Radiosynthesis and in vivo study of [18F]1-(2-fluoroethyl)-4- [(4-cyanophenoxy)methyl]piperidine: A promising new sigma-1 receptor ligand

Article abstract of DOI:10.1002/jlcr.945

The novel sigma-1 receptor PET radiotracer [¹⁸F]1-(2- fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([¹⁸F]WLS1.002, [¹⁸F]-2) was synthesized (n = 6) by heating the corresponding N-ethylmesylate precursor in an anhydrou

Full text of DOI:10.1002/jlcr.945

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 547–555.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.945
Research Article
Radiosynthesis and in vivo study of [18F]1-(2-
fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine:
a promising new sigma-1 receptor ligand
Jun Zhao1, Raymond Chang1, Patty Carambot1 and Rikki N. Waterhouse1,2,
1 Department of Psychiatry, Columbia University, New York, NY 10032, USA
2 Department of Radiology, Columbia University, New York, NY 10032, USA
*
Summary
The novel sigma-1 receptor PET radiotracer [18F]1-(2-fluoroethyl)-4-[(4-cyanophe-
noxy)methyl]piperidine ([18F]WLS1.002, [18F]-2) was synthesized ðn ¼ 6Þ by heating
the corresponding N-ethylmesylate precursor in an anhydrous acetonitrile solution
containing [18F]fluoride, Kryptofix K222 and potassium carbonate for 15 min.
Purification was accomplished by reverse-phase HPLC methods, providing [18F]-2
in 59 ꢀ 8% radiochemical yield (EOB), with specific activity of 2.89 ꢀ 0.80 Ci/mmol
(EOS) and radiochemical purity of 98.3 ꢀ 2.1%. Rat biodistribution studies revealed
relatively high uptake in many organs known to contain sigma-1 receptors, including
the lungs, kidney, heart, spleen, and brain. Good clearance from normal tissues was
observed over time. Blocking studies (60 min) demonstrated high (>80%) specific
binding of [18F]-2 in the brain, with reduction also noted in other organs known to
express these sites. Copyright # 2005 John Wiley & Sons, Ltd.
Key Words: sigma receptor; radiotracer; fluorine-18; PET
Introduction
Over the past 20 years, much research has been carried out with the aim of
determining the biological role and therapeutic value of sigma receptor
ligands.1–9 Sigma receptors are thought to be involved in several diseases of the
central nervous system (CNS), such as schizophrenia, depression, dementia,
ischemia, and even in peripheral nervous system diseases.1 Sigma receptors are
classified into two main subtypes; these are termed sigma-1 and sigma-2.
Sigma-1 receptors are the best characterized of the two subtypes and are
*Correspondence to: Rikki N. Waterhouse, Department of Psychiatry, New York State Psychiatric
Institute, 1051 Riverside Drive, Box #126, New York, NY 10032, USA. E-mail: rnw7@columbia.edu
Contract/grant sponsor: National Institutes of Health; contract/grant number: 1RO1 NS40402-03
Copyright # 2005 John Wiley & Sons, Ltd.
Received 11 January 2005
Revised 31 January 2005
Accepted 23 February 2005

548
J. ZHAO ET AL.
thought to regulate glutamate NMDA receptor function as well as the release
of neurotransmitters, such as dopamine. The sigma-1 receptor is thought to be
involved in certain neuropsychiatric disorders, and in learning and memory
processes.10,11 In addition, sigma-1 receptors are expressed in relatively high
densities in many human cancer cell types, including malignancies of the
breast, lung and prostate.1,12,13 Our laboratory is developing imaging agents
suitable for in vivo tomographic assessment of sigma-1 receptors in animal
models and in humans. Such agents would allow for the determination and
direct comparison of sigma receptor subtype densities in normal humans and
in subjects with various neurological disorders or cancer.14
Several receptor tracers incorporating radioisotopes of carbon, fluorine,
iodine, and hydrogen have been reported. These include [18F]-a-(4-fluorophenyl)-
4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol,15 123I]-iodobenzamides,16 125I]-
[ [
iodobenzovesamical,17
[
125I]-iodophenyl-3-(adamantyl)guanidine,18 [18F]halo-
peridol,19 N-[11C]-benzyl-N-normetazocine,20 [18F]memantine,21 [11C]nemona-
pride,22 [11C]NE100,23 [18F]FE-SA4503,24 and [11C]SA6298.25 In our previous
work, we reported a series of selective sigma-1 receptor compounds that could
be labeled with common PET and SPECT radioisotopes, including the title
compound.26 From this series, [18F]1-(3-fluoropropyl)-4-(4-cyanophenoxy-
methyl)piperidine ([18F]FPS) [KD¼ 0:5 nM, log P ¼ 2:8] has been evaluated in
rodents, baboons and more recently in humans. PET scanning in27,28 health
participants recently revealed that [18F]FPS does not reach transient equilibrium
by 4 h post-administration, supporting the development of a lower affinity tracer
for brain imaging studies (Waterhouse et al., unpublished data). As an extension
of this effort, we report here the synthesis and first in vivo evaluation of [18F]1-(2-
fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([18F]WLS1.002, [18F]-2)
(KD¼ 5 nM, log P ¼ 2:4), a structurally similar but lower affinity tracer in
comparison to [18F]FPS.
Materials and methods
General
Proton NMR spectra were recorded on a Brucker 400 MHz FT-NMR
spectrometer (Department of Chemistry, Columbia University). Chemical
shifts were recorded in ppm (d) from an internal tetramethylsilane standard in
either chloroform-d3, and coupling constants (J) are reported in Hertz (Hz).
Chromatographic purification of unlabeled compounds was performed using
silica gel (Aldrich, 200–400 mesh, ASTM) and solvent systems indicated in the
following text. 4-[4-Cyanophenoxy)methyl]piperidine3 was prepared using a
reported method, and the spectroscopic and melting point data matched that
previously published.26 All other reagents were purchased from commercial
sources and were used without further purification.
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RADIOSYNTHESIS AND IN VIVO STUDY
549
With respect to radiochemistry, high specific activity [18F]fluoride was
provided by Columbia University PET Center. It was produced from enriched
[18O] water by the 18O(p,n)18F nuclear reaction. High-performance liquid
chromatography (HPLC) purification and quality control analyses were
performed via a system comprised of a Waters 515 HPLC pump, a Waters
PDA UV detector, and a Bicron Flow-Scint radiation detector. The HPLC
columns were packed with26,27 reverse-phase base-deactivated stationary
phase (Phenomenex, ODS, analytical: 4.6 ꢁ 250 mm, 5 mm particle size;
semipreparative: 10 ꢁ 250 mm, 10 mm particle size), and the mobile phases
and flow rates used are indicated in the text below.
Synthesis
1-(2-hydroxyethyl)-4-[(4-cyanophenoxy)methyl]piperidine.4 To a solution of
4-[(4-cyanophenoxy)methyl]piperidine3 (300 mg, 1.39 mmol) in dichloro-
methane (20 ml) was added 3-bromoethanol (187 mg, 106 ml, 1.50 mmol) and
potassium carbonate (770 mg, 5.56 mmol). The resulting mixture was stirred at
room temperature for 24 h and deionized (DI) water (15 ml) was added. The
compound was extracted with dichloromethane (3 ꢁ 10 ml), and the organic
layers were combined, dried over sodium sulfate, and evaporated under
reduced pressure. The product was purified by column chromatography
(100% ethanol, Rf ¼ 0:25) to afford a clear, colorless oil product that
1
solidified to a white solid (256 mg, 1.00 mmol, 72%); H-NMR: d (ppm) 7.60
(d, J¼ 8:4 Hz, 2H), 6.96 (d, J¼ 8:4 Hz, 2H), 3.87 (d, J¼ 5:9 Hz, 2H), 3.66 (t,
J¼ 5:3 Hz, 2H), 3.02 (d, J¼ 11:6 Hz, 2H), 2.60 (t, J¼ 5:3 Hz, 2H), 2.17 (d,
J¼ 11:6 Hz, 2H), 1.88 (m, 3H), 1.47 (m, 2H).
1-(2-methylsulfonylethyl)-4-[(4-cyanophenoxy)methyl]piperidine.5 1-(2-Hy-drox-
yethyl)-4-[(4-cyanophenoxy)methyl]piperidine4 (150 mg, 0.59 mmol) was dissolved
in a mixture of triethylamine (2 ml) and dichloromethane (15 ml) and to this was
added methansulfonyl chloride (79 mg, 0.69 mmol). The resulting solution was
stirred for 1 h at room temperature. The volatile components were removed under
reduced pressure, and the product was purified by column chromatography (silica
gel; 100% ethyl acetate, Rf ¼ 0:28) to provide product 5 as a clear, white solid
(126 mg, 64%), m.p.=86–888C; 1H-NMR: 7.60 (dd, J ¼ 2:00, 7.04 Hz, 2H), 6.95
(dd, J ¼ 2:00, 7.04 Hz, 2H), 3.87 (d, J¼ 5:88 Hz, 2H), 3.65 (m, 2H), 3.02 (m, 2H),
2.80 (m, 2H), 2.19 (m, 2H), 1.87 (m, 3H), 1.50 (m, 2H).
1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine.2 To dichloromethane
(6ml) was added 4-[4-cyanophenoxy)methyl]piperidine (280mg, 1.3 mmol),
potassium carbonate (716 mg, 5.18 mmol) and 2-bromo-1-fluoropropane
(104 ml, 1.09 mmol). The resulting solution was stirred at room temperature
for 24h. The reaction mixture was then diluted with DI water (100 ml) and the
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J. ZHAO ET AL.
product extracted into dichloromethane (2ꢁ 20ml). The organic extracts
were combined, dried over magnesium sulfate and the solvent was removed
in vacuo to provide the crude product as a yellow oil. The product was
purified by column chromatography (silica gel, mobile phase:ethyl acetate/
ethanol (9/2 (v/v)) to provide a white solid (311mg, 91%), m.p.=46–478C;
1H-NMR: d (ppm) 7.60 (d, J¼ 8:9 Hz, 2H), 6.95 (d, J¼ 8:9 Hz, 2H), 4.61
(m, 2H), 3.87 (d, J¼ 5:9 Hz, 2H), 3.06 (d, J¼ 9:2 Hz, 2H), 2.76 (m, 2H), 2.16
(t, J¼ 9:2 Hz, 2H), 1.86 (m, 3H), 1.50 (m, 2H). LCMS: (M/Z, %), 263.1
(M+H+, 100%).
Radiolabeling
[18F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine, ([18F]-2). The
[18F]fluoride was trapped on a quaternary ammonium (QMA) cartridge,
and was subsequently eluted into a 5 ml V-vial by passing an aqueous of
5 mg K2CO3 and 2 mg Kryptofix222 (1.1 ml total volume) through the
cartridge. Azeotropic drying in a reaction vial under argon with acetonitrile
(4 ꢁ 1 ml) furnished the dry complex that was used for the fluorination
reaction. The mesylate precursor (1.8–2.1 mg) in anhydrous acetronitrile
(1 ml) was added to the reaction vial. The mixture was heated at 908C
for 15 min, DI water was added and the mixture was heated for another
10 min at this temperature to convert the non-reacted precursor to the
corresponding alcohol for easy purification. Isolation of [18F]-2 was achieved
by diluting the crude reaction mixture with DI water (100 ml) and trapping
the product on a C-18 Sep-Pak. The crude product was eluted into the
vial with acetonitrile (1 ml). The acetonitrile solution containing crude
product was diluted with 2 ml 0.1 M ammonium acetate buffer, and this
solution was directly injected onto the HPLC system (mobile phase: 0.1 M
ammonium acetate solution/acetonitrile 70/30 (v/v); flow rate: 10 ml/min,
Rt=27–29 min) to provide purified [18F]-2. The HPLC product fraction
containing [18F]-2 was mixed with DI water (100 ml) and was passed across the
C-18 Sep-Pak. After washing with 10 ml of DI water, the final product was
recovered into a sample vial by slowly flushing the C-18 Sep-Pak with 1 ml of
absolute ethanol.
Chemical and radiochemical purity, and specific activity was assessed using
analytical HPLC methods (mobile phase: 0.1 M ammonium acetate solution/
acetonitrile 78/22 (v/v), Phenomenex1 ODS column, flow rate: 2 ml/min) to
test a sample (ꢂ1 mCi) of the final product. For the internal standard identity
test, a standard of 2 (10 ml of 10 mg/ml in 10% ethanol/water) was mixed with
an aliquot of product prior to analysis. To prepare solutions suitable for
in vivo administration, the ethanol solution containing [18F]-2 was diluted with
sterile saline and then passed through a 22 mm filter into a 10 ml sterile
evacuated vial.
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RADIOSYNTHESIS AND IN VIVO STUDY
551
Biological
All in vivo experimental procedures were approved by the NYSPI Institutional
Animal Care and Use Committee and were carried out in compliance with
State and Federal laws governing animal experimentation.
Rat distribution and blocking studies. For the biodistribution and blocking
studies, [18F]-2 (15 mCi, 100 ml saline including 55% (v/v) ethanol) was
administered to awake 10–14 week old male Sprague–Dawley rats (225–280 g)
via tail vein injection. At pre-selected times, the rats were killed by
decapitation while anesthetized with CO2 gas. For the blocking study, rats
were administered either saline (100 ml), or the sigma-1 subtype selective
antagonist BD 1008 (1 mg/kg) 5 min prior to radiotracer administration. For
all studies, selected organs and tissues were removed post mortem, weighed,
and assayed for radioactivity. The percent of injected dose (% ID) and the
percent of injected dose of [18F]-2 per gram of tissue (% ID/g) were determined
for each sample by comparison with a 5% aliquot of the injected dose as a
standard. For the blocking study, the significance between groups was
evaluated using a two-tailed t-test. The criterion for significance was p40.05.
In vitro binding assays. [18F]FPS or [18F]2 (1 nM, approximately 1 mCi/tube)
was incubated for 1.5 h in a total volume of 1.0 ml phosphate buffer (pH ¼ 8:0,
228C) in the presence of rat forebrain membranes (3 mg/tube). The effect of
different concentrations of the haloperidol (as a standard), FPS or 2 (10ꢃ12
–
10ꢃ4 M) on tracer binding was examined. All assays were performed in
triplicate. The inhibition constant of haloperidol was calculated to confirm
appropriate assay conditions.
Experiments will be terminated by the addition of 3 ml ice cold buffer, and
unbound tracer removed by washing twice more (approx 4 ml/wash) with cold
buffer using a 48 well cell harvester (Brandel). Membranes were placed into
separate 7 ml tubes and assayed for radioactivity with a gamma counter
(Cobra II, Packard Instruments). Analysis of binding data (Ki for haloperidol,
and KD for SFE and FPS) was performed using non-linear regression (Prism
3.0.cx, Graphpad).
Results and discussion
The title compound was synthesized using straightforward established
methods (Scheme 1). 4-((4-cyanophenoxy)methyl)piperidine, 3, was prepared
in five steps from ethyl isonepecotate as previously described.27,28 Alkylation
of 3 with 2-bromo-1-fluoroethane in the presence of potassium carbonate
provided standard compound 2 in good yield. Likewise, compound 4 was
prepared by alkylating 3 with 2-bromo-1-ethanol. The alkyl mesylate
precursor 5 was synthesized by treating 4 with methanesulfonyl chloride in
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552
J. ZHAO ET AL.
O
OEt
O
a
CN
b
CN
H
N
N
O
H
N
HO
5 Steps
4
3
d
c
O
CN
O
CN
N
MsO
N
5
F
2
Scheme 1. Synthesis of standard 2 and precursor 5. Reagents and conditions: (a)
see References;27,28 (b) 1-Bromo-2-ethanol, K2CO3, CH2Cl2; (c) 1-Bromo-2-
ethane, K2CO3, CH2Cl2; (d) MsCl, Et3N, CH2Cl2
18
-
F
18F
O
O
O
O
Kryptofix/K2CO3
S
N
N
Me
O
Acetonitrile
90þ°C
NC
NC
5
18
F-2
Scheme 2. Radiosynthesis of target compound [18F]-2
%
the presence of triethyl amine. This precursor was purified by normal-phase
flash column chromatography in good yield. The material was stable at room
temperature for at least 1 month; the longest period of examination.
After drying the [18F]-fluoride as described in the experimental section,
[18F]-2 was synthesized by heating 5 at 908C for 15 min in an anhydrous
solution of [18F]fluoride and Kryptofix–potassium carbonate mixture in
acetonitrile (Scheme 2). Purification of [18F]-2 was accomplished using a
semipreparative reverse-phase HPLC. The average isolated product yield after
HPLC purification was 59 ꢀ 8% EOB ðn ¼ 6Þ. The average time for
radioligand synthesis and HPLC purification was about 100 min.
The specific activity of the product was 2.89 ꢀ 0.80 Ci/mmol EOS and the
radiochemical purity was 98.3 ꢀ 2.1%. No significant chemical impurities
were detected by HPLC (UV, 250 nm). The identity of the [18F]-2 was
supported by co-elution of the radiolabeled product and unlabeled standard, 2.
In vitro binding assays provided KD values of 0.5 and 5.0 nM for FPS and 2,
respectively. These values are lower from previously published result inhibition
constant values, and this is likely due to the use of a phosphate buffer instead
of Tris buffer. We found in past studies that Tris buffer (0.1 M) interfered with
the binding of sigma tracers to the sigma-1 receptor, and that IC50s are lower
(representing higher affinities) when a phosphate buffer is used. In any case
these data reveal that 2 exhibits lower affinity compared to FPS in rat
forebrain tissues. As previously published, the sigma-2 receptor affinities for
FPS and SFE are 144 and 361 nM, respectively.26
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RADIOSYNTHESIS AND IN VIVO STUDY
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[18F]-2 was administered via tail vein injection to awake male rats at a
concentration of 15 mCi in 100 ml sterile saline. For blocking studies, either
saline or the sigma-1 subtype selective antagonist BD 1008 was administered.
The results of the biodistribution in selected organs at 5, 15, 30, 60, 150 and
330 min post-injection (PI) are presented in Table 1. In this table the results of
BD 1008 blocking experiment at 60 min post-administration of [18F]-2 are
presented.
From Table 1, high initial uptake of radioactivity was observed in most
organs, peaking by 5 min followed by clearance over time. In the brain,
radioactivity concentrations observed over time included 1.41 ꢀ 0.05% ID/g
at 5 min, 1.08 ꢀ 0.23% ID/g at 60 min and 0.33 ꢀ 0.03% ID/g at 330 min PI.
This is in stark contrast to the higher affinity sigma-1 tracer [18F]FPS
ðKD¼ 0:5 nMÞ, where no significant decrease of the tracer from the brain
occurs over the same time period in adult male rats.25,28 In organs known to
contain sigma-1 receptor, including the lungs, kidneys, heart and spleen,
uptake was between 1.01 and 7.71% ID/g at 5 min, with the radioactivity
quickly clearing thereafter from most organs. The relative amount of
radioactivity in bone was low and did not significantly increase over time,
indicating that this tracer is relatively stable to in vivo defluorination. Relative
uptake in fat was also low. Finally, we note that concentration of radioactivity
in the blood remained low, just 0.14 ꢀ 0.03% ID/g at 5 min and 0.07 ꢀ 0.02%
ID/g at 60 min. Administration of the sigma-1 selective compound BD 1008
via tail vein 5 min before tracer injection reduced brain activity by 80% at
60 min. Likewise, the amount of radioactivity in peripheral organs including
Table 1. Biodistribution of [18F]-2 in awake male rats (n=4–5)
Time
Blood
Kidney
Muscle
Heart
Liver
Spleen
5
15
30
60
150
330
0.14 ꢀ 0.03 2.99 ꢀ 0.10 0.63 ꢀ 0.12 1.75 ꢀ 0.15 0.68 ꢀ 0.17 1.01 ꢀ 0.21
0.11 ꢀ 0.02 2.05 ꢀ 0.50 0.36 ꢀ 0.26 0.85 ꢀ 0.15 0.80 ꢀ 0.28 2.11 ꢀ 0.70
0.07 ꢀ 0.01 1.45 ꢀ 0.19 0.35 ꢀ 0.02 0.66 ꢀ 0.06 1.16 ꢀ 0.13 1.78 ꢀ 0.11
0.07 ꢀ 0.02 1.20 ꢀ 0.29 0.23 ꢀ 0.08 0.45 ꢀ 0.05 1.31 ꢀ 0.22 1.63 ꢀ 0.29
0.06 ꢀ 0.01 0.73 ꢀ 0.25 0.19 ꢀ 0.05 0.26 ꢀ 0.09 1.95 ꢀ 0.73 1.08 ꢀ 0.33
0.04 ꢀ 0.01 0.35 ꢀ 0.02 0.09 ꢀ 0.02 0.11 ꢀ 0.01 1.13 ꢀ 0.37 0.36 ꢀ 0.02
60 (Block) 0.17 ꢀ 0.04 0.60 ꢀ 0.38 0.19 ꢀ 0.03 0.21 ꢀ 0.10 2.68 ꢀ 0.24 0.30 ꢀ 0.06
Time
5
15
30
60
Brain
Lung
Testes
Intestine
Fat
Bone
1.41 ꢀ 0.06 7.71 ꢀ 0.93 0.27 ꢀ 0.06 1.40 ꢀ 0.32 0.30 ꢀ 0.12 0.32 ꢀ 0.12
1.15 ꢀ 0.35 4.63 ꢀ 1.01 0.28 ꢀ 0.09 1.23 ꢀ 0.57 0.29 ꢀ 0.13 0.38 ꢀ 0.17
1.17 ꢀ 0.09 3.21 ꢀ 0.39 0.32 ꢀ 0.06 1.47 ꢀ 0.10 0.30 ꢀ 0.08 0.50 ꢀ 0.09
1.08 ꢀ 0.23 1.78 ꢀ 0.64 0.33 ꢀ 0.11 1.24 ꢀ 0.32 0.23 ꢀ 0.36 0.39 ꢀ 0.16
0.96 ꢀ 0.30 0.84 ꢀ 0.19 0.45 ꢀ 0.07 1.04 ꢀ 0.51 0.31 ꢀ 0.11 0.39 ꢀ 0.09
0.33 ꢀ 0.03 0.31 ꢀ 0.05 0.34 ꢀ 0.03 1.22 ꢀ 0.24 0.18 ꢀ 0.04 0.21 ꢀ 0.07
150
330
60 (Block) 0.21 ꢀ 0.01 0.38 ꢀ 0.09 0.67 ꢀ 0.07 0.35 ꢀ 0.04 0.45 ꢀ 0.06 0.19 ꢀ 0.01
Data are mean of % ID/g ꢀ SD.
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J. ZHAO ET AL.
the heart, lungs, kidney, spleen, intestines was also significantly reduced. These
data support that saturable binding of the tracer occurs in vivo.
Currently one fluorine-18-labeled sigma receptor tracer has been evaluated
in rodents and non-human primates; namely [18F]FE-SA4503 that possesses a
high affinity for both sigma-1 ðKi¼ 6:48 nMÞ and sigma-2 subtypes
ðKi¼ 2:11 nMÞ.24 The regional brain uptake and clearance rates of [18F]FE-
SA4503 in the rat CNS appears similar to that of [18F]SFE. However, the
binding of [18F]FE-SA4503 is likely to both sigma receptor subtypes and, in
addition, the saturable binding of [18F]FE-SA4503 appears is lower than for
SFE (50% compared to 80%).
Conclusion
We have successfully synthesized [18F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)-
methyl]piperidine ([18F]-2) as a potential sigma-1 receptor ligand for in vivo
use. The radiosynthesis of this novel compound proved to be a highly
reproducible and feasible method. The radioligand has been prepared in high
specific activity and good radiochemical purity in sufficient quantities to
permit in vitro and in vivo evaluations. The rat biodistribution study showed
this compound had significant uptake in the lungs, kidney, heart, spleen, and
brain. These data demonstrate that [18F]-2 exhibits promising characteristics
for in vivo use and may provide a superior brain imaging radiotracer due to its
lower affinity ðKi¼ 5 nMÞ and faster clearance rates from the brain compared
to [18F]FPS. The blocking study (60 min) showed a greater than 80%
reduction in [18F]-2 brain uptake by sigma-1 selective ligand BD 1008, and the
activity in other sigma-1 receptor expressing organs was also reduced,
indicating saturable binding in peripheral tissues as well. Further studies of
this new promising sigma-1 tracer are warranted.
Acknowledgements
This work was funded by the National Institutes of Health (1RO1 NS40402-
03; PI: R. Waterhouse).
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