aldrich, Fluka,
Merck or Sigma. Unless otherwise noted all chemicals were used
without further purification. Moisture sensitive reactions were car-
ried out under an argon or nitrogen atmosphere using dry solvents
over molecular sieve.
Chromatographic purifications were conducted on Silica Gel 60
(0.040–0.063 mm, Acros) columns. TLCs were run on pre-coated
plates of Silica Gel 60F254 (Merck).
4.2.3.2. 4-(2,3-Bismethoxy-benzoyl)-1-piperidinecarboxylic
acid t-butyl ester (8). 10.65 g veratrole (6) (58 mmol), n-BuLi
(77 mmol), 20.63 g (3) (74.3 mmol) and 200 mL dry THF yielded
18 g of (8) (51.72 mmol; 68%). Rf 0.27 (silica gel, 4.5:1 PE/EtOAc).
1H NMR: (300 MHz, CDCl3)
d [ppm] = 7.087–6.922 (m, 3H);
4.095–4.048 (m, 2H); 3.861 (s, 3H); 3.832 (s, 3H); 3.241–3.167
(m, 1H); 2.839–2.747 (m, 2H); 1.843–1.789 (dd, 2H); 1.611–
1.490 (m, 2H); 1.414 (s, 9H) MS (FD) m/z (% rel Int.): 349.4
(100.0 [M]+); 350.4 (20.69 [M+1]+).
4.1.2. Analytical HPLC
Systems were equipped with a Sykam S 1100 Solvent Delivery
System, S 8110 Low Pressure Gradient Mixer, Rheodyne 9725i
Inject Valve; Linear UVIS-205 Absorbance Detector; Axxiom
4.2.4. General procedure for TBDPS-deprotection
A solution of TBDPS-protected substance (4 mmol) and NH4F
(9 mmol) in anhydrous MeOH (30 mL) was stirred for 15 min at
70 °C. After evaporation of the solvent, the residue was taken up
in NH4OH and extracted 3Â with CHCl3. The combined organic
extracts were washed with brine, dried (Na2SO4), filtered and evap-
orated. Chromatography of the residue gave the pure product.
Chromatography 900–200 Pyramid; Pyramid 2.07; loop: 20 lL.
4.1.3. Spectroscopy
300 and 400 MHz NMR spectra were recorded on a Bruker
300 MHz-FT-NMR-spectrometer AC 300 or on a Bruker-Biospin
DRX 400 MHz spectrometer. Chemical shifts were reported in parts
per million (ppm). FD mass spectrometry was performed on a Finn-
igan MAT90-Spectrometer. Optical rotations were determined
with a polarimeter Perkin–Elmer 241 using 10 cm, 1 mL cell.
4.2.4.1. 4-(3-Hydroxy-2-methoxy-benzoyl)-1-piperidinecarb-
oxylic acid t-butyl ester (9a). 0.75 g (7) (1.31 mmol), 0.41 g NH4F
(5.54 mmol) and 15 mL MeOH yielded 0.27 g of (9a) (0.8 mmol;
61%). Rf 0.32 (silica gel, 1:1 PE/EtOAc). 1H NMR (300 MHz, CDCl3)
d [ppm] = 7.079–6.917 (m, 3H); 6.151 (br s, 1H); 4.065 (d, 2H);
3.779 (s, 3H); 3.211 (tt, 1H); 2.816 (t, 2H); 1.787 (dd, 2H); 1.639–
1.496 (m, 2H); 1.427 (s, 9H) MS (FD) m/z (% rel Int.): 473.3
(100.0 [M]+); 474.3 (56.7 [M+1]+); 475.3 (12.5 [M+2]+).
4.1.4. Microwave
Syntheses were carried out in a commercially available micro-
wave oven (CEM LabMate).
4.2. Chemistry
4.2.4.2. 4-(3-Hydroxy-2-methoxy-benzoyl)-1-(2-p-toluylethyl)-
piperidine (42). 0.88 g (17) (1.49 mmol), 0.2 g NH4F (2.64 mmol)
and 30 mL MeOH yielded 185 mg of (42) (0.52 mmol; 35%). Rf
0.45 (silica gel, 8:1 CHCl3/MeOH). 1H NMR (300 MHz, CDCl3) d
[ppm] = 7.173–6.882 (m, 7H); 3.789 (s, 3H); 3.200–3.154 (m,
1H); 3.077–3.038 (m, 2H); 2.889–2.852 (m, 3H); 2.436 (br s, 1H);
2.277 (s, 3H); 2.038–2.005 (m, 2H); 1.934–1.812 (m, 2H) MS (FD)
m/z (% rel Int.): 354.3 (100.0 [M]+); 353.3 (98.37 [MÀ1]+); 475.3
(12.5 [M+2]+).
4.2.1. 4-(N-Methoxy-N-methyl-carboxamido)-1-piperidinecarboxylic
acid t-butyl ester (3)
4-(N-Methoxy-N-methyl-carboxamido)-1-piperidinecarboxylic
acid t-butyl ester (3) was synthesized as described by Carr et al.27
4.2.2. t-Butyldiphenylsilyl-guaiacol (5)
t-Butyldiphenylsilyl-guaiacol (5) was synthesized as described
by Mathis et al.28
4.2.4.3. 4-(3-Hydroxy-2-methoxy-benzoyl)-1-(2-p-nitrophenyl-
ethyl)-piperidine (43). 900 mg (18) (1.45 mol), 300 mg NH4F
(8 mmol) and 16 mL dry MeOH yielded 475 mg of (43) (1.23 mmol;
86%). Rf 0.55 (silica gel, 8:1 CHCl3/MeOH). 1H NMR (300 MHz,
CDCl3) d [ppm] = 8.118 (dt, 2H); 7.320 (dt, 2H); 7.073–6.994 (m,
2H); 6.930 (dd, 1H); 3.905 (t, 1H); 3.784 (s, 3H); 3.095 (t, 1H);
2.998–2.864 (m, 4H); 2.635 (t, 2H); 2.204 (t, 2H); 1.884 (br d,
4.2.3. 4-(2-Methoxy-3-(t-butyldiphenylsilyloxy)-benzoyl)-1-
piperidinecarboxylic acid t-butyl ester (7) and 4-(2,3-Bismethoxy-
benzoyl)-1-piperidinecarboxylic acid t-butyl ester (8)
n-Butyllithium (64.5 mL of
a 2.5 M solution in hexane,
161 mmol) was added to a stirred solution of t-butyldiphenylsi-
lyl-guaiacol (5) or veratrole (6) (161 mmol) under nitrogen at
0 °C. The ice bath was removed and the solution was allowed to stir

M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
2997
2H); 1.826–1.689 (m, 2H) MS (FD) m/z (% rel Int.): 384.2 (100.0
4.2.5. Alkylating procedure for 1,2-bromofluoroethane
[M]+); 385.2 (66.1 [M+1]+); 386.2 (13.3 [M+2]+).
NaH (0.42 mmol) was gradually added to the corresponding
phenolic derivatives (0.42 mmol) diluted in 20 mL of dry, cold
DMSO (0 °C) and stirred for 30 min. To the resulted mixture 1,2-
bromofluoroethane (0.42 mmol) was injected slowly and after-
wards stirred for 20 h at 60 °C. After evaporation of the solvent,
the residue was taken up in EtOAc, washed with H2O and brine
and finally extracted 3Â with EtOAc. The combined organic ex-
tracts were dried (Na2SO4), filtered and evaporated. Chromatogra-
phy of the residue gave the pure product.
4.2.4.4. 4-(3-Hydroxy-2-methoxy-benzoyl)-1-(2-p-methoxyphe-
nylethyl)-piperidine (44). 591 mg (19) (0.88 mmol), 0.9 g NH4F
(24 mmol) and 20 mL MeOH yielded 290 mg of (44) (0.78 mmol;
80%). Rf 0.53 (silica gel, 8:1 CHCl3/MeOH). 1H NMR (300 MHz,
CDCl3) d [ppm] = 7.193–7.076 (m, 3H); 7.005 (t, 1H); 6.915 (dd,
1H); 6.801 (dt, 2H); 3.790 (s, 3H); 3.751 (s, 3H); 3.298 (br s, 1H);
3.092 (br s, 2H); 2.918 (dt, 4H); 2.884–2.594 (m, 2H); 2.174 (br s,
2H); 2.044–1.905 (m, 2H) MS (FD) m/z (% rel Int.): 369.2 (100.0
[M]+); 370.2 (62.1 [M+1]+); 371.2 (11.7 [M+2]+).
4.2.5.1. 4-(3-(2-Fluoroethoxy)-2-methoxybenzoyl)-1-piperdine-
carboxylic acid t-butyl ester (9). 6.27 g (9a) (20 mmol), 481 mg
NaH (20 mmol), 2.54 g 1,2-bromofluoroethane (20 mmol) and
100 mL dry DMF yielded 7.77 g of (9) (20 mmol; 100%). Rf 0.79 (sil-
4.2.4.5.
4-(3-Hydroxy-2-methoxy-benzoyl)-1-(2-p-fluorophe-
nylethyl)-piperidine (45). 2.99 g (20) (5 mmol), 0.91 g NH4F
(12.43 mmol) and 30 mL MeOH yielded 1.65 g of (45) (4.63 mmol;
92%). Rf 0.64 (silica gel, 5:1 CHCl3/MeOH). 1H NMR (300 MHz,
CDCl3) d [ppm] = 7.144–6.906 (m, 7H); 3.785 (s, 3H); 3.108–2.967
(m, 3H); 2.814–2.759 (m, 2H); 2.611–2.557 (m, 2H); 2.192 (br s,
2H); 1.935–1.766 (m, 4H) MS (FD) m/z (% rel Int.): 358.2 (100.0
[M]+); 359.2 (17.19 [M+1]+).
ica gel, 20:1 CHCl3/MeOH). 1H NMR (300 MHZ, CDCl3)
d
[ppm] = 7.083–6.978 (m, 3H); 4.856 (t, 1H); 4.698 (t, 1H); 4.296
(t, 1H); 4.201 (t, 1H); 4.047 (br d, 2H); 3.882 (s, 3H); 3.215 (tt,
1H); 2.800 (t, 2H); 1.806 (dd, 2H); 1.623–1.478 (m, 2H); 1.423 (s,
9H) MS (FD) m/z (% rel Int.): 381.3 (100.0 [M]+); 382.3 (17.49
[M+1]+); 383.3 (1.57 [M+2]+).
4.2.4.6. (3-Hydroxy-2-methoxyphenyl)-(1-(2-p-nitrophenyleth-
yl)-piperidine-4-yl)-methanol (46). 932 mg (21) (1.5 mmol),
300 mg NH4F (8 mmol) and 20 mL MeOH yielded 515 mg of
(46) (1.33 mmol; 89%). Rf 0.52 (silica gel, 8:1 CHCl3/MeOH). 1H
NMR (300 MHz, CDCl3) d [ppm] = 9.202 (s, 1H); 8.111 (d, 2H);
7.490 (d, 2H); 6.889–6.679 (m, 2H); 4.891 (d, 1H); 4.552 (t,
1H); 3.684 (s, 3H); 3.333 (br s, 1H); 3.039–2.795 (m, 4H);
2.589–2.487 (m, 4H); 2.015–1.689 (m, 2H); 1.429 (br s, 1H);
1.330–1.119 (m, 2H) MS (FD) m/z (% rel Int.): 386.9 (100.0
[M]+); 387.9 (20.5 [M+1]+).
4.2.5.2.
(3-(2-Fluorethoxy)-2-methoxyphenyl)-(1-(2-p-nitro-
phenylethyl)-piperidine-4-yl)-methanol (VK-1) (32). 415 mg
(46) (1 mmol), 24 mg NaH (1 mmol), 0.13 g 1,2-bromofluoroe-
thane (1 mmol) and 10 mL dry DMF yielded 430 mg of (32)
(0.93 mmol; 93%). Rf 0.64 (silica gel, 8:1 CHCl3/MeOH). 1H
NMR (300 MHz, CDCl3) d [ppm] = 8.095–8.123 (d, 2H); 7.314–
7.343 (d, 2H); 7.010 (t, 1H); 6.907 (d, 1H); 6.822 (d, 1H);
4.845 (q, 1H); 4.688 (q, 1H); 4.611 (d, 1H); 4.274 (t, 1H);
4.180 (t, 1H); 3.888 (s, 3H); 3.078 (d, 1H); 2.918 (t, 3H); 2.602
(t, 2H); 1.938–2.120 (m, 3H); 1.612–1.750 (m, 1H); 1.205–
1.573 (m, 4H) MS (FD) m/z (% rel Int.): 432.0 (100.0 [M]+);
433.0 (45.8 [M+1]+); 434.0 (8.0 [M+2]+).
4.2.4.7. (3-Hydroxy-2-methoxyphenyl)-(1-(2-p-methoxyphenyl-
ethyl)-piperidine-4-yl)-methanol (47). 420 mg (22) (0.69 mmol),
600 mg NH4F (16 mmol) and 15 mL MeOH yielded 223 mg of
(47) (0.6 mmol; 87%). Rf 0.26 (silica gel, 8:1 CHCl3/MeOH). 1H
NMR (300 MHz, CDCl3) d [ppm] = 7.065 (dt, 2H); 6.985–6.752 (m,
5H); 4.635 (d, 1H); 3.788 (s, 3H); 3.743 (s, 3H); 3.177 (dd, 2H);
2.887 (d, 1H); 2.779 (dt, 4H); 2.221 (q, 1H); 2.108 (d, 2H); 1.709
(q, 1H); 1.535 (q, 1H); 1.318 (d, 1H) MS (FD) m/z (% rel Int.):
371.0 (100.0 [M]+); 372.0 (71.9 [M+1]+).
4.2.5.3. 4-(3-(2-Fluoroethoxy)-2-methoxy-benzoyl)-1-(2-p-tolu-
ylethyl)-piperidine (50). 150 mg (42) (0.42 mmol), 10.1 mg NaH
(0.42 mmol), 53.45 mg 1,2-bromofluoroethane (0.45 mmol) and
20 mL dry DMF yielded 150 mg of (50) (0.38 mmol; 91%). Rf 0.69
(silica gel, 12:1 CHCl3/MeOH).1H NMR (300 MHz, CDCl3)
d
[ppm] = 7.094–6.997 (m, 7H); 4.868–4.841 (m, 1H); 4.710–4.683
(m, 1H); 4.307–4.280 (m, 1H); 4.214–4.187 (m, 1H); 3.889 (s,
3H); 3.323 (br s, 1H); 3.097–2.694 (m, 7H); 2.349–2.164 (s, 5H);
2.071–1.900 (br s, 3H) MS (FD) m/z (% rel Int.): 399.3 (100.0
[M]+); 400.3 (29.86 [M+1]+).
4.2.4.8.
(3-Hydroxy-2-methoxyphenyl)-(1-(2-p-fluorophenyl-
ethyl)-piperidine-4-yl)-methanol (48). 1 g (23) (1.82 mmol),
0.71 g NH4F (9.6 mmol) and 30 mL MeOH yielded 0.65 g of (48)
(1.8 mmol; 95%). Rf 0.64 (silica gel, 5:1 CHCl3/MeOH). 1H NMR
(300 MHz, CDCl3), d [ppm] = 7.083–7.181 (m, 2H); 6.811–7.073
(m, 5H); 4.649 (d, 1H); 3.810 (s, 3H); 3.063–3.175 (m, 1H);
2.884–3.004 (m, 1H); 2.768 (t, 2H); 2.542 (t, 2H); 1.855–2.147
(m, 3H); 1.624–1.797 (m, 1H); 1.197–1.586 (m, 3H) MS (FD) m/z
(% rel Int.): 360.5 (100.0 [M]+); 359.5 (55.81 [MÀ1]+); 361.4
(14.00 [M+1]+]; 358.5 (11.09 [MÀ2]+).
4.2.5.4.
nitrophenylethyl)-piperidine (51). 360 mg (43) (0.94 mmol),
23 mg NaH (0.94 mmol), 25 1,2-bromofluoroethane
(0.94 mmol) and 15 mL dry DMF yielded 203 mg of (51)
(0.47 mmol; 50%). Rf 0.86 (silica gel, 8:1 CHCl3/MeOH). 1H NMR
(300 MHz, CDCl3) d [ppm] = 8.094 (d, 2H); 7.317 (d, 2H); 7.082–
7.007 (t, 3H); 4.857 (t, 1H); 4.699 (t, 1H); 4.296 (t, 1H); 4.203 (t,
1H); 3.882 (s, 3H); 3.077 (t, 1H); 2.971–2.849 (q, 2H); 2.918 (t,
2H); 2.587 (t, 2H); 2.120 (t, 2H); 1.871 (d, 2H); 1.727 (dt, 2H) MS
(FD) m/z (% rel Int.): 429.9 (100.0 [M]+); 430.9 (2.64 [M+1]+).
4-(3-(2-Fluoroethoxy)-2-methoxy-benzoyl)-1-(2-p-
lL
4.2.4.9. (R)-(3-Hydroxy-2-methoxyphenyl)-(1-(2-p-fluorophe-
nylethyl)-piperidine-4-yl)-methanol (49). 1 g (29) (1.82 mmol),
0.71 g NH4F (9.6 mmol) and 30 mL MeOH yielded 0.64 g of (49)
(1.75 mmol; 93%). Rf 0.6 (silica gel, 5:1 CHCl3/MeOH). 1H NMR
(300 MHz, CDCl3) d [ppm] = 7.087–7.180 (m, 2H); 6.814–7.079
(m, 5H); 4.643 (d, 1H); 3.816 (s, 3H); 3.066–3.172 (m, 1H);
2.881–3.008 (m, 1H); 2.767 (t, 2H); 2.541 (t, 2H); 1.852–2.145
(m, 3H); 1.623–1.792 (m, 1H); 1.197–1.586 (m, 3H) MS (FD)
m/z (% rel Int.): 360.5 (100.0 [M]+); 359.5 (52.98 [MÀ1]+);
4.2.5.5.
methoxyphenylethyl)-piperidine (52). 20 mg (44) (0.54 mmol),
13 mg NaH (0.54 mmol), 14 1,2-bromofluoroethane
(0.54 mmol) and 15 mL dry DMF yielded 223 mg of (52)
(0.53 mmol; 98%). Rf 0.71 (silica gel, 8:1 CHCl3/MeOH). 1H NMR
(300 MHz, CDCl3) d [ppm] = 7.126–7.036 (m, 5H); 6.821 (d, 2H);
4.854 (t, 1H); 4.696 (t, 1H); 4.294 (t, 1H); 4.200 (t, 1H); 3.892 (s,
3H); 3.749 (s, 3H); 3.416 (s, 1H); 3.052 (m, 4H); 2.329 (m, 2H);
4-(3-(2-Fluoroethoxy)-2-methoxy-benzoyl)-1-(2-p-
lL
361.4 (11.77 [M+1]+); 358.5 (11.34 [MÀ2]+)
[a]D = +16.65 (c
0.1; MeOH).

2998
M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
2.122 (m, 2H); 2.027 (s, 2H); 1.220 (s, 2H) MS (FD) m/z (% rel Int.):
3.23 g of (10a) (6.8 mmol; 75%). Rf 0.33 (CHCl3/MeOH 5:1). 1H
NMR (300 MHz, CDCl3) d [ppm] = 7.727–7.670 (m, 4H); 7.466–
7.319 (m, 6H); 6.881 (dt, 1H); 6.751–6.631 (m, 2H); 6.417 (br
s, 1H); 3.908 (s, 3H); 3.383 (br s, 2H); 3.083 (br d, 2H); 2.098
(br s, 2H); 2.029–1.839 (m, 2H); 1.114 (s, 9H) MS (FD) m/z (%
rel Int.): 473.3 (100.0 [M]+); 474.3 (56.7 [M+1]+); 475.3 (12.5
[M+2]+).
415.2 (100.0 [M]+); 416.2 (35.5 [M+1]+); 417.3 (2.84 [M+2]+).
4.2.5.6. 4-(3-(2-Fluoroethoxy)-2-methoxy-benzoyl)-1-(2-p-flu-
orophenylethyl)-piperidine (MA-1) (53). 0.6 g (45) (1.68 mmol),
44.25 mg NaH (1.68 mmol), 124
lL
1,2-bromofluoroethane
(1.68 mmol) and 20 mL dry DMF yielded 420 mg of (53)
(1.04 mmol; 63%). Rf 0.8 (silica gel, 8:1 CHCl3/MeOH). 1H NMR
(300 MHz, CDCl3) d [ppm] = 7.155–6.908 (m, 7H); 4.872–4.845
(m, 1H); 4.712–4.687 (m, 1H); 4.312–4.285 (m, 1H); 3.885 (s,
3H); 3.128–3.078 (m, 1H); 3.032–2.931 (m, 2H); 2.823–2.771 (m,
2H); 2.611–2.539 (m, 2H); 2.021–1.929 (m, 2H); 1.840–1.686 (m,
2H) MS (FD) m/z (% rel Int.): 403.1 (100.0 [M]+); 404.1 (26.75
[M+1]+); 402.1 (26.17 [MÀ1]+).
4.2.6.2. 4-(2,3-Bismethoxy-benzoyl)-piperidine (11a). 18 g (8)
(51 mmol) and 120 mL TFA yielded 7.7 g of (11a) (31 mmol;
62%). Rf 0.57 (CHCl3/MeOH 5:1). 1H NMR: (300 MHz, DMSO-d6) d
[ppm] = 7.077–6.917 (m, 3H); 3.851 (s, 3H); 3.823 (s, 3H); 3.235–
3.068 (m, 3H); 2.897 (br s, 2H); 1.903–1.788 (d, 2H); 1.621–
1.489 (m, 2H) MS (FD) m/z (% rel Int.): 249.4 (100.0 [M]+); 250.4
(23.31 [M+1]+).
4.2.5.7. (3-(2-Fluoroethoxy)-2-methoxyphenyl)-(1-(2-p-meth-
oxyphenylethyl)-piperidine-4-yl)-methanol (54). 150 mg (47)
(0.4 mmol), 9.8 mg NaH (0.4 mmol), 11 lL 1,2-bromofluoroethane
4.2.6.3. 4-(3-(2-Fluoroethoxy)-2-methoxybenzoyl)-piperidine
(12a). 7.68 g (9) (20 mmol) and 100 mL TFA yielded 5.15 g of (12a)
(18.3 mmol; 92%). Rf 0.15 (CHCl3/MeOH 10:1). 1H NMR (300 MHz,
CDCl3) d [ppm] = 7.075–6.964 (m, 3H); 4.852 (t, 1H); 4.694 (t, 1H);
4.294 (t, 1H); 4.198 (t, 1H); 3.879 (s, 3H); 3.197 (tt, 1H); 3.100 (dt,
2H); 2.659 (td, 2H); 2.538 (br s, 1H); 1.834 (dd, 2H); 1.622–1.480
(m, 2H) MS (FD) m/z (% rel Int.): 281.1 (100.0 [M]+); 282.1 (16.6
[M+1]+); 283.1 (1.56 [M+2]+).
(0.4 mmol) and 15 mL dry DMF yielded 71 mg of (54) (0.17 mmol;
43%). Rf 0.4 (silica gel, 8:1 CHCl3/MeOH). 1H NMR (300 MHz, CDCl3)
d [ppm] = 7.080 (d, 2H); 7.088 (t, 1H); 6.926 (dd, 1H); 6.809 (t, 3H);
4.840 (m, 1H); 4.688 (m, 1H); 4.634 (d, 1H); 4.161–4.283 (dt, 2H);
3.884 (s, 3H); 3.749 (s, 3H); 3.026–3.276 (dd, 2H); 2.635–2.864 (dt,
4H); 2.016–2.038 (m, 3H); 1.708 (m, 2H); 1.575 (t, 1H); 1.366 (d,
2H) MS (FD) m/z (% rel Int.): 417.2 (74.1 [M]+); 418.2 (100.0
[M+1]+); 419.3 (20.6 [M+2]+).
4.2.7. General procedure for reduction of carbonyl compounds
via NaBH4
4.2.5.8.
(3-(2-Fluoroethoxy)-2-methoxyphenyl)-(1-(2-p-fluor-
30 mmol of the corresponding hydroxyl derivative was dis-
solved in 150 mL dry MeOH. Under nitrogen atmosphere 55 mmol
NaBH4 was added gradually at 25–30 °C, and the solution was stir-
red until no more gas evolved, generally overnight. After evapora-
tion of the solvent, the residue was taken up in NH4OH and
extracted 3Â with CHCl3. The combined organic extracts were
washed with brine, dried (Na2SO4), filtered and evaporated to af-
ford pure product.
ophenylethyl)-piperidine-4-yl)-methanol (MH.MZ) (55). 0.2 g
(48) (0.55 mmol), 20 mL DMF, 13.2 mg NaH (0.55 mmol) and
70 mg 1,2-bromofluoroethane (0.041 mL, 0.55 mmol) yielded
90 mg of (55) (0.22 mmol; 40%). Rf 0.36 (CHCl3/MeOH/concd NH3
9:1:0.2). 1H NMR (300 MHz, CDCl3) d [ppm] = 7.107–7.061 (m,
2H); 7.017–6.873 (m, 4H); 6.810–6.784 (d, 1H); 4.839–4.812 (m,
1H); 4.668–4.653 (m, 1H); 4.611–4.584 (d, 1H), 4.260–4.233 (m,
1H); 4.167–4.140 (m, 1H); 3.861 (s, 3H); 3.122–3.086 (d, 1H);
2.989–2.923 (d, 1H); 2.811–2.765 (m, 2H); 2.580–2.526 (m, 2H);
2.065–1.916 (m, 3H); 1.694–1.629 (m, 1H); 1.583–1.367 (m, 3H)
MS (FD) m/z (% rel Int.): 405.2 (100.0 [M]+); 406.2 (35.64 [M+1]+).
4.2.7.1. (2-Methoxy-3-(t-butyldiphenylsilyloxy)-phenyl)-(piper-
idine-4-yl)-methanol (10). 4.22 g (10a) (8.9 mmol), 800 mg
NaBH4 (21 mmol) and 40 mL MeOH yielded 3.45 g of (10)
(7.3 mmol; 81%). Rf 0.36 (CHCl3/MeOH 8:1). 1H NMR (300 MHz,
CDCl3) d [ppm] = 7.756–7.676 (m, 4H); 7.450–7.286 (m, 6H);
6.767 (dd, 1H); 6.614 (t, 1H); 6.408 (dd, 1H); 4.595 (d, 1H); 3.964
(s, 3H); 3.059 (dd, 2H); 2.616–2.435 (m, 2H); 2.314–1.956 (m,
2H); 1.720 (br s, 1H); 1.352–1.136 (m, 4H); 1.102 (s, 9H) MS (FD)
m/z (% rel Int.): 475.2 (100.0 [M]+); 476.2 (64.6 [M+1]+); 477.2
(18.6 [M+2]+).
4.2.5.9. (R)-(3-(2-Fluoroethoxy)-2-methoxyphenyl)-(1-(2-p-flu-
orophenylethyl)-piperidine-4-yl)-methanol
((R)-MH.MZ)
(56). 0.1 g (49) (0.275 mmol), 20 mL DMF, 6.6 mg NaH
(0.275 mmol) and 35 mg 1,2-bromofluoroethane (0.020 mL,
0.275 mmol) yielded 56 mg of (56) (0.15 mmol; 52%). Rf 0.36
(CHCl3/MeOH/concd NH3 9:1:0.2). 1H NMR (300 MHz, CDCl3) d
[ppm] = 7.107–7.061 (m, 2H); 7.017–6.873 (m, 4H); 6.810–6.784
(d, 1H); 4.839–4.812 (m, 1H); 4.668–4.653 (m, 1H); 4.611–4.584
(d, 1H), 4.260–4.233 (m, 1H); 4.167–4.140 (m, 1H); 3.861 (s, 3H);
3.122–3.086 (d, 1H); 2.989–2.923 (d, 1H); 2.811–2.765 (m, 2H);
2.580–2.526 (m, 2H); 2.065–1.916 (m, 3H); 1.694–1.629 (m, 1H);
1.583–1.367 (m, 3H) MS (FD) m/z (% rel Int.): 405.5 (100.0 [M]+);
4.2.7.2. (2,3-Dimethoxyphenyl)-(piperidine-4-yl)-methanol
(11). 7.7 g (11a) (31 mmol), 2.3 g NaBH4 (62 mmol) and 200 mL dry
MeOH yielded 6.7 g of (11) (27 mmol; 87%). Rf 0.39 (CHCl3/MeOH
8:1). 1H NMR (300 MHz, CDCl3) d [ppm] = 7.042–6.990 (t, 1H);
6.877–6.790 (q, 2H); 4.595–4.568 (d, 1H); 3.834 (s, 6H); 3.104–
3.062 (d, 1H); 2.984–2.942 (d, 1H); 2.566–2.405 (m, 2H); 2.242
(br s, 2H); 2.030–1.999 (d, 1H); 1.788–1.658 (m, 1H); 1.333–
1.091 (m, 3H) MS (FD) m/z (% rel Int.): 251.4 (100.0 [M]+); 252.4
(16.48 [M+1]+).
406.5 (57.17 [M+1]+) [
a]D = +6.84 (c 0.16; CHCl3).
4.2.6. General procedure for boc-deprotection
Ketones (7), (8) and (9) (70 mmol) were carefully and gradually
dissolved in trifluoroacetic acid (160 mL). After 2 h of stirring at
room temperature, the solutions were diluted with 500 mL of ether
and carefully neutralized with NH4OH and ice bath cooling. The
layers were separated and the aqueous layer was extracted 3Â
with ether. The combined organic extracts were washed with
water, dried (Na2SO4), filtered and evaporated to afford a viscous
oil. Chromatography of the residues gave the pure products.
4.2.7.3. (3-(2-Fluoroethoxy)-2-methoxy-phenyl)-(piperidine-4-
yl)-methanol (12). 4.24 g (12a) (15.1 mmol), 1.15 g NaBH4
(30.2 mmol) and 70 mL dry MeOH yielded 2.4 g of (12) (8.4 mmol;
56%). Rf 0.2 (CHCl3/MeOH 8:1). 1H NMR: (300 MHz, DMSO-d6) d
[ppm] = 7.027–6.873 (m, 3H); 4.913 (br s, 1H); 4.832 (t, 1H);
4.671 (t, 1H); 4.570 (dd, 1H); 4.270 (t, 1H); 4.170 (t, 1H); 3.720
(s, 3H); 3.328 (br s, 2H); 2.906–2.782 (m, 2H); 2.334–2.220 (m,
2H); 1.663 (d, 1H); 1.482 (br s, 1H); 1.094 (q, 2H) MS (FD) m/z (%
rel Int.): 283.0 (100.0 [M]+); 284.0 (19.1 [M+1]+).
4.2.6.1.
4-(2-Methoxy-3-(t-butyldiphenylsilyloxy)-benzoyl)-
piperidine (10a). 5.2 g (7) (9.1 mmol) and 100 mL TFA yielded

M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
2999
4.2.7.4.
(3-(2-Fluoroethoxy)-2-methoxyphenyl)-(1-(2-p-fluor-
mide (5 mmol) and 25 mL dry DMF yielded 1 g of (18) (1.6 mmol;
32%). Rf 0.9 (CHCl3/MeOH 8:1). 1H NMR (300 MHz, CDCl3) d
[ppm] = 8.195–8.121 (q, 2H); 7.712–7.695 (m, 4H); 7.458–7.317
(m, 8H); 6.888 (dd, 1H); 6.738–6.635 (m, 2H); 3.784 (s, 3H); 3.095
(tt, 1H); 2.998–2.864 (m, 4H); 2.635 (t, 2H); 2.204 (t, 2H); 1.884
(br d, 2H); 1.826–1.689 (m, 2H); 1.106 (s, 9H) MS (FD) m/z (% rel
Int.): 622.4 (100.0 [M]+); 623.4 (50.1 [M+1]+); 624.4 (9.3 [M+2]+).
ophenylethyl)-piperidine-4-yl)-methanol (MH.MZ) (55). 168 mg
(53) (0.42 mmol), 100 mg NaBH4 (2.6 mmol) and 20 mL MeOH
yielded 158 mg of (55) (0.38 mmol; 93%). Rf 0.36 (CHCl3/MeOH/con-
cd NH3 9:1:0.2). 1H NMR (300 MHz, CDCl3) d [ppm] = 7.107–7.061
(m, 2H); 7.017–6.873 (m, 4H); 6.810–6.784 (d, 1H); 4.839–4.812
(m, 1H); 4.668–4.653 (m, 1H); 4.611–4.584 (d, 1H), 4.260–4.233
(m, 1H); 4.167–4.140 (m, 1H); 3.861 (s, 3H); 3.122–3.086 (d, 1H);
2.989–2.923 (d, 1H); 2.811–2.765 (m, 2H); 2.580–2.526 (m, 2H);
2.065–1.916 (m, 3H); 1.694–1.629 (m, 1H); 1.583–1,367 (m, 3H)
MS (FD) m/z (% rel Int.): 405.5 (100.0 [M]+); 406.5 (57.17 [M+1]+).
4.2.9.3. 4-(2-Methoxy-3-(t-butyldiphenylsilyloxy)-benzoyl)-1-
(2-p-methoxyphenylethyl)-piperidine (19). (Method A) 2.4 g
(10a) (5 mmol), 0.65 g NaHCO3 (7.5 mmol), 1.5 g p-meth-
oxyphenethylbromide (5 mmol) and 25 mL dry DMF yielded
1.28 g of (19) (2.1 mmol; 42%). Rf 0.83 (CHCl3/MeOH 8:1). 1H
NMR (300 MHz, CDCl3) d [ppm] = 7.709–7.653 (m, 4H); 7.457–
7.302 (m, 6H); 7.116 (q, 2H); 6.885 (m, 1H); 6.862–6.803 (m,
4H); 4.431 (d, 1H); 3.858 (s, 3H); 3.761 (s, 3H); 3.623 (br s, 1H);
3.382 (br d, 2H); 3.235–3.023 (m, 4H); 3.003–2.885 (m, 2H);
2.729–2.534 (m, 2H); 2.374–2.150 (m, 1H); 2.141 (s, 9H) MS (FD)
m/z (% rel Int.): 607.4 (100.0 [M]+); 608.4 (54.8 [M+1]+); 609.4
(16.5 [M+2]+).
4.2.7.5. (3-(2-Fluoroethoxy)-2-methoxyphenyl)-(1-(2-p-toluyl-
phenylethyl)-piperidine-4-yl)-methanol
(57). 90 mg
(50)
(0.15 mmol), 11.5 mg NaBH4 (0.3 mmol) and 6 mL dry MeOH
yielded 31 mg of (57) (0.08 mmol; 52%). 1H NMR (300 MHz, CDCl3)
d [ppm] = 7.135–6.815 (m, 7H); 4.860–4.832 (m, 1H); 4.709–4.673
(m, 2H); 4.283–4.255 (m, 1H); 4.189–4.162 (m, 1H); 3.888 (s, 3H);
3.674–3.618 (d, 1H); 3.550–3.511 (d, 1H); 3.164 (br s, 2H); 3.083
(br s, 2H); 2.239–1.985 (m, 6H); 1.894 (m, 1H) MS (FD) m/z (%
rel Int.): 401.2 (100.0 [M]+); 402.3 (46.56 [M+1]+).
4.2.9.4. 4-(2-Methoxy-3-(t-butyldiphenylsilyloxy)-benzoyl)-1-
(2-p-fluorophenylethyl)-piperidine (20). (Method B) 4.91 g (10a)
(8.14 mmol), 0.64 g NaHCO3 (9 mmol), 1.02 g p-fluorophenethylbr-
omide (8.14 mmol), NaI (8.14 mmol) and 50 mL dry DMF yielded
2.99 g of (20) (5.02 mmol; 61%). Rf 0.5 (EtOAc). 1H NMR
(300 MHz, CDCl3) d [ppm] = 7.719–7.663 (m, 4H); 7.457–7.302
(m, 6H); 7.114–7.055 (m, 2H); 6.962–6.921 (m, 2H); 6.806–6.748
(dd, 1H), 6.666–6.405 (t, 2H); 3.995 (s, 3H); 3.131–2.983 (m, 2H),
2.87 (m, 3H); 2.201 (m, 2H); 1.955–1.735 (m, 4H); 1.211 (s, 9H)
MS (FD) m/z (% rel Int.): 595.5 (100.0 [M]+); 596.5 (72.30
[M+1]+); 597.5 (21.48 [M+2]+); 594.5 (18.92 [MÀ1]+).
4.2.7.6. (2-Methoxy-3-(t-butyldiphenylsilyloxy)-phenyl)-(1-(2-
p-methoxyphenylethyl)-piperidine-4-yl)-methanol (22). 600 mg
(19) (0.99 mmol), 150 mg NaBH4 (4 mmol) and 20 mL dry MeOH
yielded 520 mg of (22) (0.86 mmol; 87%). Rf 0.54 (CHCl3/MeOH
8:1). 1H NMR (300 MHz, CDCl3) d [ppm] = 7.718–7.646 (m, 4H);
7.412–7.270 (m, 6H); 7.131 (d, 2H); 6.816 (q, 3H); 6.615 (t, 1H);
6.433 (d,1H); 4.695 (d, 1H); 3.946 (s, 3H); 3.753 (s, 3H); 3.523 (s,
1H); 3.242–3.012 (m, 4H); 2.662–2.4305 (m, 2H); 2.285–2.052
(m, 2H); 1.911–1.671 (m, 2H); 1.422–1.176 (m, 3H); 1.093 (s,
9H) MS (FD) m/z (% rel Int.): 607.4 (100.0 [M]+); 608.4 (54.8
[M+1]+); 609.4 (16.5 [M+2]+).
4.2.9.5. (2-Methoxy-3-(t-butyldiphenylsilyloxy)-phenyl)-(1-(2-
p-nitrophenylethyl)-piperidine-4-yl)-methanol (21). (Method A)
1.33 g (10) (2.8 mmol), 0.93 g NaHCO3 (4.2 mmol), 0.84 g p-nitro-
phenethylbromide (2.8 mmol) and 25 mL dry DMF yielded 1 g of
(21) (1.57 mmol; 56%). Rf 0.65 (CHCl3/MeOH 8:1). 1H NMR
(300 MHz, CDCl3) d [ppm] = 8.121 (d, 2H); 7.704 (dt, 5H); 7.454–
7.304 (m, 10H); 3.970 (s, 3H); 3.895 (s, 1H); 3.071 (d, 1H);
2.965–2.765 (m, 4H); 2.594 (t, 2H); 2.124–1.889 (m, 3H); 1.509–
1.185 (m, 3H); 1.101 (s, 9H) MS (FD) m/z (% rel Int.): 624.3
(100.0 [M]+); 625.3 (44.7 [M+1]+); 626.3 (8.7 [M+2]+).
4.2.8. Optical resolution
Optical resolution of (10)/(11): Optical resolution was carried
out as described by Ullrich and Ice.23 NMR and mass spectral data
for both enantiomers are identical with (10). Enantiomeric purity
was determined via chiral HPLC separation.
4.2.9. General procedure for N-alkylation
Method A: A suspension of the appropriate amine (21.4 mmol),
NaHCO3 (32.1 mmol) and the corresponding bromo-derivative
(21.4 mmol) in anhydrous DMF (100 mL) was stirred for 90 min
at 85 °C. After evaporation of the solvent, the residue was taken
up in NH4OH and extracted 3Â with EtOAc. The combined organic
extracts were washed 3Â with brine, dried (Na2SO4) and
evaporated.
4.2.9.6. (2-Methoxy-3-(t-butyldiphenylsilyloxy)-phenyl)-(1-(2-
p-methoxyphenylethyl)-piperidine-4-yl)-methanol
(22). (Method A) 2 g (10) (4.2 mmol), 0.4 g 4-methoxyphenethylbr-
omide (4.2 mmol), 20 mL dry DMF and 0.53 g NaHCO3 (6.3 mmol)
yielded 0.38 g of (22) (0.63 mmol; 15%). Rf 0.45 (CH3Cl/MeOH 8:1).
1H NMR (300 MHz, CDCl3) d [ppm] = 7.732–7.681 (m, 4H); 7.416–
7.301 (m, 6H); 7.095–6.996 (m, 3H); 6.893–6.776 (m, 4H);
4.648–4.622 (d, 1H); 3.839 (s, 3H); 3.187–3.152 (d, 1H); 3.055–
3.014 (d, 1H); 2.818–2.744 (m, 2H); 2.637–2.583 (m, 2H); 2.131–
1.963 (m, 3H); 1.756–1.429 (m, 1H); 1.345–1.281 (m, 3H) MS
(FD) m/z (% rel Int.): 609.5 (100.0 [M]+), 610.5 (30.12 [MÀ1]+).
Method B [Finkelstein conditions]: Conducted as Method (A), but
besides mentioned raw materials NaI (21.4 mmol) was added.
4.2.9.1. 4-(2-Methoxy-3-(t-butyldiphenylsilyloxy)-benzoyl)-1-
(2-p-toluylethyl)-piperidine
(2.98 mmol), 0.60 g
(17). (Method
1-(2-bromoethyl)-4-methyl-benzene
A)
1.41 g
(7)
(2.98 mmol), 10 mL DMF, and 0.37 g NaHCO3 (4.47 mmol) yielded
0.88 g of (17) (1.49 mmol; 50%) as colourless crystals. Rf 0.53 (silica
gel, 8:1 CHCl3/MeOH). 1H NMR (300 MHz, CDCl3) d [ppm] = 7.731–
7.695 (m, 4H); 7.473–7.302 (m, 6H); 6.923–7.281 (m, 7H); 3.793 (s,
3H); 3.146–3.275 (m, 1H); 3.046–2.858 (m, 2H); 2.744–2.633 (m,
2H); 2.381–2.559 (m, 1H); 2.3 (s, 3H), 1.992–2.182 (m, 2H);
1.800–1.933 (m, 2H); 1.211 (s, 9H) MS (FD) m/z (% rel Int.): MS
(FD) m/z (% rel Int.): 591.5 (100.0 [M]+); 592.5 (22.8 [M+1]+).
4.2.9.7. (2-Methoxy-3-(t-butyldiphenylsilyloxy)-phenyl)-(1-(2-
p-fluorophenylethyl)-piperidine-4-yl)-methanol (23). (Method
B) 2 g (10) (4.2 mmol), 0.85 g p-fluorophenethylbromide
(4.2 mmol), NaI (4.2 mmol), 15 mL dry DMF and 0.53 g NaHCO3
(6.3 mmol) yielded 2.52 g (4.6 mmol; 100%) of (23). 1H NMR
(300 MHz, CDCl3) d [ppm] = 7.732–7.681 (m, 4H); 7.416–7.301
(m, 6H); 7.156–7.110 (m, 2H); 6.969–6.911 (t, 2H); 6.787–6.762
(d, 1H); 6.642–6.589 (d, 1H); 6.418–6.391 (d, 1H); 4.622–4.595
(d, 1H); 3.968 (s, 3H); 3.113–3.077 (d, 1H); 2.975–2.932 (d, 1H);
2.806–2.752 (m, 2H); 2.571–2.517 (m, 2H); 2.101–1.924 (m, 3H);
4.2.9.2. 4-(2-Methoxy-3-(t-butyldiphenylsilyloxy)-benzoyl)-1-
(2-p-nitrophenylethyl)-piperidine (18). (Method A) 2.4 g (10a)
(5 mmol), 0.65 g NaHCO3 (7.5 mmol), 1.5 g p-nitrophenethylbro-

3000
M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
1.650–1.639 (m, 1H); 1.554–1.215 (m, 3H); 1.102 (s, 9H) MS (FD)
m/z (% rel Int.): 597.6 (100.0 [M]+); 598.6 (77.39 [M+1]+); 599.6
(24.91 [M+2]+); 595.6 (24.91 [MÀ1]+).
yielded 2.3 g (4.2 mmol; 91%) of (29). 1H NMR (300 MHz, CDCl3)
d [ppm] = 7.732–7.681 (m, 4H); 7.416–7.301 (m, 6H); 7.156–
7.110 (m, 2H); 6.969–6.911 (t, 2H); 6.787–6.762 (d, 1H); 6.642–
6.589 (d, 1H); 6.418–6.391 (d, 1H); 4.622–4.595 (d, 1H); 3.968
(s, 3H); 3.113–3.077 (d, 1H); 2.975–2.932 (d, 1H); 2.806–2.752
(m, 2H); 2.571–2.517 (m, 2H); 2.101–1.924 (m, 3H); 1.650–1.639
(m, 1H); 1.554–1.215 (m, 3H); 1.102 (s, 9H) MS (FD) m/z (% rel
Int.): 597.5 (100.0 [M]+); 598.5 (68.22 [M+1]+); 595.5 (17.39
4.2.9.8. (2,3-Dimethoxyphenyl)-(1-(p-fluorobenzyl)-piperidine-
4-yl)-methanol (24). (Method A) 100 mg (11) (0.38 mmol), 72 mg
1-bromomethyl-4-fluorobenzene (0.38 mmol), 10 mL dry DMF
and 40 mg NaHCO3 (0.56 mmol) yielded 82 mg of (24) (0.22 mmol;
58%) Rf 0.48 (CH3Cl/MeOH 8:1). 1H NMR (300 MHz, CDCl3) d
[ppm] = 7.300–7.240 (m, 2H); 7.739–6.937 (m, 3H); 6.859–6.798
(m, 2H); 4.616–4.589 (d, 1H); 3.836 (s, 6H); 3.481 (br s, 2H);
2.983–2.945 (d, 1H); 2.861–2.817 (d, 1H); 2.345–2.326 (br s, 1H);
2.050–1.868 (m, 3H); 1.683–1.596 (m, 1H); 1.579–1.310 (m, 2H)
MS (FD) m/z (% rel Int.): 359.2 (100.0 [M]+); 360.23 (26.57 [M+1]+).
[MÀ1]+) [
D = À12.07 (c 0.9; CHCl3).
a]
4.2.9.14. (R)-(2,3-Dimethoxyphenyl)-(1-(2-p-fluorophenyleth-
yl)-piperidine-4-yl)-methanol ((R)-MDL 100907)) (30). (Method
A) 0.7 g (15) (2.78 mmol), 0.56 g (36) (2.78 mmol), 50 mL DMF
and 0.35 g NaHCO3 (4.17 mmol) yielded 786 mg of (30)
(2.33 mmol; 84%) as a colourless powder. 1H NMR: (300 MHz,
4.2.9.9.
piperidine-4-yl)-methanol
(2,3-Dimethoxyphenyl)-(1-(2-p-nitrophenylethyl)-
(25). (Method A) 1.5 g (11)
CDCl3) d [ppm] = 7.128–6.801 (m, 7H); 4.633–4.606 (d, 1H);
3.840 (s, 3H); 3.086–3.046 (d, 1H); 2.946–2.914 (d, 1H); 2.791–
2.686 (m, 2H); 2.538–2.455 (m, 2H); 2.061–1.864 (m, 3H);
1.715–1.600 (m, 1H), 1.549–1.232 (m, 3H) MS (FD) m/z (% rel
(5.95 mmol), 1.35 g 2-(4-nitrophen)-1-bromethane (5.95 mmol),
50 mL DMF and 0.75 g NaHCO3 (8.93 mmol) yielded 2.41 g of
(25) (5.91 mmol; 99%) as an orange oil. Rf 0.62 (CHCl3/MeOH
5:1 + 5% formic acid). 1H NMR (300 MHz, CDCl3) d [ppm] = 8.173–
8.081 (d, 2H); 7.323–7.294 (d, 2H); 7.046–6.993 (t, 1H); 6.878–
6.803 (q, 2H); 4.621–4.594 (d, 1H); 3.836 (s, 6H); 3.049–2.982 (d,
1H); 2.923–2.836 (m, 3H); 2.614–2.483 (m, 2H); 2.066–1.854 (m,
3H); 1.649 (br s, 1H); 1.466–1.179 (m, 3H) MS (FD) m/z (% rel
Int.): 400.5 (100.0 [M]+), 401.5 (27.80 [MÀ1]+).
Int.): 373.5 (100.0 [M]+); 374.5 (37.03 [M+1]+) [
0.06; MeOH).
a]D = +15.67 (c
4.2.9.15. (3-(2-Fluoroethoxy)-2-methoxyphenyl)-(1-(2-phenyl-
ethyl)-piperidine-4-yl)-methanol (31). (Method A) 200 mg (12)
(0.71 mmol), 90 mg NaHCO3 (1.1 mmol), 130 mg phenethylbromide
(0.71 mmol) and 10 mL dry DMF yielded 246 mg of (31) (0.64 mmol;
90%). Rf 0.43 (CHCl3/MeOH 8:1). 1H NMR: (300 MHz, CDCl3) d
[ppm] = 7.270–7.131 (m, 5H); 7.006 (t, 1H); 6.922 (dd, 1H); 6.812
(dd, 1H); 4.839 (t, 1H); 4.686 (t, 1H); 4.599 (d, 1H); 4.268 (t, 1H);
4.174 (t, 1H); 3.883 (s, 3H); 3.067 (d, 1H); 2.825 (s, 1H); 2.795–
2.498 (dt, 4H); 2.074–1.983 (m, 2H); 1.961–1.835 (m, 2H); 1.531–
1.357 (m, 2H); 1.300–1.200 (m, 2H) MS (FD) m/z (% rel Int.): 387.2
(100.0 [M]+); 388.2 (36.0 [M+1]+); 389.3 (8.0 [M+2]+).
4.2.9.10. (2,3-Dimethoxyphenyl)-(1-(2-p-methoxyphenylethyl)-
piperidine-4-yl)-methanol
(26). (Method
A)
50 mg
(11)
(0.19 mmol), 18 mg 4-methylphenethylbromide (0.19 mmol),
10 mL dry DMF and 20 mg NaHCO3 (0.28 mmol) yielded 18 mg of
(26) (0.05 mmol; 26%). Rf 0.50 (CH3Cl/MeOH 8:1). 1H NMR
(300 MHz, CDCl3) d [ppm] = 7.095–6.996 (m, 3H); 6.893–6.776
(m, 4H); 4.648–4.622 (d, 1H); 3.839 (s, 3H); 3.749 (s, 3H); 3.187–
3.152 (d, 1H); 3.055–3.014 (d, 1H); 2.818–2.744 (m, 2H); 2.637–
2.583 (m, 2H); 2.131–1.963 (m, 3H); 1.756–1.429 (m, 1H);
1.345–1.281 (m, 3H) MS (FD) m/z (% rel Int.): 385.1 (100.0 [M]+),
384.1 (91.67 [MÀ1]+).
4.2.9.16. (3-(2-Fluoroethoxy)-2-methoxyphenyl)-(1-(2-p-nitro-
phenylethyl)-piperidin-4-yl)-methanol (VK-1) (32). (Method A)
200 mg (12) (0.71 mmol), 90 mg NaHCO3 (1.1 mmol), 130 mg
p-nitrophenethylbromide (0.71 mmol) and 10 mL dry DMF yielded
276 mg of (32) (0,65 mmol; 91%). Rf 0.64 (silica gel, 8:1 CHCl3/
MeOH). 1H NMR (300 MHz, CDCl3), d [ppm] = 8.095–8.123 (d,
2H); 7.314–7.343 (d, 2H); 7.010 (t, 1H); 6.907 (d, 1H); 6.822 (d,
1H); 4.845 (q, 1H); 4.688 (q, 1H); 4.611 (d, 1H); 4.274 (t, 1H);
4.180 (t, 1H); 3.888 (s, 3H); 3.078 (d, 1H); 2.918 (t, 3H); 2.602 (t,
2H); 1.938–2.120 (m, 3H); 1.612–1.750 (m, 1H); 1.205–1.573 (m,
4H) MS (FD) m/z (% rel Int.): 432.0 (100.0 [M]+); 433.0 (45.8
[M+1]+); 434.0 (8.0 [M+2]+).
4.2.9.11.
(2,3-Dimethoxyphenyl)-(1-(2-p-toluylethyl)-piperi-
dine-4-yl)-methanol (27). (Method B) 50 mg (11) (0.19 mmol),
38 mg 4-methylphenethylbromide (0.19 mmol), NaI (0.19 mmol),
10 mL dry DMF and 20 mg NaHCO3 (0.28 mmol) yielded 42 mg of
(27) (0.11 mmol; 58%). Rf 0.4 (CH3Cl/MeOH 8:1). 1H NMR
(300 MHz, CDCl3) d [ppm] = 7.128–6.993 (m, 5H); 6.890–6.805
(m, 2H); 4.638–4.612 (d, 1H); 3.839 (s, 6H); 3.159–3.115 (d, 1H);
3.014–2.978 (d, 1H); 2.804–2.748 (m, 2H); 2.610–2.556 (m, 2H);
2.280 (s, 3H); 2.084–1.908 (m, 3H); 1.711–1.597 (m, 1H); 1.322–
1.232 (m, 3H) MS (FD) m/z (% rel Int.): 369.1 (100.0 [M]+), 370.15
4.2.9.17. 4-(3-(2-Fluoroethoxy)-2-methoxybenzoyl)-1-(2-p-flu-
orophenylethyl)-piperidine (MA-1) (53). (Method A) 400 mg
(12a) (1.42 mmol), 180 mg NaHCO3 (2.2 mmol), 287 mg p-fluor-
ophenethylbromide (1.42 mmol) and 15 mL dry DMF yielded
466 mg of (53) (1.15 mmol; 81%). Rf 0.66 (CHCl3/MeOH 8:1). 1H
NMR: (300 MHz, CDCl3) d [ppm] = 7.148–7.077 (m, 2H); 7.031–
6.903 (m, 5H); 4.857 (t, 1H); 4.699 (t, 1H); 4.296 (t, 1H); 4.203 (t,
1H); 3.883 (s, 3H); 3.077 (tt, 1H); 2.953 (dt, 2H); 2.644 (dt, 4H);
2.109 (t, 2H); 1.918 (d, 2H); 1.799–1.658 (m, 2H) MS (FD) m/z (%
rel Int.): 402.8 (100.0 [M]+); 403.8 (25.8 [M+1]+); 404.8 (3.1
[M+2]+).
(77.30 [M+1]+) [
a]D = À12.49 (c 0.12; MeOH).
4.2.9.12. (2,3-Dimethoxyphenyl)-(1-(2-p-fluorophenylethyl)-
piperidine-4-yl)-methanol (28). (Method A) 0.7 g (11)
(2.78 mmol), 0.56 g (36) (2.78 mmol), 50 mL DMF and 0.35 g NaH-
CO3 (4.17 mmol) yielded 786 mg of (28) (2.33 mmol; 84%) as a col-
ourless powder. Rf 0.24 (CHCl3/MeOH 10:1). 1H NMR: (300 MHz,
CDCl3)
d [ppm] = 7.128–6.801 (m, 7H); 4.633–4.606 (d, 1H);
3.840 (s, 3H); 3.086–3.046 (d, 1H); 2.946–2.914 (d, 1H); 2.791–
2.686 (m, 2H); 2.538–2.455 (m, 2H); 2.061–1.864 (m, 3H);
1.715–1.600 (m, 1H), 1.549–1.232 (m, 3H) MS (FD) m/z (% rel
Int.): 373.5 (100.0 [M]+); 374.5 (37.03 [M+1]+).
4.2.10. General procedure for the bromination of p-
fluorophenylalkyl alcohols
To a stirred solution of the corresponding p-fluorophenalkyl alco-
hol (0.4 mol) dissolved in 40 mL toluene 0.3 mol PBr3 was slowly
added, heated to 100 °C and then cooled, treated with ice water
and washed with saturated Na2CO3 solution and water. The aqueous
phase was extracted with toluene (3 Â 250 mL), the organic extracts
4.2.9.13. (R)-(2-Methoxy-3-(t-butyldiphenylsilyloxy)-phenyl)-
(1-(2-p-fluorophenylethyl)-piperidine-4-yl)-methanol
(29). (Method A) 2 g (14) (4.2 mmol), 0.85 g p-fluorophenethylbro-
mide (4.2 mmol), 15 mL dry DMF and 0.53 g NaHCO3 (6.3 mmol)

M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
3001
dried over Na2SO4 and the solvent evaporated under reduced pres-
sure. The products were obtained via distillation.
(250 Â 7.8 mm) and a 20
l
L loop. Soerensen buffer was used as
eluent with a flow rate of 4 mL/min. Retention times for all tested
compounds and for reference substances (ascorbic acid, benzalde-
hyde, anisol, toluene, 4-bromoanisol and 4-iodoanisol) of known
logP were assessed which enabled the calculation of the capacity
factor k. A plot of these reference values against their known logP
values gave a reference curve which was used to calculate logP val-
ues for synthesized compounds.
4.2.10.1. p-Fluorophenylmethyl bromide (35). The crude product
was purified via distillation (85 °C, 20 mbar) to yield 55.16 g
(0.29 mol; 75%) of (35) as a colourless oil. 1H NMR: (300 MHz, CDCl3)
d [ppm] = 7.413–7.382 (m, 2H); 7.034 (m, 2H); 4.555 (s, 2H) MS (FD)
m/z (% rel Int.): 189.9 (100.0 [M]+); 187.9 (33.96 [MÀ2]+).
4.2.10.2. 2-p-Fluorophenylethyl bromide (36). The crude product
was purified via distillation (105 °C, 15–20 mbar) to yield 45.68 g
(0.22 mol; 81%) of (36) as a colourless oil. 1H NMR: (300 MHz, CDCl3)
d [ppm] = 7.114 (t, 2H); 7.034 (t, 2H); 3.567 (t, 2H); 3.188 (t, 2H) MS
(FD) m/z (% rel Int.): 202.0 (100.0 [M]+); 204.0 (63.77 [M+2]+).
4.4. In vitro pharmacological evaluation
4.4.1. Binding assays
4.4.1.1. In vitro radioligand competition binding assay of 18F-
tracers on high 5-HT2A expressing GF-62 cells. Cell membrane
homogenate. NIH3T3 cells, derived from mouse fibroblasts, were
stably transfected with the rat 5-HT2A receptor cDNA before
isolation of GF-62, a clonal cell line expressing higher amounts
(5–7 pmol/mg) of the 5-HT2A receptor. Cells were homogenized
in buffer (5 mM Tris-base, 5 mM EDTA, pH 7.4, 4 °C) and incubated
for 10 min at 4 °C. Centrifuged for 10 min (33,000g) at 2–4 °C, the
pellet was suspended in 4 mg/mL wet weight assay buffer
(50 mM Tris-base, 120 mM NaCl, 50 mM KCl, 1% bovine serum
4.2.11. 2-Bromoethyl-2-(4-fluorophenyl)-(1,3)dioxo-lane (37)
Four grams of 2-bromo-4-fluoroacetophenone (18 mmol),
8.92 g ethylenglycol (144 mmol) and 0.76 p-toluenesulfonic acid
(4 mmol) were dissolved in 50 mL benzene and refluxed for 16 h.
After evaporating the solvent, the residue was taken up with
CH2Cl2, washed with K2CO3 and then extracted with CH2Cl2, and
dried with MgSO4. The solvent was reduced to afford 2.2 g of a yel-
lowish oil (16.1 mmol; 89%). 1H NMR (300 MHz, CDCl3)
d
albumin, 0.1% ascorbic acid, pH 7.4, 37 °C) and 50 lL/mL protease
[ppm] = 7.484–7.429 (m, 2H); 7.036–6.970 (m, 2H); 4.172–4.092
(m, 2H); 3.877–3.802 (m, 2H); 3.596 (s, 2H) MS (FD) m/z (% rel
Int.): 167.6 (100.0 [M]+); 168.6 (6.37 [M+1]+); 260.4 (9.95 [M+3]+).
inhibitor cocktail was added (4-(2-aminoethyl) benzenesulfonyl
fluoride (AEBSF), aprotinin, leupeptin, bestatin, pepestatin A and
E-64), aliquoted in NUNC tubes and stored at À80 °C until use.
Radioligand binding assay. Competition binding experiments
were carried out in test tubes containing [3H]MDL (0.2 nM), seven
4.2.12. (3-(2-Fluoroethoxy)-2-methoxyphenyl)-(1-(2-p-
aminophenylethyl)-piperidine-4-yl)-methanol (58)
different concentrations of the test compound (1
10–20 g GF-62 clonal cells in a total of 1 mL assay buffer
(50 mM Tris-base, 120 mM NaCl, 50 mM KCl, 1% bovine serum
albumin, 0.1% ascorbic acid, pH 7.4, 37 °C). Ketanserin (1 M)
lM–1 pM) and
Three hundred and fifty milligrams of 32 (0.81 mmol) were dis-
solved in 20 mL isopropanol. 500 mg Pd/C and 204.2 mg ammo-
nium formate (3.24 mmol) were added and then heated to 70 °C
for 20 min (70 W) in a microwave oven. Afterwards the mixture
was filtered, the solvent reduced, the residue taken up with 1 M
HCl and 3Â extracted with EtOAc. Organic layers were dried
(NA2SO4) and the solvent removed to yield 248 mg of (58)
(0.62 mmol; 76%) as colourless crystals. Rf 0.33 (CHCl3/MeOH
8:1). 1H NMR (300 MHz, CDCl3) d [ppm] = 7.030–6.890 (m, 4H);
6.817 (d, 1H); 6.586 (d, 2H); 4.840 (t, 1H); 4.688 (t, 1H); 4.608
(d, 1H); 4.267 (t, 1H); 4.173 (t, 1H); 3.885 (s, 3H); 3.528 (br s,
2H); 2.983 (dd, 2H); 2.565 (dt, 4H); 2.021 (t, 1H); 1.941–1.816
(m, 2H); 1.719–1.579 (m, 1H); 1.517–1.324 (m, 2H); 1.260 (d,
2H) MS (FD) m/z (% rel Int.): 402.3 (100.0 [M]+); 403.3 (46.1
[M+1]+); 404.3 (7.2 [M+2]+).
l
l
was used to determine non-specific binding. Incubation was car-
ried out for 1 h at 37 °C and terminated by rapid filtration over
glass fibre GF/C filters presoaked in 1% polyethyleneimine, using
a Brandel cell harvester. Filters were washed with 300 mL cold
assay buffer (tritrated to pH 7.4 at 4 °C). Filters were placed in scin-
tillation vials and 2.5 mL Ultima Gold scintillation fluid was added.
The scintillation cocktails were placed in cold and dark overnight
and counted for 4 min in a Tri-Carb 2900TR Liquid Scintillation
Analyser from Packard. Ki and error values were calculated with
Graphpad Prism 5.
4.4.1.2. In vitro radioligand binding assays through NIMH-
Psychoactive Drug Screening Programme (PDSP). Binding assays
were performed by the NIMH Psychoactive Drug Screening
Programme at the Department of Biochemistry, Case Western
Reserve University, Cleveland, Ohio, USA (Bryan Roth, Director).
Compounds (32), (50)–(53) and (55)–(57) were assayed for their
affinities for a broad spectrum of receptors and transporters in
competitive binding experiments in vitro using cloned human
receptors. Reported values of the inhibition coefficient (Ki) are
mean SD of four separate determinations.
4.2.13. (3-(2-Fluoroethoxy)-2-methoxyphenyl)-(1-
phenylacetyl-piperidine-4-yl)-methanol (39)
To 200 mg (12) (0.71 mmol) dissolved in 10 mL of dry THF
100 lL of phenacetylchloride (0.84 mmol) was added while cooling
to 0 °C. The resulting mixture was then stirred for 2 h and after-
wards the solvent evaporated. The residue was taken up with
EtOAc, washed with water, extracted 3Â with EtOAc and finally
dried (Na2SO4). The solvent was removed to give the crude product
which was purified via chromatography yielding 180 mg of (39)
(0.45 mmol; 64%). Rf 0.71 (CHCl3/MeOH 8:1). 1H NMR: (300 MHz,
CDCl3) d [ppm] = 7.325–7.158 (m, 5H); 7.000 (t, 1H); 6.887–6.787
(m, 2H); 4.841 (t, 1H); 4.684 (t, 1H); 4.552 (d, 1H); 4.267 (t, 1H);
4.173 (t, 1H); 3.956–3.671 (m, 2H); 3.874 (s, 3H); 3.692 (d, 2H);
2.960–2.740 (m, 1H); 2.566–2.361 (m, 1H); 2.044.1.722 (m, 3H);
1.367–0.948 (m, 3H) MS (FD) m/z (% rel Int.): 401.2 (100.0 [M]+);
402.2 (23.3 [M+1]+); 403.2 (3.1 [M+2]+).
Acknowledgements
Financial support by Friedrich-Naumann-Stiftung and the Euro-
pean Network of Excellence (EMIL) are gratefully acknowledged.
Mikael Palner was supported by an unlimited grant by Cimbi,
SUND, DRC. We also thank the VCI (Verband der chemischen
Industrie e.V.) for the donation of solvents.
4.3. Lipophilicity
References and notes
1. Fischer, W. Pharm. Unserer Zeit 1991, 20, 21.
2. Barch, D. M. Psychopharmacology 2004, 174, 126.
Lipophilicities were determined using the HPLC system
described above with
a
LiChrospher 100 RP 18 EC-5l

3002
M. M. Herth et al. / Bioorg. Med. Chem. 17 (2009) 2989–3002
3. Ohuoha, D. C.; Hyde, T. M.; Kleinman, J. F. Psychopharmacology 1993, 112, 5.
4. Hoyer, D.; Martin, G. R. Behav. Brain Res. 1996, 73, 263.
5. Glennon, R.; Dukat, M. ID Res. Alert 1997, 2, 107.
6. Kennett, G. A. Curr. Res. Serotonin 1998, 3, 1.
7. Meltzer, H. Y.; Matsubara, S.; Lee, J. C. J. Pharmacol. Exp. Ther. 1989, 238.
8. Remington, G.; Kapur, S. Psychopharmacology 2000, 148, 3.
9. Zhang, W.; Bymaster, F. P. Psychopharmacology 1999, 141, 291.
10. Ito, H.; Nyberg, S.; Halldin, C.; Lundkvist, C.; Farde, L. J. Nucl. Med. 1998, 39,
208.
17. Mintun, M. A.; Sheline, Y. I.; Moerlein, S. M.; Vlassenko, A. G.; Yiyun Huang, Y.;
Snyder, A. Z. Biol. Psychiatry 2004, 55, 217.
18. Scot, D.; Heath, T. G. J. Pharm. Biomed. Anal. 1998, 17, 17.
19. Herth, M. M.; Debus, F.; Piel, M.; Palner, M.; Knudsen, G. M.; Lüddens, H.;
Rösch, F. Bioorg. Med. Chem. Lett. 2008, 18, 1515.
20. Herth, M. M.; Piel, M.; Debus, P.; Schmitt, U.; Lüddens. H.; Rösch, F. J. Nucl. Med.
Biol., 2009, doi:10.1016/j.nucmedbio.2009.01.012.
21. Andersen, K.; Liljefors, T.; Gundertofe, K.; Perregaard, J.; Bogeso, K. P. J. Med.
Chem. 1994, 37, 950.
11. Smith, G. S.; Price, J. C.; Lopresti, B. J.; Huang, Y.; Simpson, N.; Holt, D.; Mason,
N. S.; Meltzer, C. C.; Sweet, R. A.; Nichols, T.; Sashin, D.; Mathis, C. A. Synapse
1998, 30, 380.
12. Johnson, M. P.; Siegel, B. W.; Carr, A. A. Naunyn Schmiedebergs Arch. Pharmacol.
1996, 354, 205.
13. Tan, P.; Baldwin, R. M.; Fu, T.; Charney, D. S.; Innis, R. B. J. Labelled Compd.
Radiopharm. 1999, 42, 457.
14. Hall, H.; Farde, L.; Halldin, C.; Lundkvist, C.; Sedvall, G. Synapse 2000, 38,
421.
22. Heinrich, T.; Böttcher, H.; Prücher, H.; Gottschlich, R.; Ackermann, K.-A.; van
Amsterdam, C. Chem.Med.Chem. 2006, 1, 245.
23. Ullrich, T.; Ice, K. C. Bioorg. Med. Chem. 2000, 8, 2427.
24. Schmidt, C. J.; Kehne, J. H.; Carr, A. A. CNS Drug Rev. 1997, 3, 49.
25. Krass, J. D.; Jastorff, B.; Genieser, H. G. Anal. Chem. 1997, 69, 2575.
26. Rowley, M.; Kulagowski, J. J.; Watt, A. P.; Rathbone, D.; Stevenson, G. I.; Carling,
R. W.; Baker, R.; Marshall, G. R.; Kemp, J. A.; Foster, A. C.; Grimwood, S.;
Hargreaves, R.; Hurley, C.; Saywell, K. L.; Tricklebank, M. D.; Leeson, P. D. J. Med.
Chem. 1997, 40, 4053.
15. Meltzer, C. C.; Smith, G.; DeKosky, S. T.; Pollock, B. G.; Mathis, A. M.; Moore, R.
Y.; Kupfer, D. J.; Reynolds, C. F. Neuropsychopharmacology 1998, 18, 407.
16. Huang, Y.; Mahmood, K.; Mathis, C. A. J. Labelled Compd. Radiopharm. 1999, 42,
949.
27. Carr, A. A.; Kane, J. M.; Hay, D. A.; Schmidt, C. J. PCT WO 91/18602 1996; Chem.
Abstr. 1996, 116, 106031.
28. Mathis, C. A.; Mahmood, K.; Huang, Y.; Simpson, N. R.; Gerdes, J. M.; Price, J. C.
Med. Chem. Res. 1996, 6, 1.