Synthesis and monoamine transporter affinity of front bridged tricyclic 3β-(4′-halo or 4′-methyl)phenyltropanes bearing methylene or carbomethoxymethylene on the bridge to the 2β-position

Article abstract of DOI:10.1016/j.bmcl.2006.05.098

A series of front bridged tricyclic 3β-(4′-halo or 4′-methyl)phenyltropanes bearing methylene or carbomethoxymethylene on the bridge to the 2β-position was synthesized, and their binding affinities were determined in cells transfected to express human nor

Full text of DOI:10.1016/j.bmcl.2006.05.098

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4661–4663
Synthesis and monoamine transporter affinity of front bridged
tricyclic 3b-(40-halo or 40-methyl)phenyltropanes bearing methylene
or carbomethoxymethylene on the bridge to the 2b-position
Fanxing Zeng,a Nachwa Jarkas,a Michael J. Owens,b Clinton D. Kilts,b
Charles B. Nemeroffb and Mark M. Goodmana,*
aDepartment of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322, USA
bDepartment of Psychiatry and Behavior Sciences, Emory University, Atlanta, GA 30322, USA
Received 10 May 2006; revised 25 May 2006; accepted 30 May 2006
Available online 19 June 2006
Abstract—A series of front bridged tricyclic 3b-(40-halo or 40-methyl)phenyltropanes bearing methylene or carbomethoxymethylene
on the bridge to the 2b-position was synthesized, and their binding affinities were determined in cells transfected to express human
norepinephrine transporter (NET), serotonin transporter (SERT), and dopamine transporter (DAT) via competition binding assays.
All compounds studied in this series exhibit a moderate to high potency at all three transporters with SERT or DAT selectivity.
3b-(40-iodo)phenyltropane bearing methylene on the bridge to the 2b-position (24) presents a particularly attractive pharmacological
profile, with very high SERT affinity (Ki = 0.09 nM) and selectivity versus NET (65-fold) and DAT (94-fold).
Ó 2006 Elsevier Ltd. All rights reserved.
8
Cocaine (1, Fig. 1) elicits its behavioral and pharmaco-
N
N
logical effects by binding with moderate and roughly
equal affinity to all three of the monoamine transporters
(dopamine [DAT], serotonin [SERT], and norepineph-
rine [NET]).1,2 In recent years, cocaine analogues have
been extensively explored to develop compounds with
defined selectivities at particular monoamine transport
sites.3–7 Such selectivity is useful in developing biochem-
ical probes for behavioral studies and for transporter
imaging.
CO2CH3
2
1
7
6
5
4
O
3
O
2
Cocaine 1
Figure 1.
methylphenyl substituent on the tropane moiety was
found to show low nanomolar inhibition of monoamine
uptake for the NET (IC50 = 2.2 nM vs (ꢀ)-[3H]NE) and
to be 30 and 15 times more selective for the NET than
the DAT and SERT, respectively.9 These findings
prompted us to synthesize new front bridged tricyclic
3b-phenyltropane derivatives bearing methylene on the
bridge to the 2b-position which may offer promise as po-
tential NET imaging agents. Target molecules were de-
signed and prepared to allow radiolabeling with 11C,
76Br, or 124I for PET or 123I for SPECT. Reported herein
are the synthesis and in vitro monoamine transporter
binding evaluation of several front bridged tricyclic tro-
panes bearing methylene or carbomethoxymethylene
substituents on the bridge to the 2b-position and bearing
3b-(40-halo-, 40-methyl)phenyl substituents.
Kozikowski et al. reported a structure–activity relation-
ship study exploring the factors influencing the binding
selectivity for 3b-tropane based ligands at specific
monoamine transporters.8 In this study Kozikowski
and coworkers determined that rigidified tricyclic ana-
logues bearing linkages from the nitrogen to the 2b-po-
sition and 7-position of the tropane moiety yielded
analogues that showed low nanomolar uptake inhibition
for the NET and higher selectivity for NET over
DAT and SERT. A front bridged tricyclic analogue
(2, Fig. 1) bearing a methylene and bearing a 3b-40-
Keywords: PET; NET; SERT; Tropane; Carbon-11.
*
Corresponding author. Tel.: +1 404 727 9366; fax: +1 404 727
3488; e-mail: mgoodma@emory.edu
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.05.098

4662
F. Zeng et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4661–4663
H
Troc
N
N
N
CO2CH3
CO2CH3
CO2CH3
R = CH3
N
CO2CH3
a
b
R
R
R
OCOPh
6 R = CH3
7 R = Br
8 R = Cl
9
3 R = CH3
4 R = Br
5 R = Cl
10 R = Br
11 R = Cl
1
O
OEt
CO2CH3
N
N
N
O
c
d
e
R
R
R
2 R=CH3
18 R = Br
19 R = Cl
12 R = CH3
13 R = Br
14 R = Cl
15 R = CH3
16 R = Br
17 R = Cl
N
N
11CH3
h
i
N
N
CO2CH3
R
g
15
16
17
[
11C] 2
f
18
SnBu3
20 R = CH3
21 R = Br
22 R = Cl
23
I
24
Scheme 1. Reagents and conditions: (a) Troc-Cl, toluene, reflux; (b) Zn dust, AcOH, H2O, rt; (c) ethyl bromoacetate, EtOH, K2CO3, rt; (d) NaH,
toluene, 130 °C; AcOH, 5 N HCl, reflux; (e) PPh3CH2Br, n-BuLi, THF, 37 °C; (f) methyl diethylphosphonoacetate, NaH, THF, 60 °C; (g) (Bu3Sn)2,
Pd(PPh3)4, toluene, 130 °C; (h) [11C]CH3I, Pd2(dba)3, (o-Tol)3P, CuCl, K2CO3, DMF, 60 °C; (i) I2, CH2Cl2, rt.
The synthesis of front bridged tricyclic tropanes was
performed (as shown in Scheme 1) based on the proce-
dure reported by Kozikowski with some modification.9
Tropanes 3–5 were synthesized in three steps starting
from cocaine (1) in good yield according to known liter-
ature procedures.10 The conversion of 3–5 to its corre-
sponding carbamate using trichloroethylchloroformate
followed by Zn-acetic acid reduction gave the nortro-
pane 9–11, respectively. Alkylation of 9–11 using ethyl
bromoacetate gave diesters 12–14, which then under-
went Dieckmann condensation (effected with NaH) fol-
lowed by decarboxylative hydrolysis with HOAc and
HCl at reflux to lead to the formation of tricyclic ke-
tones 15–17. Wittig reaction of 15–17 with methyltri-
phenylphosphonium bromide gave tropanes 2, 18, and
19, bearing methylene substituent on the bridge to the
2b-position. Reaction of 15–17 with methyl diet-
hylphosphonoacetate produced (E)-vinyl methyl esters
20–22 whose relative stereochemistry was assigned by
NMR methods. Tributylstannyl tropane 23, prepared
by palladium-catalyzed coupling of 18 with bis(tribu-
tyl)tin, was used as the precursor for radiosynthesis of
[11C]2. Iodotropane 24 was prepared by halodestannyla-
tion of 23 with I2.
The affinities of tropanes 2, 18–22, and 24 for the human
NET, SERT, and DAT were determined through in vitro
competition assays in transfected HEK-293 cells accord-
ing to a previously reported procedure.11
The data shown in Table 1 indicate that all methylene
bearing tricyclic tropanes 2, 18, 19, and 24 display
Table 1. Transporter binding properties of front bridged tricyclic tropanesa
Compound
Ki for hNET
Ki for hSERT
Ki for hDAT
2
18
19
24
20
21
22
17.28 2.36
2.94 0.14
4.84 0.14
5.87 1.30
25.50 2.83
12.53 1.47
13.03 2.65
7.77 3.21
0.28 0.01
0.82 0.06
0.09 0.02
98.31 3.24
5.63 1.42
18.75 1.88
40.99 4.05
41.92 3.44
12.25 3.17
8.48 1.72
13.25 1.68
2.94 0.46
4.54 0.83
a All Ki values are reported with nanomolar (nM) units. The data are expressed as means standard deviation of at least three separate experiments
performed in triplicate. The following radiotracers were used: [3H]nisoxetine for hNET, [3H]citalopram for hSERT, and [125I]RTI-55 for hDAT.

F. Zeng et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4661–4663
4663
9
8
7
6
5
4
3
2
1
0
In summary, we have synthesized and determined the
monoamine transporter binding affinity of several new
methylene or carbomethoxymethylene bearing front
bridged tricyclic tropane derivatives. The binding results
showed that all of these derivatives exhibited a moderate
to high potency at all three transporters with SERT or
DAT selectivity, instead of NET selectivity. Compound
24 presented a particularly attractive pharmacological
profile, with very high SERT affinity (Ki = 0.09 nM)
and selectivity versus NET (65-fold) and DAT (94-fold).
Caud
Put
Thal
Midbrain
pons
Medulla
Occip CX
Cere
Front CX
0
20
40
60
80
100
120
Acknowledgment
Time (min)
This work was supported by a grant from Wyeth
Pharmaceuticals.
Figure 2. MicroPET time–activity curves for brain regions for a rhesus
monkey after intravenous injection of 10.37 mCi [11C]2. Images were
acquired for a total time of 120 min.
greater affinity for the SERT than for NET or DAT,
with 3b-40-iodophenyl compound 24 having the highest
affinity (Ki = 0.09 nM) for SERT and selectivity versus
the NET (65-fold) or DAT (94-fold). To our disappoint-
ment, 3b-40-methylphenyl compound 2 exhibited moder-
ate affinity for both the NET (Ki = 17.28 nM) and SERT
(Ki = 7.77 nM), and relatively low affinity for the DAT
(Ki = 41 nM) which differs from the literature reports
based on uptake inhibition studies.9 To confirm the
affinity of 2, microPET imaging studies were performed
with [11C]212 to assess the regional distribution in anes-
thetized rhesus monkeys according to a previously
reported procedure.11 Time–activity curves obtained
after administration of [11C]2 demonstrated a mix of
SERT and NET selectivity profile with a high uptake
in putamen, midbrain, pons, thalamus, medulla, cau-
date, and cerebellum (Fig. 2). The highest ratios relative
to occipital cortex, a brain region with low SERT and
NET density, occurring at 105 min were 1.83, 1.53,
1.52, 1.48, 1.47, and 1.36 for the putamen, midbrain,
pons, thalamus, caudate, and medulla, respectively,
while 1.39 for cerebellum which occurred at 25 min.
The uptake of [11C]2 reflects the known distribution of
the SERT and NET in monkey brain, and is in agree-
ment with its in vitro binding affinities we found. Intro-
duction of methyl ester group on methylene as in
analogues 20–22 led to a significant reduction of binding
affinity at the SERT by 13- to 23-fold and a increase of
DAT activity by 3-, 14-, and 3-fold, respectively, while
the potency at the NET slightly decreased by 1.2- to 4-
fold. Selectivity profiles of these compounds switch to
selectivity for the DAT versus SERT and NET.
References and notes
1. Hytell, J. Prog. Neuropsychopharmacol. Biol. Psychiatry
1982, 6, 277.
2. Carroll, F. I.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J.
J. Med. Chem. 1992, 35, 969.
3. For papers published before 2003, see Zhou, J.; Zhang, A.;
Kla¨ss, T.; Johnson, K. M.; Wang, C. Z.; Ye, Y. P.;
Kozikowski, A. P. J. Med. Chem. 2003, 46, 1997, and
references cited there.
4. Carroll, F. I. J. Med. Chem 2003, 46, 1175.
5. Carroll, F. I.; Pawlush, N.; Kuhar, M. J.; Pollard, G. T.;
Howard, J. L. J. Med. Chem. 2004, 47, 296.
6. Carroll, F. I.; Tyagi, S.; Blough, B. E.; Kuhar, M. J.;
Navarro, H. A. J. Med. Chem. 2005, 48, 3852.
7. Tamagnan, G.; Alagille, D.; Fu, X.; Kula, N. S.;
Baldessarini, R. J.; Innis, R. B.; Baldwin, R. M. Biorg.
Med. Chem. Lett. 2006, 16, 217.
8. Smith, M. P.; Johnson, K. M.; Zhang, M.; Flippen-
Anderson, J. L.; Kozikowski, A. P. J. Am. Chem. Soc.
1998, 120, 9072.
9. Tamiz, A. P.; Smith, M. P.; Kozikowski, A. P. Bioorg.
Med. Chem. Lett. 2000, 10, 297.
10. Holmquist, C. R.; Keverline-Frantz, K. I.; Abraham, P.;
Boja, J. W.; Kuhar, M. J. K.; Carroll, F. I. J. Med. Chem.
1996, 39, 4139.
11. Plisson, C.; McConathy, J.; Martarello, L.; Malveaux, E.
J.; Camp, V. M.; Williams, L.; Votaw, J. R.; Goodman,
M. M. J. Med. Chem. 2004, 47, 1122.
12. [11C]2 was prepared by palladium-catalyzed cross coupling
of tin precursor 23 with [11C]CH3I according to a
procedure developed by Bjo¨rkman et al.; see Bjo¨rkman,
M.; Doi, H.; Resul, B.; Suzuki, M.; Noyori, R.; Watana-
˚
ble, Y.; Langstrom, B. J. Labelled Cpd. Radiopharm 2000,
43, 1327.