Synthesis and evaluation of novel tropane derivatives as potential PET imaging agents for the dopamine transporter

Article abstract of DOI:10.1016/j.bmcl.2012.05.030

A novel series of tropane derivatives containing a fluorinated tertiary amino or amide at the 2β position was synthesized, labeled with the positron-emitter fluorine-18 (t_1/2 = 109.8 min), and tested as potential in vivo dopamine transporter (D

Full text of DOI:10.1016/j.bmcl.2012.05.030

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4303–4306
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of novel tropane derivatives as potential PET
imaging agents for the dopamine transporter
Hongwen Qiao a,b, Lin Zhu a,b, Brian P. Lieberman b, Zhihao Zha b, Karl Plössl b, Hank F. Kung a,b,c,
⇑
a Key Laboratory of Radiopharmaceuticals, Beijing Normal University, Ministry of Education, Beijing 100875, PR China
b Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
c Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 February 2012
Revised 4 May 2012
Accepted 8 May 2012
Available online 15 May 2012
A novel series of tropane derivatives containing a fluorinated tertiary amino or amide at the 2b position
was synthesized, labeled with the positron-emitter fluorine-18 (t1/2 = 109.8 min), and tested as potential
in vivo dopamine transporter (DAT) imaging agents. The corresponding chlorinated analogs were
prepared and employed as precursors for radiolabeling leading to the fluorine-18-labeled derivatives
via a one-step nucleophilic aliphatic substitution reaction. In vitro binding results showed that the 2b-
amino compounds 6b, 6d and 7b displayed moderately high affinities to DAT (Ki <10 nM). Biodistribution
studies of [18F]6b and [18F]6d showed that the brain uptakes in rats were low. This is likely due to their
low lipophilicities. Further structural modifications of these tropane derivatives will be needed to
improve their in vivo properties as DAT imaging agents.
Keywords:
Dopamine transporter
Tropane
Fluorine-18
Imaging tracers
PET
Ó 2012 Published by Elsevier Ltd.
The dopamine transporter (DAT) is located on the membrane of
presynaptic dopaminergic neurons in the central nervous system
(CNS). A rapid and efficient reuptake of dopamine from the synap-
tic cleft back into presynaptic neuronal site terminates and regu-
lates the dopaminergic neurotransmission.1–4 The concentration
of DAT is highest in the caudate, putamen, nucleus accumbens,
and olfactory tubercle, while lower in the substantia nigra, amyg-
dala, and hypothalamus. Changes in DAT concentration are associ-
ated with numerous neurodegenerative and neuropsychiatric
diseases, including Parkinson’s disease (PD), attention deficient-
hyperactivity disorder (ADHD), drug abuse, Huntington’s chorea
and schizophrenia. PET imaging is a sensitive technique to measure
the density and activity of DAT in the brain, which is potentially
useful for diagnosing, monitoring and evaluating treatment of
these diseases, especially for movement disorders associated with
PD.5–9
A large number of positron emission tomography (PET) radio-
tracers labeled with carbon-11 and fluorine-18 for imaging DAT
have been developed extensively in the past three decades.10–12
An effective DAT imaging tracer should meet a set of minimum
requirements13: (1) adequate binding affinity to DAT (Ki <10 nM)
and more than 50-fold lower binding affinities to the serotonin
transporter (SERT) and norepinephrine transporter (NET); (2)
appropriate lipophilicity to allow the imaging agents to cross the
blood–brain barrier (BBB); (3) reasonable in vivo metabolite
profiles from peripheral tissues without producing unwanted
radioactive metabolites able to enter the brain; (4) appropriate
pharmacokinetics for quantification of the DAT concentration in
the brain; (5) simple and effective radiolabeling procedure pre-
pared via a limited number of chemical transformations within a
short time to give a radioactive compound with high radiochemi-
cal yield, purity and specific activity.
It is well known that 18F has a longer half-life (109.8 min) than
11C (20 min), and has been widely used for labeling DAT imaging
tracers.2,14 Numerous compounds labeled with 18F have been eval-
uated for imaging DAT binding sites in the brain, and most of them
are tropane derivatives. They include leading candidates such as
[
[
18F]FECT,15 18F]FP-CIT,16 18F]FECNT,17,18 18F]FE-PE2I19 and
[ [ [
18F]LBT-99920,21. It was reported that [18F]FECNT displayed a high
affinity and selectivity to human DAT, and the most favorable DAT
binding kinetics in human studies, attaining quasi-equilibrium at
90 min post injection. However, analyses of arterial plasma from
rats, monkeys and humans showed an inactive radiometabolite
of [18F]FECNT that entered the brain and distributed nonspecifi-
cally in the brain, contributing to a higher background.22 Another
tracer, [18F]FE-PE2I, developed from [11C]PE2I,23–25 displayed a de-
sired high binding affinity (Ki = 12 1.7 nM) to DAT with more
than 50-fold lower affinity to other monoamine transporters.26
A
relatively new generation of highly selective DAT ligand, LBT-
999, has been reported. It is a close structural analog of [11C]PE2I
and has been labeled with 18F as well as with 11C.20,21,27 However,
⇑
Corresponding author. Tel.: +1 215 662 3096; fax: +1 215 349 5035.
E-mail address: kunghf@sunmac.spect.upenn.edu (H.F. Kung).
0960-894X/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmcl.2012.05.030

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H. Qiao et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4303–4306
similar to [18F]FECNT, [11C]PE2I also undergoes in vivo metabolism
forming polar components: two polar radiometabolites were found
in the brain.28,29 Therefore, it can be expected that [18F]FE-PE2I and
84%). In addition, 5 was reacted with 2-(2-chloroethoxy)ethyl-4-
methylbenzenesulfonate or its fluorinated analog in the presence
of Cs2CO3 to give compound 7a or 7b in 11% and 64% yields.
Compound 8 was synthesized from 1 following a previously
published method33 in good yield (84%). It was then reacted with
1-bromo-2-chloroethane, 1-bromo-2-fluoroethane, 1-bromo-3-
chloropropane or 1-iodo-3-fluoropropane to give 9a–9d in the
range of 68–82% yields. These were hydrolyzed in 1 N HCl, and
then changed to 2b-acyl chloride derivatives 11a–11d with oxalyl
chloride. The acyl chloride derivatives, 11a–11d, were reacted with
dimethylamine in CH2Cl2 to give fluorinated and chlorinated
2b-amide compounds 12a–12d in good yields ranging from 71%
to 85%. These amide intermediates, 12a–12d, were successfully re-
duced with BH3ÁTHF under reflux for 4 h to give the corresponding
2b-amine derivatives 13a–13d. The yields of chlorinated analogs
13a and 13c were only 18% and 13%, fluorinated analogs 13b and
13d were 71% and 74%.
[
18F]LBT-999 may also undergo similar metabolism.15,30 The objec-
tive of optimization of novel DAT imaging tracers is to improve the
metabolic stability, while retaining the high affinity and selectivity
to DAT. Based on previously reported structure–activity relation-
ships of tropane derivatives,31 we have elected a new strategy by
introducing a tertiary amino or amide group to replace the ester
group at the 2b position of tropane. We reasoned that the 2b
substituted tropanes may be less likely to produce undesired brain
penetrating metabolites and have less complicated metabolite pro-
files. Therefore, we have prepared and tested tropane derivatives
containing 2b-fluoroalkylamines and their corresponding amides,
and we also prepared several N-fluoroalkyl substituted tropanes
for comparison. Synthesis and evaluation of these tropane deriva-
tives are reported herein.
The general strategy for the synthesis of the tropane derivatives
is shown in Scheme 1. Following a published route32, compound 1
was hydrolyzed in 1 N HCl under reflux for 12 h to give acid 2. The
carboxyl group at 2b position of 2 was transformed to acyl chloride
with oxalyl chloride in CH2Cl2 at room temperature to give 3,
which reacted directly with methylamine hydrochloride and
triethylamine in CH2Cl2 to yield 4 in 75% overall yield from 1. Com-
pound 4 was reduced with BH3ÁTHF in THF under reflux for 12 h to
give 5 in 85% yield. Compound 5 was reacted with 1-bromo-2-
chloroethane or 1-bromo-3-chloropropane in the presence of
triethylamine to give compounds 6a or 6c in 13% and 83% yields
as precursors for radiolabeling with fluorine-18 via nucleophilic
aliphatic substitution. Reaction of 5 with 1-bromo-2-fluoroethane
or 1-iodo-3-fluoropropane afforded compounds 6b and 6d as stan-
dards under the same reaction conditions in good yields (89% and
The in vitro binding affinities (Ki) to DAT for the fluorinated tro-
pane derivatives were evaluated by competition binding assays
with [125I]IPT, which has high affinity to DAT (Kd = 1.2 nM).34 Mem-
brane homogenates of transfected LLC-PK1 cell line that overex-
press DAT were used for binding assays. The Ki of GBR12909
binding to DAT was also tested for comparison (Table 1). The
2b-amide derivatives 12b and 12d showed low affinities to DAT
(699 11.3 and 135 4.50 nM), but when the 2b-amide was re-
duced to 2b-amine, the binding affinities of 13b and 13d increased
to 18.3 3.10 and 26.9 0.80 nM. Significantly, other 2b-amines,
6b, 6d and 7b, in which the methyl at 8-N position of tropane
structure was preserved, displayed high affinities to DAT
(3.79 1.04, 2.64 0.03 and 4.63 0.31 nM).
In the literature, most of the 18F labeled tropane derivatives
developed as DAT imaging tracers were radiolabeled by a two-step
N
nX
N
e
f
Cl
6a, n = 2, X = Cl
6b, n = 2, X = F
6c, n = 3, X = Cl
6d, n = 3, X = F
O
O
O
O
N
N
N
N
N
O
OH
Cl
N
H
N
H
a
b
c
d
Cl
Cl
Cl
Cl
Cl
5
1
2
3
4
O
N
X
N
Cl
7a, X = Cl
7b, X = F
H
O
O
O
O
O
n
N
n
n
X
N
N
X
N
X
N
g
e
a
Cl
O
O
O
OH
b
Cl
Cl
Cl
Cl
Cl
8
1
9a, n = 2, X = Cl
9b, n = 2, X = F
9c, n = 3, X = Cl
9d, n = 3, X = F
10a, n = 2, X = Cl
10b, n = 2, X = F
10c, n = 3, X = Cl
10d, n = 3, X = F
11a, n = 2, X = Cl
11b, n = 2, X = F
11c, n = 3, X = Cl
11d, n = 3, X = F
O
n
n
N
X
N
X
N
N
h
i
Cl
Cl
12a, n = 2, X = Cl
12b, n = 2, X = F
12c, n = 3, X = Cl
12d, n = 3, X = F
13a, n = 2, X = Cl
13b, n = 2, X = F
13c, n = 3, X = Cl
13d, n = 3, X = F
Scheme 1. Reagents and reaction conditions: (a) 1 N HCl, reflux, 12 h; (b) (COCl2)2, CH2Cl2, rt, 4 h; (c) CH3NH2ÁHCl, Et3N, CH2Cl2, rt, 8 h, 4: 75%; (d) BH3ÁTHF, THF, reflux, 12 h,
5: 85%; (e) Y(CH2)nX (Y = Br, I; X = Cl, F), Et3N, MeCN, rt, 12 h, 6a: 13%, 6b: 83%, 6c: 89%, 6d: 84%, 9a: 82%, 9b: 68%, 9c: 75%, 9d: 76%; (f) TsO(CH2)2O(CH2)2X (X = Cl, F), Cs2CO3,
DMF, rt, 12 h, 7a: 11%, 7b: 64%; (g) 1. ACE-Cl, CH2ClCH2Cl, reflux, 6 h; 2. MeOH, reflux, 4 h, 8: 84%; (h) (CH3)2NH, CH2Cl2, rt, 8 h, 12a: 79%, 12b: 81%, 12c: 71%, 12d: 85%; (i)
BH3ÁTHF, THF, reflux, 4 h, 13a: 18%, 13b: 71%, 13c: 13%, 13d: 74%.

H. Qiao et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4303–4306
4305
Table 1
buffer (pH 7.4). In this experiment a labeled compound was added
to 3 g of 1-octanol and 3 g of NaH2PO4 buffer. The mixture was vor-
texed for 1 min, and centrifuged for 3 min. The 1-octanol layer was
removed and the partition step was repeated two more times. The
partition coefficient was determined by calculating the ratio of
counts/mL between 1-octanol and buffer after the third partition.
The partition coefficients (logP) of the 18F labeled tropane deriva-
tives are shown in Table 1. For an effective brain DAT imaging tra-
cer, appropriate logP should be between 1 and 3.13,36 Compounds
Binding affinity, radiolabeling yield and logP of tropane derivatives
Compound
Ki (n = 3, nM)a
RCYb
logP
[
[
[
[
[
[
[
18F]6b
3.79 1.04
2.64 0.03
4.63 0.31
699 11.3
135 4.50
18.3 3.10
26.9 0.80
2.42
33.5 14.9%
40.3 4.3%
—
32.9 8.8%
22.9 4.9%
24.5 5.3%
26.7 6.7%
—
1.52
1.72
—
À0.11
À0.07
1.88
1.98
—
18F]6d
18F]7b
18F]12b
18F]12d
18F]13b
18F]13d
[
18F]6b, [18F]6d, [18F]13b and [18F]13d displayed suitable lipophi-
GBR12909
licities for imaging DAT in brain. Lipophilicities of 2b-amide deriv-
atives [18F]12b and [18F]12d were too low for brain penetration,
and also their binding affinities to DAT were too low to be useful.
Compounds [18F]6b and [18F]6d have high binding affinities to
DAT, [18F]13d has similar affinity and slightly better lipophilicity
than [18F]13b. The three 18F labeled compounds were evaluated
with biodistribution studies in rats.
a
LLC-DAT membrane homogenates incubated with 0.1 nM
(Kd = 1.2 nM).
[
125I]IPT
b
RCY: radiochemical yield, n = 3, non-decay-corrected. The total time for the
radiolabeling was less than 60 min.
reaction: 18FÀ was first introduced to active intermediates, and the
purified 18F labeled intermediates were reacted with tropanes
leading to the desired 18F labeled tropane derivatives.15,19,20,35
One exception is worth-mentioning: the preparation of [18F]LBT-
999, that was first performed using a two-step approach as de-
scribed above and later using a one-step chloro-for-fluorine radio-
fluorination reaction.20,21 In this project, we tested an alternative
strategy by using a direct one-step nucleophilic fluorination to pre-
pare the 18F labeled tropane. To our surprise, the precursors con-
taining –OTs, –OMs or –Br as the leaving group for direct one-
step nucleophilic 18F labeling were unstable. It was found that only
the chlorine atom was suitable as the leaving group, which pro-
vided the stability for these precursors. Therefore, we prepared,
6a, 6c, 7a, 12a, 12c, 13a and 13c for 18F radiolabeling via a one-step
reaction, through which 18F labeled tropane derivatives were suc-
cessfully prepared (Scheme 2). A mixture of 18FÀ/K222/K2CO3 in
acetonitrile was co-evaporated to dryness, and 1 mL solution of
1 mg precursor in anhydrous DMSO was added. The reaction mix-
ture was heated at 110 °C for 10 min, and the resulting mixture
was purified with semi-preparative reversed phase HPLC. The
radiochemical yields of the desired 18F labeled tropane derivatives
are shown in Table 1. The identities of the radiotracers were con-
firmed by co-injection with standard compounds. As expected
the HPLC profiles of these radiotracers showed the same retention
time as those of standard cold compounds. The total time for radio-
labeling was less than 60 min, radiochemical purities were higher
than 99% and specific radioactivities were greater than 80 GBq/
Initial evaluation of [18F]6b, [18F]6d and [18F]13d was per-
formed in normal male Sprague–Dawley rats at 30 min post iv
injection (30 lCi per rat, n = 3). The organs of interest were
removed and weighed, and the radioactivity was counted with
an automatic gamma counter. The percent initial dose per gram
of organs was calculated by a comparison of the tissue counts to
suitably diluted aliquots of the injected dose. Different regions of
rat brain corresponding to striatum (ST), hippocampus (HP), cere-
bellum (CB) and cortex (CX) were dissected and counted to obtain
the regional distribution of the tracers. Biodistribution results
showed that all three tested tracers,
[
[ [
18F]6b, 18F]6d and
18F]13d, have high accumulations in lung and kidney at 30 min
after injection (Table 2). [18F]6b and [18F]6d displayed lower up-
take in bone than [18F]13d, suggesting a slower de-fluorination
reaction in vivo. Brain uptakes of these labeled tracers were
0.72 0.04%, 0.52 0.05% and 0.39 0.03% dose per gram, respec-
tively. The results of brain uptake demonstrated that the com-
pounds moderately penetrated the BBB. The lipophilicities of
labeling compounds appear to play an important role in brain up-
take. The logP of [18F]6b, [18F]6d and [18F]13d (1.52, 1.72 and 1.98)
was lower than the optimal logP value (2.0–3.5) required for cross-
ing the BBB36. This may have been the reason that these tracers
only displayed a low brain uptake. It will be necessary to improve
lipophilicities of these 18F labeled tropane derivatives for better
brain penetration. Regional brain distribution of the derivatives
l
mol. It was found that [18F]7b was not produced as expected. This
was mostly likely due to the fact that the precursor 7a was unsta-
Table 2
Organs and regional brain biodistribution of [18F]6b, [18F]6d and [18F]13d in normal
Sprague–Dawley rats (% dose per gram, average of 3 rats S.D.)
ble under the labeling condition as described above.
The lipophilicities of these 18F labeled tropane derivatives were
measured by partition between 1-octanol and 0.1 M NaH2PO4
[
18F]6b
[
18F]6d
[
18F]13d
Organs
Blood
Heart
Muscle
Lung
Kidney
Liver
Bone
0.10 0.01
0.80 0.08
0.27 0.05
5.93 0.30
3.65 0.17
3.01 0.18
0.43 0.06
0.72 0.04
0.10 0.01
1.56 0.24
0.22 0.07
11.5 1.80
4.63 0.19
2.08 0.20
0.50 0.02
0.52 0.05
0.14 0.01
0.57 0.04
0.30 0.04
5.58 0.60
2.08 0.31
0.86 0.12
1.04 0.27
0.39 0.03
18F
N
n
N
Cl
n
N
N
18F-/K222/K2CO3
DMSO, 110 °C, 10 min
Cl
Cl
[
[
18F]6b, n = 2
18F]6d, n = 3
6a, n = 2
6c, n = 3
Brain
Regions
Cerebellum
Striatum
Hippocampus
Cortex
0.65 0.09
1.07 0.12
0.79 0.07
0.91 0.11
0.82 0.10
0.66 0.09
0.63 0.04
0.54 0.04
0.68 0.03
0.63 0.06
0.44 0.03
0.49 0.05
0.44 0.04
0.52 0.04
0.43 0.03
X
X
18F
n
N
Cl
nN
18F-/K222/K2CO3
N
N
DMSO, 110 °C, 10 min
Cl
Cl
Hypothalamus
18F]12b, n = 2, X = O
18F]12d, n = 3, X = O
18F]13b, n = 2, X = H2
18F]13d, n = 3, X = H2
12a, n = 2, X = O
12c, n = 3, X = O
13a, n = 2, X = H2
13c, n = 3, X = H2
[
[
[
[
Ratio (vs CB)
Striatum
Hippocampus
Cortex
1.63
1.21
1.39
1.26
0.94
0.80
1.02
0.94
1.10
0.99
1.17
0.97
Hypothalamus
Scheme 2. Radiosynthesis of the series of novel 18F labeled tropane derivatives.

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H. Qiao et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4303–4306
suggested that [18F]6b exhibited moderate accumulation in the ST
region, the ST/CB ratio showed specific binding of this tracer to the
region where dopamine neurons are highly concentrated. The
brain uptakes of [18F]6d and [18F]13d were too low to warrant
further in vivo studies to measure their regional brain dissection.
In conclusion, a series of novel 18F labeled tropane derivatives
containing specific substitution groups at the 2b-position was syn-
thesized, labeled with the positron-emitter 18F (t1/2 = 109.8 min)
and evaluated as DAT imaging tracers. Compound 6b, 6d and 7b
showed moderately high binding affinities to DAT by in vitro bind-
ing assays. The 18F labeled tropane derivatives were radiolabeled
efficiently via a one-step nucleophilic aliphatic substitution reac-
tion using the corresponding chlorine analogs as precursors. The
biodistribution studies of [18F]6b, [18F]6d and [18F]13d demon-
strated moderate brain penetration in rats, and [18F]6b displayed
specific uptake in the striatum region. However, the brain uptakes
of these derivatives were relatively low, which is likely due to their
low lipophilicities. Further structural modifications of these
tropane derivatives are needed to improve their lipophilicities
and in vivo brain uptake before they can be useful as DAT imaging
agents.
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Acknowledgments
This work was supported by Grants from the National 973 Pro-
gram (2011CB504105) and the National 863 Program (SS2012A
A020831) from Ministry of Science and Technology, China.
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