Synthesis and biological evaluation of a series of novel N- or O-fluoroalkyl derivatives of tropane: Potential positron emission tomography (PET) imaging agents for the dopamine transporter

Article abstract of DOI:10.1016/S0960-894X(01)00626-6

A series of novel fluoroalkyl-containing tropane derivatives was synthesized, and their binding affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) were determined via competitive binding assays. Among these derivatives, the fluoropropyl ester of β-CIT (19), the fluoroethyl ester of β-CIT (20), the N-fluoropropyl derivative of β-CBT (12), and the fluoropropyl ester of β-CMT (18) displayed higher affinity and greater selectivity for the DAT versus SERT and NET than FP-CIT, which indicates that they are attractive candidates for the development of ¹⁸F-labeled PET imaging agents for the DAT.

Full text of DOI:10.1016/S0960-894X(01)00626-6

Bioorganic & Medicinal Chemistry Letters 11 (2001) 3049–3053
Synthesis and Biological Evaluation of a Series of Novel
N- or O-Fluoroalkyl Derivatives of Tropane: Potential Positron
Emission Tomography (PET)Imaging Agents for the
Dopamine Transporter
Xiao-Hui Gu,a,c Rushi Zong,a,c Nora S. Kula,b Ross J. Baldessarinib
and John L. Neumeyera,c,*
aMedicinal Chemistry Laboratory, Alcohol and Drug Abuse Research Center, Belmont, MA 02478-9106, USA
bNeuroscience Program, Mailman Research Center, McLean Hospital, Harvard Medical School, Belmont, MA 02478-9106, USA
cNatural Pharmacia International, Inc., 115 Mill Street, Belmont, MA 02478-9106, USA
Received 24 July 2001; accepted 10 September 2001
Abstract—A series of novel fluoroalkyl-containing tropane derivatives was synthesized, and their binding affinities for the dopamine
transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) were determined via competitive binding
assays. Among these derivatives, the fluoropropyl ester of b-CIT (19), the fluoroethyl ester of b-CIT (20), the N-fluoropropyl deri-
vative of b-CBT (12), and the fluoropropyl ester of b-CMT (18) displayed higher affinity and greater selectivity for the DAT versus
SERT and NET than FP-CIT, which indicates that they are attractive candidates for the development of 18F-labeled PET imaging
agents for the DAT. # 2001 Elsevier Science Ltd. All rights reserved.
Positron emission tomography (PET) is a sensitive and
specific non-invasive imaging technology that can pro-
vide information about the functional status of neuro-
transmitter systems in vivo.1ꢀ3 PET has emerged as an
important tool in drug discovery, research and devel-
opment.4ꢀ8 Desirable properties of a PET radiotracer
include: (1) high affinity for target and low affinity for
nontargets, (2) sufficient lipophilicity or carrier system
to cross cell membranes, (3) low peripheral metabolism,
and (4) efficient labeling with radioactive isotopes.
neuropsychiatric diseases such as Parkinson’s dis-
ease,10,11 major depression,12 Huntington’s chorea,13
schizophrenia,14 and attention deficit-hyperactivity dis-
order (ADHD).15,16 DAT also plays a prominent role in
the reinforcing effects of cocaine and other
stimulants.17ꢀ20
There has been a great deal of recent effort to prepare
PET-based radiotracers for use in studies of DAT
abundance and pharmacology. Most such PET radio-
tracers for DAT labeling have been carbon-11 labeled
2b - carbomethoxy - 3b - (4 - substituted - phenyl)tropane
derivatives.21ꢀ28 Several fluorine-18 labeled tropane
derivatives are also known. These include CFT,29 FP-
CFT,28 FP-CIT,30ꢀ32 FECT,33 FETT,33 FPCT,34
FECNT,35 and FIPCT,36 in which the methyl group at
the 8-position of the tropane was replaced by a 3-fluor-
opropyl group or a 2-fluoroethyl group or the 2b-
methyl ester by a 2b-20-fluoroethyl ester and a 2b-10-
fluoro-isopropoxy ester. Most recently, the fluorine-18
labeled 2b-propanoyl-3b-(4-substituted-phenyl)tropane
derivatives FTT and FCT, which contain a 2b-ketone
moiety instead of a 2b-ester group, were reported by
Mach et al.37 Some of these radioligands show promise
The dopamine transporter (DAT) is a membrane-bound
protein with 12 putative transmembrane segments,
selectively expressed by dopamine neurons and located
with relatively high density at the presynaptic dopami-
nergic nerve terminals. The function of the DAT is to
terminate the neurochemical action of released dopa-
mine by reuptake into the presynaptic dopaminergic
neurons.9 Changes in the density and function of DAT
have been implicated in neurodegenerative and
*Corresponding author. Tel.: +1-617-855-3388; fax: +1-617-855-
2519; e-mail: neumeyer@mclean.harvard.edu
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00626-6

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X.-H. Gu et al. / Bioorg. Med. Chem. Lett. 11 (2001) 3049–3053
as clinical PET imaging agents for the DAT, but their
affinity and selectivity for the DAT still require
improvement.
Reaction of the trimethylsilyl 3 with NaBr and NCS in
HOAc40 afforded b-CBT (5)41 in nearly quantitative
yield. b-CIT (6) was obtained in excellent yield after
treatment of 3 in absolute MeOH with ICl or iodine in
the presence of AgBF4.42 We also found that treatment
of 3 with iodine or ICl in HOAc without the expensive
catalyst AgBF4 gave 75% yield of b-CIT. N-Demethy-
lation of 4–6 using a-chloroethyl chloroformate (ACE-
Cl) in ethylene dichloride followed by treatment with
MeOH43 afforded the nortropanes (7–9) (Scheme 2).
The N-(fluoroalkyl)phenyltropanes (10–13) were pre-
pared by alkylation of the corresponding nortropanes
(7–9) with fluoroethyl bromide or fluoropropyl bromide
according to the procedure we reported previously.44,45
Fluorine-18 is a more attractive positron-emitting
radionuclide for radiolabeling because it has a longer
half-life (t1/2=110 min) than carbon-11 (t1/2=20.4 min),
enabling imaging studies to be carried out over longer
periods of time (2–4 h). Further, fluorine-18 is also the
lowest energy positron emitter (0.635 MeV, 97% abun-
dant) and it affords the highest resolution images (max-
imum 2.4 mm positron range). Accordingly, we have
focused our recent efforts on developing 18F-labeled
tropane derivatives as DAT imaging agents.30,31 We
now report the synthesis and monoamine transporter
binding evaluation of a series of novel fluoroalkyl-sub-
stituted derivatives of tropane. The results of our study
indicate that several fluoroalkyl-containing tropane
derivatives possess high affinity and selectivity for DAT,
and so are attractive potential PET radioligands for in
vivo imaging the DAT in human forebrain.
The fluoroalkyl-containing ester analogues of tropane
18–20 were synthesized according to the general syn-
thetic route shown in Scheme 3. Hydrolysis of 4 and 6 in
aqueous dioxane46 gave the corresponding acids 14 and
15 in excellent yields. Treatment of 14 and 15 with
POCl3 yielded the acid chlorides, which were treated
with 1,3-propane-diol monomesylate47 yielding esters
16–17. Treatment of the mesylate 16–17 with TBAF in
refluxing THF afforded the 3-fluoropropyl ester 18–19
in good yields. The acid chloride of 14 was treated with
2-fluoroethanol in dry CH2Cl2 in the presence of Et3N
to give the desired 2-fluoroethyl ester 20 in good yield.
Hydrolysis of FP-CIT (13) in aqueous dioxane afforded
the acid 21 (Scheme 4). Without isolation, the acid 21
Anhydroecgonine methyl ester (2) was initially prepared
from cocaine in 97% overall yield after bulb-to-bulb dis-
tillation by the procedure of Clarke et al. (Scheme 1).38
Treatment of 2 with appropriate 4-substituted phe-
nylmagnesium bromide afforded the 2b-carbomethoxy-
3b-(4-substituted phenyl) tropanes (3–4) after quenching
the reaction with trifluoroacetic acid at low temperature.39
Scheme 1. Reagents and conditions: (a) HCl (6 N), reflux; (b) POCl3; (c) MeOH; (d) ArMgBr, Et2O; (e) ICl or I2, AgBF4, MeOH; (f) NaBr, NCS,
HOAc.
Scheme 2. Reagents and conditions: (a) ACE–Cl, ClCH2CH2Cl, reflux; (b) MeOH, rt; (c) F(CH2)nBr, KI, Et3N, EtOH, reflux.

X.-H. Gu et al. / Bioorg. Med. Chem. Lett. 11 (2001) 3049–3053
3051
was converted to the acid chloride by treatment with
POCl3, and the resulting acid chloride was reacted with
2-fluoroethanol to give 22 in good yield. The physical
data of all these novel derivatives are listed in Table 1.
over SERT and NET. However, the N-fluoroethyl (11)
and N-fluoropropyl (10) derivatives of b-CMT showed
lower affinity for all three transporters than FP-CIT,
but the decrease is relatively greater for the SERT and
the NET, resulting in higher selectivity for DAT than
was shown by FP-CIT.
The Ki values for the inhibition of radioligand binding
at the DAT, SERT, and NET in rat forebrain tissue by
these novel fluoroalkyl-containing tropane derivatives
are summarized in Table 2 along with our previously
reported Ki values for b-CIT, nor-CIT, and FP-CIT for
comparison. Binding potencies at DAT, SERT, and
NET were determined with competitive binding assays
using previously reported procedures.48,49 Ratios of Ki
values (SERT/DAT and NET/DAT) were used to indi-
cate the in vitro selectivity of these novel compounds for
the DAT.
It is interesting to note that the N-fluoropropyl deriva-
tive of b-CMT (11) showed higher (3-fold and 4-fold,
respectively) selectivity for the DAT over the SERT and
the NET than the corresponding N-fluoroethyl deriva-
tive 10 due to its lower affinity for the SERT and the
similar affinity for the DAT. Remarkably, all fluor-
oalkyl esters except 22 displayed higher binding affinity
and selectivity for the DAT than FP-CIT. The fluor-
opropyl ester of b-CIT (19) had similar affinity for the
DAT to that of b-CIT, whereas the fluoroethyl ester 20
showed somewhat higher DAT affinity. The fluoroethyl
ester of FP-CIT (22) possessed similar affinity, but
increased selectivity for the DAT relative to the methyl
ester FP-CIT. The fluoropropyl ester of b-CMT (18)
had similar affinity for the DAT as FP-CIT, but 18
possessed 193-fold and 4-fold lower affinity for the
SERT and the NET, respectively, than FP-CIT.
In marked contrast to b-CIT and FP-CIT, all of these
novel derivatives displayed selectivity for the DAT ver-
sus both the SERT and the NET. Among them, the
fluoropropyl ester of b-CMT (18) displayed the highest
selectivity (45-fold) for the DAT over the SERT while
the fluoroethyl ester of b-CIT (20) exhibited the highest
affinity for the DAT (Ki=0.93 nM) and the highest
selectivity (125-fold) for the DAT over the NET. Com-
pared to FP-CIT, the N-fluoropropyl derivative of b-
CBT (12) showed enhanced affinity (2.5-fold) for DAT
and decreased affinity at both SERT (22-fold) and NET
(3.1-fold), resulting in enhanced selectivity for DAT
In summary, we have synthesized and determined the
cerebral monoamine transporter binding affinity of a
series of novel fluoroalkyl-containing tropane deriva-
tives. All of these derivatives except the N-fluoroalkyl
Scheme 3. Reagents and conditions: (a) dioxane/H2O (1:1), reflux; (b) POCl3; HOCH2CH2CH2OMs, Et3N, CH2Cl2; (c) TBAF, THF, reflux; (d)
POCl3; HOCH2CH2F, Et3N, CH2Cl2.
Scheme 4. Reagents and conditions: (a) dioxane/H2O (1:1), reflux; (b) POCl3; HOCH2CH2F, Et3N, CH2Cl2.

3052
X.-H. Gu et al. / Bioorg. Med. Chem. Lett. 11 (2001) 3049–3053
Table 1. Physical properties of novel fluoroalkyl derivatives of tropane
Compd
R1
R2
X
Mp (ꢁC)
Formulaa
Analysisb
c
.
C22H30FNO8 0.5H2O
10
11
12
18
19
20
22
CH2CH2F
CH2CH2CH2F
CH2CH2CH2F
CH3
CH3
CH3
CH2CH2CH2F
CH3
CH3
CH3
CH3
CH3
Br
CH3
I
95–96
62–63
84–85
Syrup
80–81
117–118
Syrup
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C19H26FNO2
C18H23BrFNO2
.
CH2CH2CH2F
CH2CH2CH2F
CH2CH2F
CH2CH2F
C19H26FNO2 0.25H2O
C18H23FINO2
C17H21FINO2
I
I
C19H24F2INO2
aAll compounds exhibit 1H NMR spectra in agreement with their assigned structures.
bCHN analyses were withinꢂ0.4% of the theoretical values.
cThis compound was characterized and tested as its tartrate salt.
Table 2. Transporter binding affinity and SAR of fluoroalkyl derivatives of tropane
Affinity (KiꢂSE, nM)a
Selectivityb
Compd
R1
R2
X
DAT [3H]b-CIT SERT [3H]paroxetine NET [3H]nisoxetine SERT/DAT NET/DAT
10
11
12
18
19
20
22
CH2CH2F
CH2CH2CH2F
CH2CH2CH2F
CH3
CH3
CH3
CH2CH2CH2F
H
CH3
CH3
CH3
CH3
CH3
CH3
Br
32.1ꢂ2.2
375ꢂ26
1311ꢂ307
36.4ꢂ2.2
325ꢂ15
268ꢂ25
1208ꢂ176
196ꢂ14
11.7
34.9
10.9
45.3
1.1
4.3
1.5
0.1
0.4
8.4
32.1
58.9
36.3
112
125
83
2.9
2.1
7.6
37.6ꢂ3.8
3.33ꢂ0.99
7.17ꢂ0.71
1.54ꢂ0.09
0.93ꢂ0.02
8.71ꢂ0.50
0.64ꢂ0.097
1.33ꢂ0.15
8.29ꢂ0.53
CH2CH2CH2F CH3
260ꢂ12
CH2CH2CH2F
CH2CH2F
CH2CH2F
CH3
I
I
I
I
I
I
1.65ꢂ0.23
4.02ꢂ0.48
13.3ꢂ3.3
0.06ꢂ0.001
0.46ꢂ0.06
1.68ꢂ0.13
173ꢂ15
116ꢂ12
723ꢂ38
Nor-CITc
b-CITc
FP-CITc
1.85ꢂ0.21
2.80ꢂ0.40
63.0ꢂ4.0
CH3
CH3
CH2CH2CH2F
0.2
aTransporter binding affinity assays are detailed previously:48,49 rat striatal homogenates with [3H]b-CIT from Tocris-Cookson (64.7 Ci/mmol) for
DAT, cerebral cortical homogenates with [3H]paroxetine from NEN (15 Ci/mmol) for SERT, and [3H]nisoxetine from NEN (80 Ci/mmol) for NET.
bSelectivity for the DAT is indicated as the ratio of Ki for the SERT or NET to that for the DAT (ratios<1.0 indicate preference for the non-DAT
site).
cReported previously 49 and listed for comparative purpose.
derivatives of b-CMT and the fluoroethyl ester of FP-
CIT (22) showed higher DAT affinity and selectivity
than FP-CIT. Among these novel ligands, the fluor-
oethyl ester of b-CIT (20) had the highest DAT affinity
(Ki=0.93 nM) and highest selectivity for DAT over
NET (NET/DAT ratio=125), while the fluoropropyl
ester of b-CMT (18) displayed the highest selectivity for
DAT over SERT (SERT/DAT ratio=45). From a
practical point of view, tropanes 12, 18, 19, and 20 are
especially attractive candidates for the development of
18F-labeled PET radiotracers for clinical imaging DAT
in human brain.
of Mental Health (MH-34006, MH-47370) and the
Bruce J. Anderson Foundation, as well as by the
McLean Hospital Private Donors Neuropharmacology
Research Fund (to R.J.B.). Cocaine was generously
donated by Mallinckrodt. We also thank Dr. Gilles
Tamagnan at Yale University for helpful discussions.
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