Synthesis and evaluation of mefway analogs as ligands for serotonin 5HT1A receptors

Article abstract of DOI:10.1007/s00044-014-1238-z

¹⁸F-Mefway (N-{2-[4-(2′methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(4′¹⁸F-fluoro-methylcyclohexane)carboxamide) was developed and evaluated for use as a PET ligand for imaging 5-HT_1A receptors. Ongoing studies of

Full text of DOI:10.1007/s00044-014-1238-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2015) 24:1480–1486
DOI 10.1007/s00044-014-1238-z
ORIGINAL RESEARCH
Synthesis and evaluation of mefway analogs as ligands
for serotonin 5HT1A receptors
•
Joanne P. Thio Christopher Liang Alisha K. Bajwa
•
•
•
Dustin W. Wooten Bradley T. Christian
•
Jogeshwar Mukherjee
Received: 27 February 2014 / Accepted: 14 August 2014 / Published online: 23 August 2014
Ó Springer Science+Business Media New York 2014
Abstract 18F-Mefway (N-{2-[4-(20-methoxyphenyl)piperaz-
inyl]ethyl}-N-(2-pyridyl)-N-(40-18F-fluoro-methylcyclohexane)
carboxamide) was developed and evaluated for use as a
PET ligand for imaging 5-HT1A receptors. Ongoing studies
of 18F-Mefway have shown it to be an effective PET radio-
tracer. We have synthesized isomers of Mefway by changing
the position of the methyl group in attempts to evaluate
stability for imaging purposes. 2-Methyl-, 3-methyl-, and
4-methyl-cyclohexane-1-carboxylic acids and 3-carbome-
thoxy-, 4-carbomethoxycyclohexane-1-carboxylic acids were
coupled with WAY-100634 to provide the methylcyclohexyl
derivatives (2-, 3-, and 4-methyl). Mefway and 3-Mefway
analogs were prepared by reduction of carbomethoxy-
derivatives followed by fluorination. In vitro binding affinities
for the methylated derivatives in rat brain homogenates were
found to be 10.4 nM (2-methyl), 77 nM (3-methyl), and 21.5
nM (4-methyl). Binding affinity of 3-Mefway and 4-Mefway
was found to be 17.4 nM and 6.26 nM, respectively. Our
results suggest that 3-methyl/3-fluoromethyl substituent has
approx. threefold lower affinities compared to the 4-methyl/4-
fluoromethyl substituent.
Introduction
Imaging serotonin 5-HT1A receptors have been underway
because of their involvement in various CNS functions (Ken-
nedy and Zubiet, 2004; Kumar and Mann, 2007; Billard et al.,
2014). 18F-Mefway (N-{2-[4-(20-methoxyphenyl)piperazi-
nyl]ethyl}-N-(2-pyridyl)-N-(40-18F-fluoromethylcyclohexane)
carboxamide) is a promising PET imaging for serotonin
5-HT1A receptors (Saigal et al., 2013; Wooten et al., 2011a,
2012). The fluoromethyl groupinMefwayis incorporatedatthe
4-position of the cyclohexyl ring. Previous studies on a related
analog, 18F-FCWAY ([N-{2-[4-(2-methoxyphenyl)piperazi-
no]ethyl}-N-(2-pyridinyl)-4-[18F]fluoro-cyclohexanecarbox-
amide) found changes in the position of the 18F-radiolabel
resulted in a change in the affinity of the compound (Ma
et al., 2006). Shifting the 18F-radiolabel from the 4 position
(18F-FCWAY) to the 3 position (18F-3-FCWAY) had the
effect of lowered affinity, faster pharmacokinetics, and lower
defluorination, giving 18F-3-FCWAY better characteristics
for measuring dynamic change in 5-HT1A receptors (Lang
et al., 2006).
In order to evaluate the sensitivity of binding affinity to the
position of the methyl substituent on the cyclohexyl ring, we first
examined methylated WAY-100635 derivatives (Fig. 1). The
intent of making the methylated analogs was to understand the
structure–activity relationship of methylation of the parent
molecule, WAY-100635 and not to develop a carbon-11 radio-
tracer. We hypothesized that changing the position of the methyl
group from the 4 position to the 2 and 3 positions (2-Me, 3-Me,
respectively) is expected to alter the binding affinity. Thus, three
analogs, 2-methyl, 3-methyl, and 4-methyl, were synthesized
and their in vitro binding affinities evaluated (Thio et al., 2013).
Subsequently, 3-Mefway (N-{2-[4-(20-methoxyphenyl)piperaz-
inyl]ethyl}-N-(2-pyridyl)-N-(30-fluoromethylcyclohexane)car-
boxamide) was synthesized and compared with 4-Mefway.
Keywords Mefway ꢀ PET imaging ꢀ Serotonin ꢀ
Fluorine-18
J. P. Thio ꢀ C. Liang ꢀ A. K. Bajwa ꢀ J. Mukherjee (&)
Preclinical Imaging, B138 Medical Sciences, Department of
Radiological Sciences, University of California,
Irvine, CA 92697-5000, USA
e-mail: j.mukherjee@uci.edu
D. W. Wooten ꢀ B. T. Christian
Department of Medical Physics, University of Wisconsin-
Madison, Madison, WI 53705, USA
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Med Chem Res (2015) 24:1480–1486
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Fig. 1 Chemical Structures of
WAY-100635 (1), 4-methyl-
WAY-100635 (2), 3-methyl-
WAY-100635 (3), and
2-methyl-WAY-100635 (4)
Materials and methods
chlorides (6) were allowed to cool to room temperature
then were immediately used for the next step of the
synthesis.
General
All chemicals and solvents used were obtained from
Aldrich Chemical Co. WAY-100634 (1-(2-methoxy-
phenyl)-4-[2-(pyridylamino)ethyl]piperazine) was synthe-
sized using reported procedures (Saigal et al., 2006).
Analytical thin-layer chromatography (TLC) was used to
monitor reactions (Baker-flex, Phillipsburg, NJ, USA).
Electrospray mass spectra were obtained from a Model
7,250 mass spectrometer (Micromass LCT). Proton NMR
spectra were recorded on a Bruker OMEGA 500-MHz
spectrometer. Tritium was assayed by using a Packard Tri-
Carb Liquid scintillation counter with 65 % efficiency. All
animal studies were approved by the Institutional Animal
Care and Use Committee of University of California-
Irvine.
Synthesis of N-{2-[4-(20-methoxyphenyl)piperazinyl]ethyl}-
N-(2-pyridyl)-N-(2/3/4-methyl-cyclohexane)carboxamide
(8)
WAY-100634 (7) was reacted with the substituted cyclo-
hexylcarbonyl chlorides (6) from the previous step. For the
synthesis of 2-methyl, 30 mg (0.096 mmol) of WAY-
100634; for 3-methyl, 11 mg (0.035 mmol) of WAY-
100634; and for 4-methyl, 11 mg (0.035 mmol) of WAY
100634 were dissolved in 1 mL of dichloromethane (DCM,
CH2Cl2) and added to the respective cyclohexylcarbonyl
chlorides (6). The mixtures were allowed to stir for 24 h.
The mixtures were then purified using preparative TLC
(9:1 CH2Cl2:CH3OH). The products were isolated from the
plates to yield 11 mg (0.023 mmol) of 2-methyl (4;
[95 %), 3 mg (0.006 mmol) of 3-methyl (3; [95 %), and
6 mg (0.012 mmol) of 4-methyl (2; [96 %) and were
characterized by NMR and mass spectroscopy as described
below. The purified derivatives were used for biological
assays.
Synthesis
Synthesis of substituted cyclohexylcarbonyl chlorides (6)
The acids, 0.28 g (2 mmol) of 2-methyl-1-cyclohex-
anecarboxylic acid (5), 0.14 g (1 mmol) of 3-methyl-1-
cyclohexanecarboxylic acid, or 0.14 g (1 mmol) of
4-methyl-1-cyclohexanecarboxylic acid were treated with
oxalyl chloride in a 1:4 ratio of carboxylic acid to oxalyl
chloride in separate vials (Fig. 2). The reactions were
allowed to stir overnight. The mixtures were then heated at
70–80 °C for an hour during which time excess oxalyl
chloride was removed. The substituted cyclohexylcarbonyl
2-Methyl (4) 1H NMR (500 MHz, CDCl3) d ppm: 8.
51–8.52 (d, J = 3.95, 1H), 7.73–7.77 (t, J = 3.90, 1H), 7.
20–7.35 (m, 2H), 6.95–7.05 (m, 1H), 6.90–6.91 (d, J = 4.
30, 2H), 6.83–6.87 (m, 1H), 3.97–3.99 (m, 1H), 3.85 (s,
3H, OCH3), 3.73–3.76 (t, J = 3.50, 2H), 3.45–3.50 (m,
2H), 2.95–3.19 (br, 2H), 2.55–2.70 (br, 2H), 2.64 (s, 1H), 2.
17 (s, 1H), 2.01 (s, 1H), 1.65–1.85 (m, 4H), 1.55 (s, 3H,
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Med Chem Res (2015) 24:1480–1486
Fig. 2 Synthesis scheme of
methyl-WAY-100635. Starting
with the conversion of the
carboxylic acids (5) to the
corresponding cyclohexanoyl
chlorides (6), the amine WAY-
100634 (7) was converted to the
corresponding carboxamides (8)
Fig. 3 Chemical structures of
4-Mefway (9), 3-Mefway (10),
4-18F-Mefway (9a) and 3-18F-
Mefway (10a)
CH3), 1.15–1.27 (m, 4H), 0.93–0.94 (d, J = 7, 2H). MS,
m/z, 437 (100 %, [M ? H]?), 459 (70 %, [M ? Na]?).
MS, m/z, 437 (100 %, [M ? H]?), 459 (70 %,
[M ? Na]?).
3-Methyl (3) 1H NMR (500 MHz, CDCl3) d ppm: 8.52
(d, J = 3.90, 1H), 7.70–7.77 (t, J = 3.90, 1H), 7.20–7.32
(m, 2H), 6.98 (br, 1H), 6.89–6.91 (d, J = 4.55, 2H), 6.
85–6.85 (m, 1H), 3.84 (s, 3H, OCH3), 3.73–3.76 (t, 2H), 3.
45–3.48 (m, 2H), 2.98–3.02 (br, 2H), 2.61 (br, 2H), 2.17 (s,
1H), 2.01 (s, 1H), 1.65–1.85 (m, 4H), 1.84–1.88 (m, 2H), 1.
55 (s, 3H, CH3), 1.18–1.30 (m, 4H), 0.84–0.90 (d, 2H). MS,
m/z, 437 (100 %, [M ? H]?), 459 (70 %, [M ? Na]?).
Synthesis of N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-
N-(2-pyridyl)-N-(3/4-fluoro-methylcyclohexane)
carboxamide (9,10, Fig. 3)
Using the previous two steps described for (6), 372 mg
(2.62 mmol) of 3-carboxymethyl-1-cyclohexanecarboxylic
acid (11) was converted to its corresponding substituted
cyclohexylcarbonyl chloride (12). The ester (12; 57 mg,
0.4 mmol) was then diluted with 3 mL of diethyl ether and
placed into a reaction flask and was reacted with 80 mg
(0.26 mmol) of WAY-100634 for 24 h. The isolated yield
of 44 mg (0.09 mmol; [95 % pure) of ester (13) was
obtained.
4-Methyl (2) 1H NMR (500 MHz, CDCl3) d ppm: 8.53
(d, J = 4.25, 1H), 7.75 (t, J = 4.5, 1H), 7.20–7.32 (m, 2H),
6.98 (m, 1H), 6.89–6.91 (d, J = 4.1, 2H), 6.83–6.85 (m,
1H), 3.98 (br, 1H), 3.84 (s, 3H, OCH3), 3.73–3.76 (t, J = 6.
65, 2H), 3.47–3.49 (m, 2H), 3.02 (br, 1H), 2.98 (br, 2H), 2.
62 (br, 2H), 2.17 (s, 1H), 2.01 (s, 1H), 1.65–1.85 (m, 4H),
1.56 (s, 3H, CH3), 1.15–1.27 (m, 4H), 0.93–0.94 (d, 2H).
The anhydrous ether solution of the ester (13; 39 mg;
0.08 mmol 3 mL of diethyl ether) was stirred in an ice bath
for 15 min to bring the solution temperature down to 0 °C.
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Med Chem Res (2015) 24:1480–1486
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7
13
11
12
LiAlH4
DAST
14
9: 4-Mefway
10: 3-Mefway
Fig. 4 Synthesis scheme of Mefway. Starting with the conversion of
the carboxylic acids (11) to the corresponding cyclohexanoyl
chlorides (12), the amine WAY-100634 (7) was converted to the
corresponding carboxamides (13). Reduction of the carboxylic acid
esters with lithium aluminum hydride (LiAlH4) gave the correspond-
ing alcohols (14) which were subsequently fluorinated with DAST to
provide 4-Mefway (9) and 3-Mefway (10)
Once the solution reached 0 °C, 0.08 mL (0.08 mmol) of
1 M LiAlH4 in diethyl ether was slowly added to the flask
and allowed to stir for 30 min. Subsequently the reaction
was quenched with 1 N hydrochloric acid to pH * 7. The
reaction mixture was then taken up in ethyl ether. The ether
layer was then isolated and dried to yield 24 mg of crude
product. It was then purified using preparative TLC (9:1
CH2Cl2:CH3OH). The product was isolated from the pre-
parative TLC plate and filtered to yield 8 mg (0.018 mmol)
of alcohol (14; [90 % pure) and 20 mg of recovered
reactant ester (13).
OCH3), 3.74 (t, 2H), 3.40–3.49 (m, 2H), 3.25 (br, 1H), 3.02
(br, 2H), 2.70 (br, 2H), 2.45 (s, 1H), 1.84–1.88 (m, 1H),
1.50–1.70 (m, 4H), 1.19–1.27 (m, 4H), 0.84–0.88 (d, 2H).
MS, m/z, 455 ([M ? H]?), 477 ([M ? Na]?).
Homogenate binding assay
Binding affinities of methyl derivatives of WAY-100635
were measured using rat brain homogenate assays. Rat
brain homogenates were labeled with 3H-WAY 100635
were carried out to measure the binding affinity of
2-methyl, 3-methyl, 4-methyl-WAY-100635 and were
compared with WAY-100635 to 5-HT1A receptor. The
cerebrum (0.85 g of tissue per assay) of each male rat was
isolated and homogenized in 30 mL of assay buffer for
30 s (50 mM Tris–HCl, pH 7.6) using Tekmar tissumizer
(15 s, half maxima speed). The homogenate was centri-
fuged at 27,000 g for 20 min at 4 °C and the supernatant
was discarded. The resulting pellet was resuspended in
30 mL of buffer, homogenized, and then centrifuged at
27,000 g for 20 min at 4 °C. Once again the supernatant
was removed and the pellet was diluted with incubation
The alcohols (4.5 mg; 0.01 mmol) (14) were reacted
with diethylaminosulfur trifluoride (DAST) (4 lL;
0.03 mmol) in 1 mL of DCM at room temperature for
24 h. The reaction mixture was washed with saturated
sodium bicarbonate (NaHCO3) and dried over magnesium
sulfate. The crude product in the organic layer was purified
using preparative TLC (9:1 CH2Cl2:CH3OH) to yield 2 mg
(0.004 mmol; [90 % pure) of 4-Mefway (9) and 2 mg
(0.004 mmol; [90 % pure) of 3-Mefway (10) (Fig. 4).
4-Mefway was characterized as described previously (Sa-
igal et al., 2006). For 3-Mefway (10): 1H-NMR (500 MHz,
CDCl3) d ppm: 8.52 (d, J = 4, 1H), 7.77 (t, J = 7.5, 1H),
7.74–7.79 (m, 2H), 7.05 (br, 1H), 6.80–6.93 (m, 2H),
4.10–4.21 (dd, J = 5.5, JH,F = 48, 2H, CH2F), 3.86 (s,
3
buffer. A fixed concentration of H-WAY 100635 (1 nM)
was incubated with the rat homogenate in the presence of
various concentrations of 2-methyl, 3-methyl, 4-methyl-
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Med Chem Res (2015) 24:1480–1486
WAY-100635, 4-Mefway, 3-Mefway, and WAY-100635
(10-12–10-4 M) in the assay buffer (50 mM Tris–HCl, pH
7.6). Non-specific binding was determined by including
10 lM of WAY-100635. Total assay volume was 0.5 mL.
To start, 0.2 mL of the rat brain homogenate was added to
120
100
80
60
40
20
0
2-Me
3-Me
4-Me
WAY
3
each test tube containing H-WAY-100635, different con-
centrations of drugs, and 10 lM of WAY-100635 for non-
specific binding. The test tube samples were incubated for
1 h in a 37 °C water bath. After incubation, a rapid vacuum
filtration was implemented through Whatman GF/C filter
paper (pre-soaked in 0.1 % polyethylamine in 10 mL of
Millipore water) using Brandel tissue harvester. The filter
was washed three times with 5 mL of cold buffer and was
transferred to vials with 5 ml Bio-Safe II scintillation
cocktail and counted for 10 min in a scintillation counter.
The same procedures were followed when performing the
binding assay for WAY-100635 as the test compound. Data
were analyzed using following procedure: (a) the non-
specific binding of 3H-WAY-100635 was subtracted for all
samples; (b) the specific binding was normalized to 100 %
(no competitive ligand); and (c) the binding isotherms were
fit to the Hill equation (KELL BioSoft software (v 6),
Cambridge, U.K.).
-20
10-12
10-11
10-10
10-9
10-8
10-7
10-6
10-5
10-4
Log[Drug, (mol/L)]
Fig. 5 Binding affinity curves of methyl-WAY-100635 derivatives.
Competition experiments on rat brain cerebrum labeled with 3H-
WAY 100635 showing higher affinity of WAY-100635 [ 2-methyl-
WAY-100635 C 4-methyl-WAY-100635 [ 3-methyl-WAY-100635
Table 1 Binding affinities for serotonin 5HT1A receptor
Serial number Compound
IC50 (nM)a Relative affinityb
1
2
3
4
5
6
7
a
WAY-100635
3.97
1
2-Methyl (cis/trans) 10.4
3-Methyl (cis/trans) 77
4-Methyl (cis/trans) 21.5
3-Mefway (cis/trans) 17.4
4-Mefway (cis/trans) 6.26
2.62
19.4
Results and discussion
5.42
4.38
1.58
0.78
18F-Mefway is a promising PET radioligand for 5-HT1A
receptors. In order to further understand how the binding
properties are affected based on the position of the methyl
and fluoromethyl group, four new compounds were
investigated. For this study, the methyl group was placed
on the 2, 3, and 4 positions (2, 3, 4) and the fluoromethyl
group was placed on the 3 and 4 positions (9, 10).
4-Mefway (trans)
3.11
Affinity measures from competition assay in rat brain homogenates
3
labeled with H-WAY-100635 (1 nM)
b
Relative affinity compared to WAY-100635
Synthesis
as shown in Fig. 5, the respective carboxamides (13) were
produced in modest yields (approx. 30 %). Reduction of
the esters (13) proceeded with the use of LiAlH4 resulting
in a very modest yields of the alcohols (10–20 %, 14). The
alcohols (14) were treated with DAST, resulting in the
formation of 3- and 4-Mefway (9a, 10a) in yields of
approx. 40 %.
Synthesis of 2-methyl, 3-methyl, and 4-methyl-WAY-
100635 took place in 2 steps. At the start of the synthesis,
we used the alternate mechanism of an acid chloride cou-
pling (Choi et al., 2010) instead of the BOP catalyst as
outlined by Saigal et al. (2006). The reaction of the 2-/3-/4-
methyl-1-cyclohexanecarboxylic acid (5, 6, 7) in the pre-
sence of oxalyl chloride produced the corresponding
substituted cyclohexylcarbonyl chlorides which were cou-
pled with WAY-100364 to give a modest yield of products
in the range of 17–34 %. The yield provided by the cou-
pling of the acid chlorides was modest and not necessarily
better than the previously reported BOP coupling method
(Saigal et al., 2006). However, the reactions from the acid
chloride pathway led to fewer impurities.
Binding affinity
2-Methyl, 3-methyl, 4-methyl-WAY-100635, and WAY-
100635 exhibited an IC50 of 10.4 nM, 77 nM, 21.5 nM, and
3.97 nM, respectively (Fig. 5). As shown in Table 1, rel-
ative affinities of 2-methyl, 3-methyl, and 4-methyl were
all lower than the affinity of WAY with affinities of
2-methyl and 4-methyl being better and 3-methyl having
the lowest affinity (19-fold weaker). The decrease in
affinity appears to be regioselective with the order being
Synthesis of 3-Mefway and 4-Mefway took place in
5-steps. Using acid chlorides of carboxymethyl esters (12)
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Med Chem Res (2015) 24:1480–1486
1485
Several recent efforts have been made to study effects of
replacing the cyclohexyl group in WAY-100635 with other
cyclic rings. One study examined the effects of bridgehead
fluoromethyl group (cubyl, adamantly, and others) with
some success (Al Hussainy et al., 2011). RWAY- which
contains a cycloheptyl has been studied with 11C-RWAY,
although human studies have indicated interference by a
lipophilic metabolite (Zhang et al., 2007). More recently, a
rather large derivative has been shown to have some
promising properties in vivo. Among the various fluorine-
18 derivatives reported thus far, it appears that 18F-Mefway
has comparable properties to 11C-WAY-100635, in rodents
and monkeys (Saigal et al., 2013). Studies on demethylated
11C-WAY-100635 (11C-DWAY-100635) have shown
higher brain uptake in humans (Pike et al., 1998); however,
despite this higher uptake of 11C-DWAY-100635, not
many studies have reported using it. It may be anticipated
that demethylated 18F-Mefway may mimic the increased
brain uptake in humans.
Fig. 6 Binding affinity curves of Mefway. Competition experiments
3
on rat brain cerebrum labeled with H-WAY 100635 showing higher
affinity of 4-Mefway compared to 3-Mefway
2-Me \ 4-Me \ 3-Me. Thus, it appears that in vitro
binding assays show that a methyl group on the cyclohexyl
ring of WAY-100635 decreases binding affinity. It must be
noted, however, that the methyl derivatives were a mixture
of cis/trans isomers. Our previous work has shown dif-
ferences in the binding profile of cis- versus the trans-
isomer for 18F-Mefway (Wooten et al., 2011b). Thus, it is
possible that the affinities of the pure isomers may be
different and provide more accurate information.
In conclusion, amongst the three methylated derivatives
investigated in this study, the 3-methyl has the weakest
affinity for PET studies. Thus, the 2- and 4-methyl deriv-
atives are more optimal. Our ongoing PET imaging studies
with 4-18F-Mefway in different species confirms this suit-
ability (Bajwa et al., 2014).
Acknowledgment This research was financially supported by a
Grant from National Institutes of Health, R21/R33 AG 030524.
In the case of the fluorinated derivatives, 3-Mefway had
an IC50 of 17.4 nM (about 4.4 times weaker than WAY-
100635) while 4-Mefway had an IC50 of 6.26 nM (about
1.6 times weaker than WAY-100635) (Fig. 6). The ratio
between the two derivatives is approximately similar to the
results found for the 3-methyl and 4-methyl derivatives.
The presence of the fluorine on the methyl group increases
the binding affinity of the compounds (by approximately
threefold). The trans-isomer of 4-Mefway was found to be
the most potent amongst the compounds studied in this
paper, with an IC50 of 3.11 nM. This high affinity is con-
firmed by PET studies showing the distinct binding pattern
of 4-18F-Mefway in serotonin 5-HT1A receptor-rich areas
in the brain of rats and monkeys (Saigal et al., 2013;
Wooten et al., 2011a). Hippocampus (dorsal and ventral)
and entorhinal cortex were the high binding regions fol-
lowed by the cortex. Striatum and cerebellum showed little
binding consistent with the lack of receptors in these brain
regions. Preliminary comparative in vivo studies of 3-18F-
Mefway and 4-18F-Mefway have been carried out in
monkeys. The lower binding seen in the brain regions in
PET studies using 3-18F-Mefway confirms the lower
in vitro binding affinity of 3-Mefway compared to
4-Mefway for the serotonin 5HT1A receptors (Wooten
et al., 2014).
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