Synthesis and C-11 labeling of three potent norepinephrine transporter selective ligands ((R)-nisoxetine, lortalamine, and oxaprotiline) for comparative PET studies in baboons

Article abstract of DOI:10.1016/j.bmc.2005.04.062

Three potent antidepressants, (R)-nisoxetine, lortalamine, and oxaprotiline, with high affinity and high selectivity for the norepinephrine transporter (NET) were synthesized and radiolabeled with C-11 via [ ¹¹C]methylation. The reference compo

Full text of DOI:10.1016/j.bmc.2005.04.062

Bioorganic & Medicinal Chemistry 13 (2005) 4658–4666
Synthesis and C-11 labeling of three potent norepinephrine
transporter selective ligands ((R)-nisoxetine, lortalamine,
and oxaprotiline) for comparative PET studies in baboons
Kuo-Shyan Lin and Yu-Shin Ding*
Chemistry Department, Brookhaven National Laboratory, Bldg 555, Upton, NY 11973, USA
Received 15 March 2005; revised 22 April 2005; accepted 22 April 2005
Available online 23 May 2005
Abstract—Three potent antidepressants, (R)-nisoxetine, lortalamine, and oxaprotiline, with high affinity and high selectivity for the
norepinephrine transporter (NET) were synthesized and radiolabeled with C-11 via [11C]methylation. The reference compounds and
their corresponding normethyl precursors were synthesized via multi-step synthetic approaches. The radiochemical syntheses were
performed by simple alkylation of the corresponding normethyl precursors with no-carrier-added [11C]CH3I in DMF. After HPLC
purification, (R)-[N–11CH3]nisoxetine, [11C]lortalamine, and [11C]oxaprotiline were obtained in 63–97% radiochemical yields,
whereas (R)-[O–11CH3]nisoxetine was obtained in 23–29% radiochemical yields due to substantial formation of the undesired
N-[11C]methylated byproduct (64–70%). These C-11 labeled tracers allowed us to carry out comparative studies of NET in baboons
with positron emission tomography (PET) and evaluate their potential as PET tracers for imaging brain NET.
Published by Elsevier Ltd.
1. Introduction
would facilitate the development of therapeutic agents
for depressive illness, optimize the therapeutic dosage,
and monitor the efficacy of treatment.
The norepinephrine transporter (NET) is a member of a
large family of Na+/ClÀ-dependent transporters, and is
located at the pre-synaptic neurons of nerve endings.1
Its functions include the removal of norepinephrine
(NE) from the synaptic cleft to terminate the action of
NE and avoid overstimulation and the recycling of NE
into the intracellular vesicle for re-release.2 Down regu-
lation of the density of NET in the brain possibly result-
ing from low levels of NE has been associated with
major depression.3,4 Therapeutic agents with high affin-
ity and selectivity toward NET have been developed to
treat depressive illness.5–7 Since other neurotransmitter
transporters, including dopamine and serotonin trans-
porters (DAT and SERT), have also been shown to be
involved in major depression,8,9 suitable radiotracers
capable of mapping specific transporter systems in vivo
would help to tease out the roles of individual transport-
ers (NET, DAT, and SERT) underlying depressive
illness. Furthermore, these target-specific radiotracers
Potent NET-selective antidepressants have been the
molecular models for the development of PET tracers
for imaging the brain NET. Van Dort et al.10 reported
the synthesis of 11C-labeled tricyclic antidepressants,
desipramine and 2-hydroxydesipramine, but the in vivo
evaluation was not included. McConathy et al.11 re-
ported the preparation of [11C]talopram and [11C]talsup-
ram. Although both compounds displayed high affinity
and selectivity for the human NET in vitro, the biodis-
tribution studies in rats showed that the brain uptake
of these two C-11 labeled tracers was low, which dimin-
ished their potential application for imaging brain NET.
Our initial effort was focused on radiolabeled analogs of
reboxetine (Fig. 1), a potent and NET-selective antide-
pressant, since they have high specificity and selectivity
toward NET,12 and reasonable calculated log P values
(Table 1). We have developed synthetic strategies to pre-
pare the precursor, followed by chiral resolution, and
selective C-11 methylation to obtain a C-11 labeled
methyl analog of reboxetine, (S,S)-[11C]MRB (Fig.
1).17 We and other research groups demonstrated its
specific binding to NET in rats,18 monkeys,19 and
baboons.20 Recently (S,S)-[11C]MRB has been used to
Keywords: Norepinephrine transporter; Nisoxetine; Lortalamine;
Oxaprotiline.
*
Corresponding author. Tel.: +1 631 344 4388; fax: +1 631 344
5815; e-mail: ding@bnl.gov
0968-0896/$ - see front matter. Published by Elsevier Ltd.
doi:10.1016/j.bmc.2005.04.062

K.-S. Lin, Y.-S. Ding / Bioorg. Med. Chem. 13 (2005) 4658–4666
4659
OC2H5
OCD2F
OCH3
OCD2CD2F
O
H
O
H
O
H
O
H
NH
NH
NH
NH
O
O
O
O
(S,S)-FRB-D4
(S,S)-FMeNER-D2
(S,S)-MRB
(S,S)-Reboxetine
OCH3
O
O
Cl
N
N
N
H
HN
O
H
OH
Oxaprotiline
(R)-Nisoxetine
Figure 1. Chemical structures of selective NET ligands.
Lortalamine
Table 1. NET inhibitors: lipophilicity and their affinity (nM) and selectivity for DAT, SERT, and NET
NET inhibitors
DAT
SERT
NET
DAT/NET
SERT/NET
CS Log Pf
Reboxetinea
MRBa
>10,000
>10,000
360
1070
310
8.2
2.5
>1000
>4000
360
130
125
1.01
1.13
1.74
2.08
3.50
Nisoxetineb
Lortalaminec
Oxaprotilinee
12
1000
>100,000
3900 100
1
1000
>100,000
800
>10,000
4340 30
<1d
4.9 0.2
>10,000
890
a IC50
b Ki.13
.
14
c IC50
.
d Lortalamine is a potent NET inhibitor with a potency higher than desipramine (fivefold).14,15
e Kd.16
f Lipophilicity was calculated as CS log P using the ChemSilico LLC (Tewksbury, MA) family of property prediction software (CSPredict).
assess the NET occupancy by therapeutic doses of
reboxetine in humans.21 The syntheses of F-18 labeled
reboxetine analogs, including (S,S)-[18F]FMeNER-D2
and (S,S)-[18F]FRB-D4 (Fig. 1), were reported by Schou
et al.22 and our group,23 respectively, and their potential
values as NET radioligands were demonstrated in mon-
keys and baboons.
nisoxetine at different positions may provide useful
information. Two other potent NET-selective antide-
pressants, lortalamine14 and oxaprotiline (Fig. 1),16 with
reasonable calculated log P values (Table 1) and struc-
tures different from those of reboxetine and nisoxetine,
were also selected for comparative PET studies.
In this article, we report the synthesis of precursors ((R)-
N-nornisoxetine, (R)-O-nornisoxetine, norlortalamine,
and noroxaprotiline), and their C-11 methylation.
Results of comparative PET studies of these tracers in
baboon brain will be published separately.
With promising results from radiolabeled reboxetine
analogs in hand, we searched other potential NET-selec-
tive antidepressants for comparative PET studies.
Nisoxetine is a potent and selective NET inhibitor.13
[3H]Nisoxetine has been used as the gold standard for
the in vitro mapping of NET, and it has a structure sim-
ilar to that of reboxetine (Fig. 1). Previously, nisoxetine
has been C-11 labeled at the amino nitrogen as a R/S
racemic mixture, and evaluated for its potential to study
brain NET using a rodent model.24 Although the biodis-
tribution study of (R/S)-[N–11CH3]nisoxetine in mice
showed only modest specific binding, we think C-11
labeled nisoxetine deserves further investigation since
its ultimate value as a PET imaging agent has never been
explored. In our study, we proposed to label the more
potent (R)-enantiomer (IC50 (nM): (R)-nisoxetine, 5.8;
(S)-nisoxetine, 18)25 and label it at two different posi-
tions, namely (R)-[O–11CH3]nisoxetine and (R)-
[N–11CH3]nisoxetine, to further evaluate its potential
as a PET tracer to study NET system using a primate
model. Since the metabolic profile for the labeled N- ver-
sus O-methyl compounds may be different, labeling
2. Results and discussion
2.1. Synthesis of reference compounds and precursors
The syntheses of the reference compound, (R)-nisoxetine
6, as well as two [11C]methylation precursors, (R)-N-
nornisoxetine 5 and (R)-O-nornisoxetine 7, and a po-
tential byproduct during [11C]O-methylation ((R)-N,N-
dimethyl-O-nornisoxetine 8) are depicted in Scheme 1
by starting from the coupling of (S)-3-chloro-1-phenyl-
1-propanol with 2-substituted phenols. The reaction of
(S)-3-chloro-1-phenyl-1-propanol with guaiacol and 2-
mesyloxyphenol under Mitsunobu conditions26 afforded
(R)-1-chloro-3-(2-methoxyphenoxy)-3-phenylpropane 1
and (R)-1-chloro-3-(2-mesyloxyphenoxy)-3-phenylpro-
pane 2 in 90% and 62% yields, respectively. The (S)

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K.-S. Lin, Y.-S. Ding / Bioorg. Med. Chem. 13 (2005) 4658–4666
Scheme 1. Syntheses of (R)-enantiomers of N-nornisoxetine 5, nisoxetine 6, O-nornisoxetine 7, and N,N-dimethyl-O-nornisoxetine 8. Reagents: (a)
diethyl azodicarboxylate, PPh3, guaiacol, Et2O; (b) diethyl azodicarboxylate, PPh3, 2-mesyloxyphenol, Et2O; (c) NaI, acetone; (d) NH4OH, MeOH;
(e) CH3NH2, THF; (f) (1) CH3NH2, THF; (2) NaOH, MeOH; (g) (1) (CH3)2NH, THF; (2) NaOH, MeOH.
configuration of the benzylic carbon in (S)-3-chloro-1-
phenyl-1-propanol was inverted after Mitsunobu cou-
pling reaction to furnish the (R) form of aryl benzyl
ethers, as demonstrated by Srebnik et al.27 and Liu
et al.28 Compounds 1 and 2 were then converted into
their corresponding iodo-counterparts ((R)-1-iodo-3-(2-
methoxyphenoxy)-3-phenylpropane 3 and (R)-1-iodo-3-
(2-mesyloxyphenoxy)-3-phenylpropane 4) in quantitative
yields after overnight refluxing with excess NaI in ace-
tone. The treatment of 3 with methanolic ammonium
hydroxide at room temperature afforded (R)-N-nor-
nisoxetine 5 in 88% yield, whereas (R)-nisoxetine 6 was
obtained in 79% after the treatment of 3 with methyl-
amine at room temperature. (R)-Nisoxetine 6 has been
synthesized previously directly from compound 1 under
reflux at 130 ꢀC in the presence of excess methyl-
amine.27,28 However, the interconversion of chloride to
iodide provided a better leaving group, iodide ion, and
therefore harsh reaction conditions used for the nucleo-
philic substitution reaction could be avoided. O-Nor-
nisoxetine 7 and N,N-dimethyl-O-nornisoxetine 8 were
obtained by the treatment of 4 with excess methylamine
and dimethylamine, respectively, at room temperature
followed by the removal of the mesyl protecting group
with aqueous sodium hydroxide.
Lortalamine 11 and norlortalamine 12 were synthesized
from ethyl 6-chloro-2-oxo-2H-1-benzopyran-3-carbox-
ylate 10 in a one-pot two-step procedure as shown in
Scheme 2. Compound 10 was prepared from 5-chloro-
salicylaldehyde 9 and diethyl malonate via Knoevenagel
condensation and transesterification according to the
published procedure.29 The reaction of 10 with 1-meth-
yl-4-piperidone and ammonium acetate in ethanol
generated an intermediate b-keto ester30 that was subse-
quently decarboxylated to yield lortalamine in 53%
yield. Norlortalamine was synthesized following a simi-
lar procedure using 1-Boc-4-piperidone. Previously, nor-
lortalamine was prepared via a similar procedure using
1-benzyl-4-piperidone, followed by N-debenzylation
Scheme 2. Syntheses of lortalamine 11 and norlortalamine 12. Reagents: (a) diethyl malonate, piperidine, acetic acid, ethanol; (b) (1) 1-methyl-4-
piperidone, ammonium acetate, ethanol, (2) HCl; (c) (1) 1-Boc-4-piperidone, ammonium acetate, ethanol, (2) HCl.

K.-S. Lin, Y.-S. Ding / Bioorg. Med. Chem. 13 (2005) 4658–4666
4661
Scheme 3. Syntheses of oxaprotiline 15 and noroxaprotiline 16. Reagents: (a) HCOH, NaBH3CN, H2O, acetic acid, CH3CN; (b) CH3I, AcOEt;
(c) (1) Ag2O, CH3OH, H2O, (2) 160 ꢀC, reduced pressure; (d) peracetic acid, CH2Cl2, Na2CO3; (e) CH3NH2, THF; (f) NH4OH, MeOH.
with benzyl chloroformate and acid hydrolysis.31 The
use of 1-Boc-4-piperidone for the synthesis of norlortal-
amine provided a much simpler procedure since the Boc
protecting group was simultaneously removed during
acid decarboxylation.
2.2. Radiolabeling
The radiochemical syntheses of (R)-[N-11CH3]nisoxetine,
(R)-[O–11CH3]nisoxetine, [11C]lortalamine, and [11C]oxa-
protiline by simple alkylation of the normethyl precursors
with no-carrier-added [11C]CH3I are shown in Scheme 4,
and the results are listed in Table 2. Simple N-[11C]meth-
ylation of (R)-N-nornisoxetine, norlortalamine, and nor-
oxaprotiline in DMF provided (R)-[N–11CH3]nisoxetine,
[11C]lortalamine, and [11C]oxaprotiline in high yields (63–
97%, EOB). On the contrary, the radiochemical yields of
(R)-[O–11CH3]nisoxetine were relatively lower (23–29%,
EOB) due to substantial formation of the undesired N-
[11C]methylated byproduct, [11C]N,N-dimethyl-O-nor-
nisoxetine, in 64–70% (EOB). The radiochemical purities
of C-11 labeled (R)-nisoxetine, lortalamine, and oxaprot-
iline were >99% and the specific activities ranged from 1.7
to 3.7 Ci/lmol.
The synthesis of oxaprotiline 15 and noroxaprotiline 16
is depicted in Scheme 3. 9-(2,3-Epoxypropyl)-9,10-dihy-
dro-9,10-ethanoanthracene 14 was prepared from
maprotiline 13 via reductive methylation, formation of
alkyl trimethyl quaternary ammonium salt, Hofmann
elimination, and epoxidation according to literature
procedures.32 The treatment of 14 with excess methyl-
amine or ammonium hydroxide yielded oxaprotiline
(83%) and noroxaprotiline (56%), respectively. Racemic
[11C]oxaprotiline was then synthesized and subjected to
initial evaluation in baboons with PET. Our PET studies
in baboon brain showed that the distribution did not
match with the known NET distribution, which is con-
sistent with a bio-distribution study in mice reported
previously as an abstract.33
The structure of (R)-nornisoxetine is very similar to
that of (S,S)-desethylreboxetine. However, when we
OCH3
O
(A)
OCH3
O
[
11C]CH3I, DMF
11CH3
NH2
N
H
O11CH3
O
(B)
OH
O
OH
O
[
11C]CH3I, NaOH, DMF
+
N
N
H
N
H
11CH3
O
O
(C)
(D)
Cl
Cl
11CH3
11CH3I, DMF
NH
N
HN
O
HN
O
11CH3I, DMF
11CH3
H
NH2
N
OH
OH
Scheme 4. Radiochemical syntheses of (A) (R)-[N–11CH3]nisoxetine; (B) [O–11CH3]nisoxetine; (C) [11C]lortalamine; and (D) [11C]oxaprotiline.

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K.-S. Lin, Y.-S. Ding / Bioorg. Med. Chem. 13 (2005) 4658–4666
Table 2. Synthesis times, radiochemical yields, radiochemical purities, and specific activities of C-11 labeled (R)-nisoxetine, lortalamine, and
oxaprotiline
Radiotracers
Synthesis time
(min)
Radiochemical yield
(%) at EOB
Radiochemical purity
(%)
Specific activity
(Ci/lmol) at EOB
(R)-[N–11CH3]Nisoxetine
(R)-[O–11CH3]Nisoxetine
39
42
32
36
63–72
23–29a
85–97
67–78
>99
>99
>99
>99
1.7–3.7
2.1–2.5
2.2–3.1
1.8–3.0
[
[
11C]Lortalamine
11C]Oxaprotiline
a Low radiochemical yields were due to substantial formation (64–70%) of N-[11C]methylated byproduct, (R)-[11C]N,N-dimethyl-O-nisoxetine.
prepared (S,S)-[11C]MRB by [11C]methylation of dese-
thylreboxetine at the phenolic oxygen under the same
condition that we used for the preparation of (R)-
[O–11CH3]nisoxetine, high radiochemical yields (>60%)
of (S,S)-[11C]MRB were obtained without substantial
formation of N-[11C]methylated byproduct (<10%).17
The difference of product yields and the amount of N-
[11C]methylated byproduct between preparation of (R)-
[O–11CH3]nisoxetine and (S,S)-[11C]MRB was probably
due to different characteristics of the secondary amino
nitrogen in each structure. Compared with that of
(R)-nornisoxetine, the secondary amino nitrogen of
(S,S)-desethylreboxetine was possibly less reactive due
to limited flexibility from ring restriction, and therefore,
less N-[11C]methylated byproduct was formed during
the radiosynthesis.
formed at UCR Mass Spectrometry Facility (Riverside,
CA) on a VG 7070 high resolution mass spectrometer.
Radioactivity was measured in a Capintec CRC-
712MV radioisotope calibrator (Capintec Inc., Ramsey,
NJ). [11C]CH3I was prepared from [11C]CO2 in an auto-
mated PETtrace MeI Microlab (GE Medical Systems,
Milwaukee, WI). [11C]CO2 was produced by the BNL
JSW 1710 cyclotron via the 14N(p,a)11C nuclear reaction
using 100 ppm O2 in N2 as the target gas. The [11C]CO2
was first transformed into [11C]CH4 through Ni cata-
lyzed hydrogenation, followed by the reaction with I2
to give the no-carrier-added [11C]CH3I.
4.2. (R)-1-Chloro-3-(2-methoxyphenoxy)-3-phenylpro-
pane (1)
This compound was synthesized via a modified literature
procedure.27,28 To a solution of (S)-3-chloro-1-phenyl-1-
propanol (170 mg, 1 mmol), guaiacol (220 lL, 2 mmol),
and triphenylphosphine (393 mg, 1.5 mmol) in ether
(10 mL) was added diethyl azodicarboxylate (263 lL,
1.5 mmol) dropwise at À10 to À15 ꢀC. After completion
of addition, the mixture was stirred at À10 ꢀC for 5 h.
The mixture was then concentrated and purified by
chromatography on silica gel eluting with 85:15 hex-
ane/ethyl acetate to give the title compound 1 as a color-
3. Conclusion
C-11 labeled NET-selective antidepressants, including
(R)-[O–11CH3]nisoxetine, (R)-[N–11CH3]nisoxetine, [11C]-
lortalamine, and [11C]oxaprotiline, were prepared in
moderate to high radiochemical yields with high radio-
chemical purity and specific activity. These NET-selec-
tive radiotracers allow us to carry out comparative
PET studies, and evaluate their potential as PET radio-
tracers for imaging brain NET using a nonhuman pri-
mate model.
1
less oil (248 mg, 90%). H NMR: d 2.17–2.24 (m, 1H),
2.51–2.58 (m, 1H), 3.61–3.67 (m, 1H), 3.86–3.92 (m,
1H), 3.87 (s, 3H), 5.33 (dd, J = 8.7, 4.3 Hz, 1H), 6.70–
6.74 (m, 2H), 6.80–6.90 (m, 2H), 7.24–7.29 (m, 1H),
7.30–7.36 (m, 2H), 7.37–7.41 (m, 2H); 13C NMR: d
41.3, 41.5, 55.9, 78.5, 112.0, 116.6, 120.6, 121.8, 126.0,
127.8, 128.6, 141.0, 147.4, 150.1. HRMS (DCI/NH3)
m/z calcd for C16H21ClNO2 (MNH4+), 294.1260; found
294.1273.
4. Experimental
4.1. General methods
2-Mesyloxyphenol,17 ethyl 6-chloro-2-oxo-2H-1-benzo-
pyran-3-carboxylate 10,29 and 9-(2,3-epoxypropyl)-
9,10-dihydro-9,10-ethanoanthracene 1432 were prepared
according to the published procedures. All other chem-
icals were purchased from the Aldrich Chemical Com-
pany (Milwaukee, WI) and were used as received
without further purification. Melting points were taken
on a Fisher–Johns melting point apparatus (Fisher
Scientific Co., Pittsburgh, PA) and were uncorrected.
NMR spectra were recorded in CDCl3 solution (unless
specified) using a Bruker Avance 400 MHz NMR spec-
4.3. (R)-1-Chloro-3-(2-mesyloxyphenoxy)-3-phenylpro-
pane (2)
To
a solution of (S)-3-chloro-1-phenyl-1-propanol
(170 mg, 1 mmol), 2-mesyloxyphenol (376 mg, 2 mmol),
and triphenylphosphine (393 mg, 1.5 mmol) in ether
(10 mL) was added diethyl azodicarboxylate (263 lL,
1.5 mmol) dropwise at À10 to À15 ꢀC. After completion
of addition, the mixture was stirred at À10 ꢀC for 5 h.
The mixture was then concentrated and purified by
chromatography on silica gel eluting with 70:30 hex-
ane/ethyl acetate to give the title compound 2 as a color-
1
trometer (400 MHz for H and 100 MHz for 13C) (Bru-
ker Instruments Inc., Billerica, MA), and were reported
in parts per million downfield from internal tetrameth-
ylsilane. The central peak of CDCl3 signal at 77.0 ppm
was used as the 13C NMR reference. High resolution
mass spectrometry (HRMS) experiments were per-
1
less oil (211 mg, 62%). H NMR: d 2.28–2.34 (m, 1H),
2.53–2.59 (m, 1H), 3.25 (s, 3H), 3.57–3.62 (m, 1H),
3.82–3.88 (m, 1H), 5.48 (dd, J = 8.0, 5.0 Hz, 1H), 6.86
(dd, J = 8.3, 1.4 Hz, 1H), 6.93 (td, J = 7.9, 1.5 Hz,

K.-S. Lin, Y.-S. Ding / Bioorg. Med. Chem. 13 (2005) 4658–4666
4663
1H), 7.10 (td, J = 7.7, 1.7 Hz, 1H), 7.27–7.36 (m, 2H),
7.37–7.46 (m, 4H); 13C NMR: d 38.2, 40.9, 41.0, 78.0,
115.9, 121.3, 124.0, 125.9, 128.0, 128.3, 128.9, 138.7,
139.6, 149.8. HRMS (DEI) m/z calcd for C16H17ClO4S
(M+), 340.0536; found 340.0526.
111.9, 116.3, 120.5, 121.4, 125.9, 127.4, 128.4, 141.9,
147.5, 150.0. HRMS (DEI) m/z calcd for C16H20NO2
(MH+), 258.1494; found 258.1488.
4.7. (R)-N-Methyl-3-(2-methoxyphenoxy)-3-phenyl-1-
propylamine ((R)-nisoxetine, 6)
4.4. (R)-1-Iodo-3-(2-methoxyphenoxy)-3-phenylpropane
(3)
A solution of 3 (268 mg, 0.73 mmol) and aqueous methyl-
amine (40 wt. %, 10 mL) in THF (5 mL) was stirred at
room temperature for 3 h. After removing the solvent
under reduced pressure, the residue was worked up by
the same procedure as for compound 5 to give the title
compound 6 as a pale yellow oil (156 mg, 79%). 1H
NMR: d 1.43 (br, 1H), 2.00–2.08 (m, 1H), 2.21–2.29 (m,
1H), 2.43 (s, 3H), 2.73–2.86 (m, 2H), 3.88 (s, 3H), 5.20
(dd, J = 8.4, 4.7 Hz, 1H), 6.64–6.72 (m, 2H), 6.80–6.88
(m, 2H), 7.23–7.40 (m, 5H); 13C NMR: d 36.3, 38.2,
48.6, 55.9, 80.6, 112.0, 116.3, 120.6, 121.4, 125.9, 127.4,
128.4, 141.8, 147.5, 150.0. HRMS (DEI) m/z calcd for
C17H22NO2 (MH+), 272.1650; found 272.1641.
A solution of 1 (237 mg, 0.86 mmol) and sodium iodide
(20 g, 133 mmol) in acetone (50 mL) was refluxed for
16 h. After cooling, the solvent was removed under re-
duced pressure. Water (50 mL) was added to the residue
and the mixture was extracted with ethyl acetate
(2 · 50 mL). The combined ethyl acetate extract was
washed with water (2 · 50 mL), dried over sodium sul-
fate, and concentrated to yield the title compound 3 as a
1
colorless oil (314 mg, 99%). H NMR: d 2.30–2.38 (m,
1H), 2.57–2.66 (m, 1H), 3.31–3.36 (m, 1H), 3.47–3.53
(m, 1H), 3.90 (s, 3H), 5.25 (dd, J = 8.4, 4.3 Hz, 1H),
6.73–6.80 (m, 2H), 6.88–6.97 (m, 2H), 7.29–7.46 (m,
5H); 13C NMR: d 2.6, 42.2, 55.9, 81.4, 112.0, 116.7,
120.6, 121.8, 126.0, 127.8, 128.6, 140.8, 147.4, 150.2.
HRMS (DEI) m/z calcd for C16H17IO2 (M+), 368.0273;
found 368.0260.
4.8. (R)-N-Methyl-3-(2-hydroxyphenoxy)-3-phenyl-1-
propylamine ((R)-O-nornisoxetine, 7)
A solution of 4 (136 mg, 0.32 mmol) and aqueous
methylamine (40 wt. %, 10 mL) in THF (5 mL) was stir-
red at room temperature for 3 h. After removing the sol-
vent under reduced pressure, methanol (10 mL) and
sodium hydroxide (2.5 N, 8 mL) were added to the res-
idue and the mixture was stirred at room temperature
for 24 h. The mixture was neutralized with concentrated
HCl and then concentrated under reduced pressure.
Water (20 mL) was added to the residue and the pH
was adjusted to 2 with concentrated HCl. The mixture
was washed with ether (2 · 20 mL) and the ether frac-
tions discarded. The pH of the aqueous layer was ad-
justed to 8 with saturated aqueous sodium bicarbonate
solution and then extracted with ether (2 · 20 mL).
The combined ethereal fractions were washed with water
(2 · 20 mL), dried over sodium sulfate, and concen-
trated to give the title compound 7 as a pale yellow solid
4.5. (R)-1-Iodo-3-(2-mesyloxyphenoxy)-3-phenylpropane
(4)
A solution of 2 (197 mg, 0.58 mmol) and sodium iodide
(20 g, 133 mmol) in acetone (50 mL) was refluxed for
16 h. After cooling, the mixture was worked up by the
same procedure as for compound 3 to yield the title
1
compound 4 as a pale yellow oil (251 mg, 100%). H
NMR: d 2.35–2.41 (m, 1H), 2.53–2.60 (m, 1H), 3.21–
3.25 (m, 1H), 3.24 (s, 3H), 3.39–3.44 (m, 1H), 5.35
(dd, J = 7.6, 5.0 Hz, 1H), 6.87 (dd, J = 8.3, 1.4 Hz,
1H), 6.93 (td, J = 7.8, 1.5 Hz, 1H), 7.11 (td, J = 7.9,
1.6 Hz, 1H), 7.28–7.47 (m, 6H); 13C NMR: d 1.5, 38.3,
41.7, 80.9, 115.9, 121.3, 124.1, 125.9, 128.0, 128.3,
128.9, 138.7, 139.4, 149.8. HRMS (DCI/NH3) m/z calcd
for C16H21INO4S (MNH4+), 450.0235; found 450.0221.
1
(64 mg, 80%): mp 125–128 ꢀC. H NMR: d 1.85–1.95
(m, 1H), 2.20–2.30 (m, 1H), 2.54 (s, 3H), 2.85–2.95 (m,
1H), 3.00–3.10 (m, 1H), 4.77 (dd, J = 10.4, 1.8 Hz,
1H), 6.38–6.49 (m, 2H), 6.87–6.92 (m, 2H), 7.29–7.42
(m, 5H); 13C NMR: d 35.8, 37.0, 49.9, 85.1, 117.1,
118.2, 122.4, 124.8, 126.6, 127.8, 128.3, 142.4, 146.0,
151.1. HRMS (DEI) m/z calcd for C16H19NO2 (M+),
257.1416; found 257.1412.
4.6. (R)-3-(2-Methoxyphenoxy)-3-phenyl-1-propylamine
((R)-N-nornisoxetine, 5)
A solution of 3 (134 mg, 0.36 mmol) and aqueous
ammonium hydroxide (28 wt. %, 12 mL) in methanol
(18 mL) was stirred at room temperature for 2 days.
After removing the solvent under reduced pressure,
water (20 mL) was added to the residue and the pH
was adjusted to 2 with concentrated HCl. The mixture
was washed with ether (2 · 20 mL) and the ether frac-
tions discarded. The pH of the aqueous layer was
adjusted to 12 with 25% sodium hydroxide and then ex-
tracted with ether (2 · 20 mL). The combined ethereal
fractions were washed with water (2 · 20 mL), dried
over sodium sulfate, and concentrated to give the title
compound 5 as a pale yellow oil (82 mg, 88%). 1H
NMR: d 1.61 (br, 2H), 1.94–2.02 (m, 1H), 2.18–2.25
(m, 1H), 2.94 (m, 2H), 3.87 (s, 3H), 5.22 (dd, J = 8.5,
4.4 Hz, 1H), 6.65–6.73 (m, 2H), 6.80–6.88 (m, 2H),
7.20–7.38 (m, 5H); 13C NMR: d 39.0, 42.2, 55.8, 80.2,
4.9. (R)-N,N-Dimethyl-3-(2-hydroxyphenoxy)-3-phenyl-
1-propylamine ((R)-N,N-dimethyl-O-nornisoxetine, 8)
A solution of 4 (98 mg, 0.23 mmol) and dimethylamine
(2 M in THF, 12 mL) was stirred at room temperature
for 3 h. After removing the solvent under reduced pres-
sure, the residue was worked up by the same procedure
as for compound 7 to give the title compound 8 as a pale
1
yellow solid (60 mg, 97%): mp 78–82 ꢀC. H NMR: d
1.78–1.86 (m, 1H), 2.31–2.38 (m, 1H), 2.42 (s, 6H),
2.64–2.79 (m, 2H), 4.73 (dd, J = 10.7, 2.2 Hz, 1H),
6.35–6.50 (m, 2H), 6.87–6.92 (m, 2H), 7.27–7.37 (m,
5H); 13C NMR: d 34.8, 44.7, 57.0, 84.3, 117.1, 118.2,

4664
K.-S. Lin, Y.-S. Ding / Bioorg. Med. Chem. 13 (2005) 4658–4666
122.7, 124.9, 126.8, 127.9, 128.3, 142.3, 145.7, 151.1.
HRMS (DEI) m/z calcd for C17H21NO2 (M+),
271.1572; found 271.1576.
4.12. 9-(2-Hydroxy-3-methylaminopropyl)-9,10-dihydro-
9,10-ethanoanthracene (oxaprotiline, 15)
A solution of 9-(2,3-epoxypropyl)-9,10-dihydro-9,10-
ethanoanthracene 14 (135 mg, 0.51 mmol) and aqueous
methylamine (40 wt. %, 10 mL) in THF (5 mL) was stir-
red at room temperature for 24 h. After removing the sol-
vent under reduced pressure, HCl (2 N, 30 mL) was added
to the residue. The resulting solution was washed with
ether (2 · 30 mL) and the ether fractions were discarded.
The pH of the aqueous layer was adjusted to 12 with
NaOH (50%) and then extracted with ether (30 mL).
The phases were separated, and the ethereal fraction
was washed with water (2 · 30 mL), dried over magne-
sium sulfate, and concentrated under reduced pressure.
The residue was then transformed into its HCl salt to give
140 mg of white solid (83%); mp 243–244 ꢀC (literature34
237–239 ꢀC). 1H NMR (D2O): d 1.59–1.68 (m, 1H), 1.72–
1.89 (m, 3H), 2.69 (dd, J = 14.4, 6.8 Hz, 1H), 2.78–2.85
(m, 1H), 2.84 (s, 3H), 3.35 (dd, J = 12.5, 10.1 Hz, 1H),
3.49 (dd, J = 12.5, 2.5 Hz, 1H), 4.44 (br, 1H), 4.46–4.54
(m, 1H), 7.14–7.26 (m, 5H), 7.38–7.44 (m, 3H); 13C
NMR (D2O): d 26.9, 29.2, 32.7, 35.7, 43.5, 44.2, 54.9,
64.2, 120.8, 120.9, 123.6, 123.9, 125.6, 125.7, 125.9,
144.6, 144.9, 145.0, 145.2. HRMS (DEI) m/z calcd for
C20H23NO (M+), 293.1780; found 293.1790.
4.10. (+/À)-8-Chloro-1,2,3,4,10,10a-hexahydro-2-methyl-
4a,10-(iminoethano)-4aH-[1]benzopyrano[3,2-c]pyridin-
12-one (lortalamine, 11)
The following procedure was modified from the litera-
ture procedure.31 A solution of ethyl 6-chloro-2-oxo-
2H-1-benzopyran-3-carboxylate 10 (1.26 g, 5 mmol), 1-
methyl-4-piperidone (566 mg, 5 mmol), and ammonium
acetate (771 mg, 10 mmol) in ethanol (12 mL) was re-
fluxed for 8 h. After cooling to ambient temperature,
the volatile solvent was removed under reduced pres-
sure. Concentrated HCl (10 mL) was added to the resi-
due, and the mixture was refluxed for 30 min. The
mixture was then basified to pH 12 with NaOH (25%)
and extracted with chloroform (2 · 70 mL). The com-
bined chloroform fractions were washed with water,
dried over anhydrous magnesium sulfate, and concen-
trated under reduced pressure. The crude product was
purified by recrystallization from ethanol to yield the
title compound 11 as a white crystalline solid (770 mg,
1
53%); mp 248–249 ꢀC (literature31 245 ꢀC). H NMR:
d 1.80 (t, J = 11.5 Hz, 1H), 1.94–2.09 (m, 2H), 2.27 (s,
3H), 2.28–2.37 (m, 2H), 2.58 (dd, J = 17.3, 1.6 Hz,
1H), 2.70 (dd, J = 11.3, 3.9 Hz, 1H), 2.74–2.83 (m,
2H), 2.87–2.90 (m, 1H), 6.75 (d, J = 8.7 Hz, 1H), 6.94
(br, 1H), 7.04 (d, J = 2.5 Hz), 7.12 (dd, J = 8.7, 2.5 Hz,
1H); 13C NMR: d 32.6, 36.1, 37.4, 41.9, 45.6, 50.8,
54.6, 81.1, 118.8, 124.7, 126.4, 128.6, 128.7, 148.4,
170.8. HRMS (DEI) m/z calcd for C15H17ClN2O2
(M+), 292.0979; found 292.0970.
4.13. 9-(2-Hydroxy-3-aminopropyl)-9,10-dihydro-9,10-
ethanoanthracene (noroxaprotiline, 16)
A solution of 9-(2,3-epoxypropyl)-9,10-dihydro-9,10-
ethanoanthracene 14 (450 mg, 1.72 mmol) and aqueous
ammonium hydroxide (28 wt. %, 12 mL) in methanol
(30 mL) was stirred at room temperature for 2 days.
After removing the solvent under reduced pressure, the
residue was recrystallized from ethyl acetate to give
the title compound 14 as a white solid (270 mg, 56%);
4.11. (+/À)-8-Chloro-1,2,3,4,10,10a-hexahydro-4a,10-
(iminoethano)-4aH-[1]benzopyrano[3,2-c]pyridin-12-one
(norlortalamine, 12)
1
mp 183–184 ꢀC (literature34 176–177 ꢀC). H NMR: d
1.61–1.90 (m, 4H), 2.05 (br, 3H), 2.55–2.65 (m, 2H),
2.79 (dd, J = 12.4, 9.3 Hz, 1H), 3.20 (dd, J = 12.4,
3.1 Hz, 1H), 4.05–4.12 (m, 1H), 4.28 (br, 1H), 7.05–
7.15 (m, 5H), 7.23–7.29 (m, 2H), 7.41 (d, J = 7.1 Hz,
1H); 13C NMR: d 27.8, 30.1, 36.5, 44.4, 44.5, 48.9,
68.9, 120.9, 121.3, 123.2, 123.4, 125.1, 125.2, 125.3,
144.7, 145.1, 145.3. HRMS (DEI) m/z calcd for
C19H21NO (M+), 279.1623; found 279.1619.
To a solution of ethyl 6-chloro-2-oxo-2H-1-benzopyran-
3-carboxylate 10 (878 mg, 3 mmol) and 1-Boc-4-piperi-
done (597 mg, 3 mmol) in ethanol (100 mL) was added
ammonium acetate (462 mg, 6 mmol). The mixture was
refluxed for 15 h. After cooling to ambient temperature,
volatile solvent was removed under reduced pressure.
Concentrated HCl (8 mL) was added to the residue
and the mixture was refluxed for 30 min. The mixture
was then basified to pH 12 with NaOH (25%) and ex-
tracted with methylene chloride (2 · 75 mL). The com-
bined methylene chloride fractions were washed with
water, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The crude product
was purified by recrystallization from methanol to yield
the title compound 12 as a white solid (206 mg, 25%);
4.14. Radiosynthesis of (R)-[N–11CH3]nisoxetine
A V-shaped three-necked glass vessel containing 1 mg
(3.9 lmol) of (R)-N-nornisoxetine 5 in DMF (0.25 mL)
was dipped into a dry ice/acetonitrile bath 10 min before
the release of [11C]CH3I from the GE PETtrace MeI
Microlab. [11C]CH3I was transferred into the V-shaped
vessel using Ar as the carrier gas. After the radioactivity
trapped inside the vessel reached its maximum as moni-
tored by an NaI detector, the vessel was sealed and heated
in an oil bath at 100 ꢀC for 7 min. At the end of reaction,
water (1 mL) was added to the reaction mixture, and the
product was separated using a Phenomenex Luna C-18
semipreparative column (250 mm · 10 mm, 5 lm). This
column was connected to a Knauer HPLC system
(Sonntek Inc., Woodcliff Lake, NJ) equipped with a
1
mp 258–260 ꢀC (literature31 252–254 ꢀC). H NMR: d
1.81–1.95 (m, 2H), 2.04–2.09 (m, 1H), 2.17–2.23 (m,
1H), 2.42 (t, J = 12.0 Hz, 1H), 2.59 (dd, J = 17.4,
1.4 Hz, 1H), 2.80 (dd, J = 17.4, 5.1 Hz, 1H), 2.87–3.09
(m, 4H), 6.63 (br, 1H), 6.77 (d, J = 8.7 Hz), 7.05 (d,
J = 2.5 Hz), 7.14 (dd, J = 8.7, 2.5 Hz, 1H); 13C NMR:
d 32.5, 36.9, 38.7, 41.8, 42.0, 45.6, 81.9, 118.8, 124.6,
126.4, 128.7, 128.8, 148.4, 170.5. HRMS (DEI) m/z calcd
for C14H15ClN2O2 (M+), 278.0822; found 278.0818.

K.-S. Lin, Y.-S. Ding / Bioorg. Med. Chem. 13 (2005) 4658–4666
4665
model K-500 pump, a model 87 variable wavelength mon-
itor (set at 254 nm), an NaI radioactivity detector and two
Hewlett–Packard 3390A integrators, and was eluted with
250:250:500:8:3.2 acetonitrile/methanol/water/triethyl-
amine/acetic acid at a flow rate of 6 mL/min. The fraction
containing (R)-[N–11CH3]nisoxetine was collected from
14.5 to 15.9 min after injection. The collected eluate was
rotary evaporated, and then coevaporated with acetoni-
trile. The residue was dissolved in sterile water (4 mL)
and passed through a 0.22 lm Millipore filter into a sterile
vial to make the final injectate for baboon studies with
PET.
column was eluted with 250:250:500:8:3.2 acetonitrile/
methanol/water/triethylamine/acetic acid at 1.5 mL/min
for [11C]nisoxetine, 25:75 acetonitrile/0.2 M ammonium
formate at 1 mL/min for [11C]lortalamine, and 35:65 ace-
tonitrile/0.05 M ammonium formate at 1.4 mL/min
for [11C]oxaprotiline. The retention times of nisoxetine,
lortalamine, and oxaprotiline were 9.21, 8.21, and
6.37 min, respectively. For TLC analysis, Macherey–Na-
gel polygram sil G/UV254 plastic-back TLC plate was
used. The TLC plate was developed with 10:0.3 metha-
nol/ammonium hydroxide for [11C]lortalamine and
10:0.5 methanol/ammonium hydroxide for both [11C]ni-
soxetine and [11C]oxaprotiline. The developed TLC plate
was scanned by using a Bioscan System 200 imaging scan-
ner. The Rfs of nisoxetine, lortalamine, and oxaprotiline
were 0.37, 0.34, and 0.30, respectively.
4.15. Radiosynthesis of (R)-[O–11CH3]nisoxetine
(R)-[O–11CH3]nisoxetine was prepared by using a similar
radiosynthetic procedure as for the preparation of (R)-
[N–11CH3]nisoxetine by starting with 1 mg (3.9 lmol) of
(R)-O-nornisoxetine 7 and NaOH (5 N, 9 lL) in DMF
(0.2 mL). After 10 min incubation at 100 ꢀC, the reaction
mixture was worked up by the same procedure described
above.
Acknowledgments
This research was carried out at Brookhaven National
Laboratory under contract DE-AC02-98CH10886 with
the US Department of Energy and its Office of Biologi-
cal Environmental Research and also supported by the
National Institutes of Health (National Institute for
Biomedical Imaging and Bioengineering EB002630 and
National Institute on Drug Abuse DA-06278) and Office
of National Drug Control Policy. The authors are grate-
ful to D. Szalda, V. Garza, M. J. Schueller, D. J. Schl-
yer, and R. A. Ferrieri for their advice and their
assistance in cyclotron operation and radiosynthesis,
and to J. S. Fowler for reviewing this manuscript.
4.16. Radiosynthesis of [11C]lortalamine
[11C]Lortalamine was prepared by using a similar radio-
synthetic procedure as for the preparation of (R)-
[N–11CH3]nisoxetine by starting with 1 mg (3.6 lmol)
of norlortalamine 12 in DMF (0.25 mL). After 5 min
incubation at 100 ꢀC, the reaction mixture was worked
up by the same procedure described above. HPLC sol-
vent was 30:70 CH3CN/0.2 M HCOONH4 at a flow rate
of 5.0 mL/min. The fraction containing [11C]lortalamine
was collected from 9.4 to 11.9 min after injection.
References and notes
4.17. Radiosynthesis of [11C]oxaprotiline
1. Zahniser, N. R.; Doolen, S. Pharmacol. Ther. 2001, 92, 21.
2. Eisenhofer, G. Pharmacol. Ther. 2001, 91, 35.
3. Klimek, V.; Stockmeier, C.; Overholser, J.; Meltzer, H. Y.;
Kalka, S.; Dilley, G.; Ordway, G. A. J. Neurosci. 1997, 17,
8451.
4. Lambert, G.; Johansson, M.; Agren, H.; Friberg, P. Arch.
Gen. Psychiat. 2000, 57, 787.
5. Hajos, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.;
Brown, M. T.; Wong, E. H. F. CNS Drug Rev. 2004, 10,
23.
[11C]Oxaprotiline was prepared by using a similar radio-
synthetic procedure as for the preparation of (R)-
[N–11CH3]nisoxetine by starting with 0.8 mg (2.9 lmol)
of noroxaprotiline 16 in DMF (0.25 mL). After 5 min
incubation at 100 ꢀC, the reaction mixture was worked
up by the same procedure described above. HPLC sol-
vent was 35:65 CH3CN–0.1 M HCOONH4 at a flow rate
of 5.0 mL/min. The fraction containing [11C]oxaproti-
line was collected from 14.8 to 16.2 min after injection.
6. Lemberger, L.; Terman, S.; Rowe, H.; Billings, R. Br. J.
Clin. Pharmacol. 1976, 3, 215.
7. Charney, D. S.; Heninger, G. R.; Sternberg, D. E.; Roth,
R. H. Psychiat. Res. 1981, 5, 217.
8. Laasonen-Balk, T.; Kuikka, J.; Viinamaki, H.; Husso-
Saastamoinen, M.; Lehtonen, J.; Tiihonen, J. Psychophar-
macology 1999, 144, 282.
9. Malison, R. T.; Price, L. H.; Berman, R.; van Dyck, C. H.;
Pelton, G. H.; Carpenter, L.; Sanacora, G.; Owens, M. J.;
Nemeroff, C. B.; Rajeevan, N.; Baldwin, R. M.; Seibyl, J.
P.; Innis, R. B.; Charney, D. S. Biol. Psychiat. 1998, 44,
1090.
4.18. Quality control of purified C-11 labeled (R)-
nisoxetine, lortalamine, and oxaprotiline
The specific activities of C-11 labeled (R)-nisoxetine, lor-
talamine, and oxaprotiline were determined by the UV
absorbance of the radioactive peaks as compared with
standard curves of unlabeled reference compounds. The
radiochemical purities were determined by an analytical
radio-HPLC system and a TLC system in the presence
of the unlabeled reference compound as a carrier. The
analytical radio-HPLC system consisted of a Phenome-
nex Luna C-18 analytical column (250 mm · 4.6 mm,
5 lm), a Knauer model K-1001 pump, a Knauer model
K-1500 solvent organizer, a Knauer model K2501 UV
detector (254 nm), an NaI radioactivity detector and
two Hewlett–Packard 3390A integrators. The analytical
10. Van Dort, M. E.; Kim, J. H.; Tluczek, L.; Wieland, D. M.
Nucl. Med. Biol. 1997, 24, 707.
11. McConathy, J.; Owens, M. J.; Kilts, C. D.; Malveaux, E.
J.; Camp, V. M.; Votaw, J. R.; Nemeroff, C. B.;
Goodman, M. M. Nucl. Med. Biol. 2004, 31, 705.
12. Melloni, P.; Carniel, G.; Della Torre, A.; Bonsignori, A.;
Buonamici, M.; Pozzi, O.; Ricciardi, S.; Rossi, A. C. Eur.
J. Med. Chem. 1984, 19, 235.

4666
K.-S. Lin, Y.-S. Ding / Bioorg. Med. Chem. 13 (2005) 4658–4666
13. Wong, D. T.; Bymaster, F. P. Biochem. Pharmacol. 1976,
25, 1979.
23. Lin, K. S.; Kim, S. W.; Ding, Y.-S. J. Nucl. Med. 2004,
45(suppl), 106P.
14. Depin, J. C.; Betbeder-Matibet, A.; Bonhomme, Y.;
Muller, A. J.; Berthelon, J. J. Arzneim-Forsch Drug Res.
1985, 35, 1655.
15. Javaid, J. I.; Perel, J. M.; Davis, J. M. Life Sci. 1979, 24, 21.
16. Tatsumi, M.; Groshan, K.; Blakely, R. D.; Richelson, E.
Eur. J. Pharmacol. 1997, 340, 249.
24. Haka, M. S.; Kilbourn, M. R. Nucl. Med. Biol. 1989, 16,
771.
25. Gehlert, D. R.; Hemrick-Lueke, S. K.; Schober, D. A.;
Krushinski, J.; Howbert, J. J.; Robertson, D. W.; Wong,
D. T.; Fuller, R. W. Life Sci. 1995, 56, 1915.
26. Mitsunobu, O. Synthesis 1981, 1.
17. Lin, K. S.; Ding, Y.-S. Chirality 2004, 16, 475.
18. Wilson, A. A.; Johnson, D. P.; Mozley, D.; Hussey, D.;
Ginovart, N.; Nobrega, J.; Garcia, A.; Meyer, J.; Houle,
S. Nucl. Med. Biol. 2003, 30, 85.
27. Srebnik, M.; Ramachandran, P. V.; Brown, H. C. J. Org.
Chem. 1988, 53, 2916.
28. Liu, H.-L.; Hoff, B. H.; Anthonsen, T. J. Chem. Soc.,
Perkin Trans. 1 2000, 11, 1767.
19. Schou, M.; Halldin, C.; Sovago, J.; Pike, V. W.; Gulyas,
B.; Mozley, P. D.; Johnson, D. P.; Hall, H.; Innis, R. B.;
Farde, L. Nucl. Med. Biol. 2003, 30, 707.
20. Ding, Y.-S.; Lin, K. S.; Gaza, V.; Carter, P.; Alexoff, D.;
Logan, J.; Shea, C.; Xu, Y.; King, P. Synapse 2003, 50,
345.
29. Bonsignore, L.; Cottiglia, F.; Maccioni, A. M.; Secci, D.;
Lavagna, S. M. J. Heterocycl. Chem. 1995, 32, 573.
30. Biala, J.; Czarnocki, Z.; Maurin, J. K. Tetrahedron:
Asymmetry 2002, 13, 1021.
31. Briet, P.; Berthelon, J. J.; Depin, J. C. U.S. Patent
4,201,783, 1980.
21. Andree, B.; Seneca, N.; Schou, M.; Mozley, P. D.; Potter,
W. Z.; Farde, L.; Gulyas, B.; Halldin, C. J. Nucl. Med.
2004, 45(suppl), 68P.
22. Schou, M.; Halldin, C.; Sovago, J.; Pike, V. W.; Hall, H.;
Gulyas, B.; Mozley, P. D.; Dobson, D.; Shchukin, E.;
Shchukin, E.; Innis, R. B.; Farde, L. Synapse 2004, 53, 57.
32. Sunagawa, M.; Sato, H.; Katsube, J.; Yamamoto, H. U.S.
Patent 4,045,560, 1977.
33. Raffel, D. M.; Gildersleeve, D. L.; Van Dort, M. E.; Jung,
Y. W. J. Nucl. Med. 2002, 43(suppl), 360P.
34. Wilhelm, M.; Bernasconi, R.; Storni, A.; Beck, D.;
Schenker, K. German Patent 2,207,097, 1972.