ARTICLE IN PRESS

Applied Radiation and Isotopes 62 (2005) 737–743

www.elsevier.com/locate/apradiso

Synthesis, radiosynthesis and in vivo evaluation in mice of

[123I]-(4-fluorophenyl) {1-[2-(4-iodophenyl)ethyl]piperidin-
4-yl}methanone for visualization of the 5-HT2A receptor
with SPECT
P. Blanckaerta,, I. Burvenicha, L. Staelensa, R.A. Dierckxb, G. Slegersa
a
Laboratory for Radiopharmacy, Ghent University, Harelbekestraat 72, B-9000 Gent, Belgium
b
Division of Nuclear Medicine, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium
Received 2 June 2004; received in revised form 7 October 2004; accepted 29 October 2004

Abstract

This work reports the synthesis, radiolabelling and preliminary in vivo evaluation of [123I]-(4-fluorophenyl){1-[2-(4-
iodophenyl)ethyl]piperidin-4-yl}methanone. The tributylstannylprecursor was synthesized with a yield of 30%.
Radiolabelling was performed using an electrophilic iododestannylation. Tracer yield was 80%, radiochemical purity
was495% and specific activity was at least 55 Ci/mmol. Log P was 1.5. The tracer showed uptake in mice brain
(2.72% ID/g tissue at 5 min p.i.) and therefore will be evaluated further by regional brain biodistribution and
displacement studies in rabbits.
r 2004 Elsevier Ltd. All rights reserved.

Keywords: Serotonin; 5-HT2A receptor; SPECT; Radiotracer

1. Introduction grouped together considering their high degree of

Serotonin (5-hydroxytryptamine, 5-HT) mediates a
number of neuronal processes both in central nervous
system and peripheral tissues. Multiple 5-HT receptor
subtypes have been characterized and grouped in seven
classes (5HT1–5HT7) (Saxena, 1995). Except for the 5-
HT3 receptor, which is a ligand-gated ion channel, 5-HT
receptors belong to the G-protein-coupled receptor
(GPCR) superfamily. The 5-HT2 class includes the
subtypes 5-HT2A, 5-HT2B and 5-HT2C which are
Corresponding author. Tel.: +32 9 2648065; fax:
+32 9 2648071.
E-mail address: peter.blanckaert@ugent.be (P. Blanckaert).
transmembrane sequence homology and second messen-
ger coupling system (Claudi et al., 1999).
The 5-HT2A subtype is present in the brain (cortical
regions) (Pazos et al., 1987b) and periphery (gastro-
intestinal tract, cardiovascular system) (Peroutka and
Snyder, 1979); the 5-HT2B subtype is expressed in rat
stomach fundus and in the human brain and the 5-HT2C
subtype is widely distributed in the brain (Pazos et al.,
1987a).
It has been suggested that the 5-HT2A receptor may
be implicated in the pathology of several mental
illnesses like schizophrenia and depression (Pralong
et al., 2000). Different research groups found a
decreased 5-HT2A receptor density in cortical brain

0969-8043/$ - see front matter r 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.apradiso.2004.10.008
 ARTICLE IN PRESS
738 P. Blanckaert et al. / Applied Radiation and Isotopes 62 (2005) 737–743
regions from schizophrenic patients (Hashimoto et al.,
1993; Laruelle et al., 1993; Dean et al., 1998). The
receptor is also the site of action of different hallucino-
gens (Egan et al., 1998).
To evaluate 5-HT2A receptor malfunctioning, in vivo
quantification by positron emission tomography (PET)
or single photon emission computed tomography
(SPECT) is needed. These techniques provide highly
sensitive methods for measuring in vivo neurochemical
and pharmacological effects at specific target-receptor
proteins.
Several radioligands have been used to assess the 5-
HT2A receptor (Oh et al., 2001) including [11C]-N-
methylspiperone (Okubo et al., 2000), [11C]-
MDL100907 (Ullrich and Rice, 2000), [18F]-setoperone
(Meyer et al., 1999) and [123I]-R91150 (Audenaert et al.,
2001). The PET tracers are expensive and require a
cyclotron on-site. [123I]-R91150 shows high aspecific
binding, thereby limiting its in vitro use. Development of
better SPECT radiotracers with high specific brain
uptake, selectivity for 5-HT2A receptors, and low
aspecific binding would therefore be very useful. This
work reports the synthesis and preliminary in vivo
evaluation in Naval Medical Research Institute
(NMRI) mice of [123I]-(4-fluorophenyl){1-[2-(4-iodophe-
nyl)ethyl]piperidin-4-yl}methanone (7a) (Fig. 1), a
potential SPECT-tracer for in vivo imaging of the
5-HT2A receptor.
The compound is an antagonist, shows nanomolar
affinity for the 5-HT2A receptor (Fu et al., 2002b)
(K i ¼ 3:62 nM) and 40-fold selectivity over the 5-HT2C
receptor.
2. Materials and methods
All reagents were purchased from commercial sources
(Sigma Aldrich Fluka, Acros Organics, Belgium) and
were used without further purification, unless stated
otherwise. 4-(4-Fluorobenzoyl)piperidine was commer-
cially available as the p-toluenesulfonate. It was
extracted as the base and purified by recrystallization
from acetonitrile.
Fig. 1. [123I]-(4-fluorophenyl){1-[2-(4-iodophenyl)ethyl]piperi-
din-4-yl}methanone (7a).
Reactions were monitored by thin layer chromato-
graphy under UV (254 nm) where possible (TLC,
Polygram Sil G/UV254, Machery-Nagel, Germany).
Purification of unlabelled compounds was achieved by
column chromatography with silica gel (Sigma Aldrich,
200–400 mesh), using the solvent systems indicated in
the text. For mixed solvent systems, ratios are given with
respect to volumes.
1
H-NMR spectra were recorded on a Varian 300 MHz
FT-NMR spectrometer (Department of Medicinal
Chemistry, Ghent University). Chemical shifts were
recorded in ppm (d) from an internal tetramethylsilane
standard in either chloroform-d3, acetone-d6 or di-
methylsulfoxide-d6 (DMSO-d6). Mass spectrometry
was performed on a Waters Micromass ZMD mass-
spectrometer with electrospray-ionisation probe. Sam-
ples were dissolved in methanol.
n.c.a. (no carrier added) [123I]NaI (in 0.05 M NaOH)
was purchased from Bristol-Myers-Squibb (Brussels,
Belgium). HPLC purification and analysis of the
radioligand were performed using a Waters 515 HPLC
pump, a Waters 2487 UV detector (254 nm), a Ludlum
2200 scaler ratemeter, and a reversed-phase analytical
HPLC column (Alltech Alltima C18 4.6  250 mm,
5 mm). Mobile phase was 55/45 acetonitrile/phosphate
buffer (0.02 M, pH 9). A flow rate of 2 ml/min was
applied.
For biodistribution studies, male NMRI (Naval
Medical Research Institute) mice were used.
2.1. Synthesis
2.1.1. 2-(4-Bromophenyl)ethanol (2)
4-Bromophenylacetic acid (9.95 g; 46 mmol) (1)
(Fig. 2) was added dropwise to a cooled solution of
borohydride–tetrahydrofurane (BH3.THF) (70 mmol;
70 ml solution in THF) under nitrogen.
The mixture was slowly warmed to room temperature,
and stirred for another 2 h. It was quenched by
slowly adding a 50/50 mixture of water and acetic
acid (50 ml). THF was removed under reduced
pressure. Saturated NaHCO3 solution was added until
the pH reached 11. The mixture was extracted with
dichloromethane (3  100 ml). The organic phases
were combined, dried over anhydrous Na2SO4 and
the solvent was removed under reduced pressure. A
yellow oil was obtained (8.17 g, 88%), which was
used without further purification. ESI-MS: 182 (MH+
minus H2O).
1
H-NMR (d6-DMSO, d): 7.45- 7.15 (m, 4H, Br-ArH),
4.62 (t, 1H, –OH), 3.57 (m, 2H, R–CH2–OH), 2.66 (t,
2H, Ar–CH2–R).
2.1.2. 1-Bromo-4-(2-bromoethyl)benzene (3)
2 (5 g, 25 mmol) was added to a 25 ml vial, and the
vial was cooled to 0 1C under nitrogen. Phosphorus
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P. Blanckaert et al. / Applied Radiation and Isotopes 62 (2005) 737–743
Fig. 2. Synthesis of the tributylstannylprecursor 6.
tribromide (8.12 g, 2.8 ml, 30 mmol) was added drop-
wise. The reaction mixture was stirred at room
temperature for 20 h. The mixture was poured onto
crushed ice (100 g), saturated NaHCO3-solution
(100 ml) was added, and the mixture was stirred for
30 min. The mixture was extracted with chloroform
(3  100 ml) and the combined extracts washed once
with saturated NaHCO3-solution (100 ml) and once
with brine (100 ml). The organic phase was dried
over anhydrous Na2SO4, filtered and evaporated
under reduced pressure. A yellowish oil was obtained
(6 g, 91%).
1
H–NMR (d6–DMSO, d): 7.40–7.15 (q, 4H, Br–ArH),
3.63 ( t, 2H, Br–CH2), 3.01 (t, 2H, Ar–CH2–R).
2.1.3. (4-Fluorophenyl){1-[2-(4-
bromophenyl)ethyl]piperidin-4-yl}methanone (5)
To a solution of 4-(4-fluorobenzoyl)piperidine (4)
(1.9 g, 9.6 mmol) in dry dimethylformamide (DMF)
(50 ml) under a nitrogen atmosphere was added 3
(3.3 g, 12.5 mmol), followed by K2CO3 (5.5 g, 40 mmol).
The mixture was heated at 90 1C for 22 h. After cooling
to room temperature, the mixture was filtered, and the
precipitate was washed with DMF (20 Ml). The solvent
was evaporated under reduced pressure, and the residue
was purified by column chromatography with 20:80:10
739
EtOAc/hexane/Et3N to give 5 as a yellow solid (2.32 g,
60%). ESI-MS: 390/392 (MH+).
1
H–NMR (d6–DMSO, d): 7.43–7.33–7.18 (m, 8H,
2x Ar–H), 3.35 (m, 1H, R–CH–R), 2.93–2.69–2.50
(m, 12H, 6x R–CH2–R), 2.10(m, 2H, Ar–CH2–R),
1.74 (d, 2H, R–CH2–CH–CO–Ar), 1.53 (m, 2H,
R–CH2–CH–CO–Ar).
2.1.4. (4-Fluorophenyl){1-[2-(4-
tributylstannylphenyl)ethyl]piperidin-4-yl}methanone
(6)
To a solution of 5 (146 mg, 0.375 mmol) in anhydrous
toluene (10 ml) under nitrogen was added a catalytic
amount of tetrakistriphenylphosphinepalladium (10 mg)
and hexabutylditin (0.5 ml, 1 mmol). The mixture was
heated at 120 1C for 15 h in the dark. The mixture was
cooled to room temperature, filtered, and the solvent
was removed under reduced pressure. The residue was
purified by preparative thin layer chromatography
(TLC), using methanol:dichloromethane:triethylamine
(9:1:1) as eluent. After extraction of the silica with
methanol and removal of the solvent under reduced
pressure, pure 6 (121 mg, 0.2 mmol, 54% yield) was
obtained. ESI-MS: 602.1 (MH+).
1
H–NMR (d6–DMSO, d): 8.04–7.33–7.17 (m, 8H, 2x
Ar–R), 2.94 (q, 1H, R2–CH–CO), 2.68 (2H, t,
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740 P. Blanckaert et al. / Applied Radiation and Isotopes 62 (2005) 737–743
Ar–CH2–CH2–N–R2), 2.65 (2H, t, Ar–CH2–CH2–R),
2.29–2.19 (m, 4H, R1–N–(CH2–R2)2), 1.80–1.50
(m, 4H, R1–CO–CH–(CH2–R2)2), 0.8–1 (m, 27H,
tributylstannyl).
2.1.5. (4-Fluorophenyl){1-[2-(4-
iodophenyl)ethyl]piperidin-4-yl}methanone (7b)
6 (120 mg, 0.2 mmol) was dissolved in chloroform
(20 ml). At room temperature, iodine in chloroform
(0.53 ml, 1 M solution) was slowly added. The
reaction mixture was stirred at room temperature for
15 min. The reaction was quenched by the addition of
sodiummetabisulphite (3.2 ml; 5% solution in water)
and potassium fluoride (3.2 ml; 1 M solution in metha-
nol). The mixture was stirred for 5 min, and the phases
were separated.
The water phase was extracted with chloroform
(3  100 ml), and the combined organic phases were
dried over sodium sulphate. After filtration, the solvent
was removed under reduced pressure, and the residue
was purified by preparative TLC with methanol:dichlor-
omethane (12:88) as eluent. The silica was extracted with
methanol, the methanol was removed under reduced
pressure, and pure 7b (30 mg, 0.07 mmol, 35% yield) was
obtained.
ESI-MS: 438 (MH+).
1
H–NMR (d6–DMSO, d): 7.90 (q, 2H, F–ArH), 7.65
(m, 2H, I–ArH), 7.03 (m, 2H, F–ArH), 6.93–6.77 (m,
2H, I–ArH), 3.30–3.20 (m, 4H), 3.10 (t, 1H), 2.90
(t, 2H, Ar–CH2–CH2), 2.60 (t, 2H, Ar–CH2 ), 2.10–1.92
(m, 4H).
2.2. Radiosynthesis
The precursor 6 (400 mg, 0.6 mmol) was dissolved in
ethanol (50 mL)). n.c.a. [123I]NaI in sodium hydroxide
solution (15 mL 0.01 M), chloramine T (CT) (282 mg,
1 mmol) and glacial acetic acid (GAA) (5 mL) were
added. The mixture was stirred and left to react for
10 min at room temperature. The reaction mixture was
quenched with sodium metabisulphite (285 mg, 1.5 mmol
in 15 mL water) and injected onto an HPLC column for
purification (Alltech Alltima RPC18, 4.6  250 mm),
with 55/45 acetonitrile/phosphate buffer (0.02 M, pH9)
as eluent at 2 ml/min. The desired radiolabelled product
7a (Rt ¼ 19:6 min) was collected, and diluted with water
to bring the acetonitrile concentration below 10%. The
mixture was passed through a Sep-Pak cartridge (Waters
Sep-Pak Light tC18), and rinsed with 5 ml saline. The
cartridge was previously activated with 1 ml methanol
and rinsed with 1 ml saline. The tracer was eluted with
1 ml ethanol. An aliquot was reinjected onto the same
HPLC system for quality control and stability testing.
For biodistribution studies, the tracer was formulated in
an ethanol/saline solution (containing less then 10%
ethanol), and filtered through a 0.2 mm filter (Schlei-
cher&Schuell, FP 013/AS).
2.3. Determination of specific acitvity
Since no UV-signal was obtained from 1 mCi
of the radiolabelled tracer 7a, specific activity was
calculated by determination of the detection limit
of the UV-detector, using a calibration curve with
cold 7b.
2.4. Calculation of log P
Determination of the partition coefficient was per-
formed according to published literature (Azizian et al.,
1981; Meyer et al., 1999; Wilson et al., 2001). About
10 mL (0.1 mCi) of the radioligand 7a was added to a
separatory funnel containing n-octanol (100 ml) and
phosphate buffer (0.02 M, pH 7.4, 100 ml). The mixture
was shaken manually for 3 min and the layers were
separated. The aqueous layer was discarded, to remove
any hydrophilic impurities present. The n-octanol layer
(100 ml) was transferred to a second separatory funnel
containing phosphate buffer (100 ml). The mixture was
shaken for 3 min, and the layers were separated. A 5 ml
aliquot of both layers was counted for radioactivity. The
aqueous layer was discarded. Once again, the n-octanol
layer (95 ml) was transferred to a new separatory funnel
containing phosphate buffer (95 ml), the funnel shaken
for 3 min, the layers separated, and a 5 ml aliquot of
both layers was taken and counted for radioactivity.
This process was repeated once more. The radioactivity
counts were decay-corrected, and the partition coeffi-
cient was calculated: P ¼ counts in n-octanol/counts in
buffer. Reported log P value represents the mean of 3
determinations.
2.5. Biodistribution study in NMRI mice
A biodistribution study of the radiotracer 7a was
performed in NMRI mice. Adult white male NMRI
mice weighing 20–25 g were each injected with 1–2 mCi
of 7a in the tail vein. The mice were sacrificed at
selected time points after injection (n ¼ 3 per time
point). Blood and organs (brain, heart, lung, liver,
kidney, e.a.) were rapidly removed and weighed. Radio-
activity of the samples was measured in an automated
g-counter (Cobra, Packard Canberra). Tissue radio-
activity concentrations were expressed as percent
of injected dose per gram of tissue (% ID/g tissue).
All experiments were conducted following the
principles of laboratory animal care and the Belgian
Law on the protection of animals. Our research
protocol was approved by the local ethical committee
(ECP 03/22).
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P. Blanckaert et al. / Applied Radiation and Isotopes 62 (2005) 737–743 741

Fig. 3. Radiosynthesis and cold iodination.

Table 1
Tissue concentrations of radioactivity in NMRI mice at various times following intravenous administration of 7a

Time (min)

Tissue 0.3 0.6 1 1.5 2 3

Blood 4.070.7 2.670.8 2.370.3 1.370.3 1.570.1 1.070.1

Brain 2.570.2 2.570.6 2.370.7 1.170.3 1.470.3 2.070.4
Heart 6.770.7 5.370.8 5.370.5 2.770.4 3.270.5 2.370.8
Lungs 25.776.7 21.677.1 16.275.2 9.873.1 15.273.8 12.973.1
Stomach 0.570.1 2.570.1 1.670.1 1.170.3 1.370.3 2.570.5
Spleen 1.270.0 4.170.2 2.770.4 2.370.8 2.570.8 4.171.1
Liver 3.470.2 9.070.3 5.170.7 5.670.5 8.670.8 14.670.6
Kidneys 4.770.5 10.470.3 7.570.7 4.770.8 6.271.0 8.270.9
Sm. Int. 0.770.1 2.170.4 1.370.3 1.170.6 1.470.3 1.570.3
L. Int. 0.570.1 0.470.1 0.570.1 0.370.1 0.670.3 0.870.2
Bladder 0.970.2 1.970.6 0.670.3 0.770.2 0.870.3 1.370.2
Fat 0.670.1 1.670.1 1.170.2 1.370.3 1.970.7 0.870.2
5 10 20 40 60 120

Blood 1.170.2 0.970.1 1.170.1 0.970.1 0.970.0 1.570.1

Brain 2.770.5 2.670.2 2.570.2 2.270.5 2.170.4 1.870.6
Heart 2.171.0 1.170.4 0.970.1 1.270.1 1.170.1 1.070.4
Lungs 8.172.4 7.272.4 4.071.6 3.970.4 3.970.3 3.670.4
Stomach 2.170.8 3.770.7 5.570.1 4.270.2 3.571.1 4.671.6
Spleen 4.970.8 4.370.7 3.370.7 3.671.2 2.970.5 2.370.1
Liver 13.771.1 21.270.1 12.270.6 14.171.8 11.871.5 13.871.7
Kidneys 7.070.4 4.970.3 4.770.5 4.070.9 3.270.2 2.770.6
Sm. Int. 1.970.6 2.170.3 2.570.5 1.970.5 2.170.5 2.770.6
L. Int. 1.170.2 1.170.2 1.170.1 1.070.6 1.470.5 2.470.8
Bladder 1.970.6 1.370.4 2.270.6 2.170.7 3.770.8 3.570.8
Fat 2.370.5 1.170.6 1.970.3 2.670.8 3.070.7 5.970.2

Units are % injected dose/g tissue. Reported are the 95% confidence intervals.

3. Results and discussion
3.1. Synthesis and radiosynthesis
Synthesis of the tributylstannylprecursor 6 is shown in
Fig. 2. 4-Bromophenylacetic acid 1 was reduced to the
alcohol 2 with BH3.THF, after which the hydroxyl
group was replaced by bromine using phosphorous
tribromide, thus creating a much better leaving group.
This ethylbromide 3 was then coupled with 4-(4-
fluorobenzoyl)piperidine 4 by nucleophilic substitution
(Fu et al., 2002a). The bromine-atom of 5 was replaced
by a tributylstannyl-group by reaction with hexabutyl-
ditin. The cold iodinated product 7b was obtained by
reacting the tributylstannylderivative 6 with iodine in
chloroform (Fig. 3). The overall yield was about 30%.
The radiolabelling was conducted by an electrophilic
iododestannylation on the tributylstannylprecursor (Fig.
3). A radiochemical yield of 80%75% was obtained.
The radiochemical purity of the tracer was495%.
Identification of the collected tracer was performed by
comparing retention times on HPLC between the
 ARTICLE IN PRESS
742 P. Blanckaert et al. / Applied Radiation and Isotopes 62 (2005) 737–743
radioactive labelled product 7a and the unlabelled
iodinated molecule 7b.
Tracer stability at room temperature in phosphate
buffer pH 7.4 was tested by reinjecting the tracer into the
HPLC system; the radiochemical purity was 95,3% at
12 h after synthesis.
3.2. Specific activity and log P determination
Specific activity was calculated to be at least 55 Ci/
mmol. This is an excellent value for performing brain
SPECT studies with this tracer, and for in vitro work. A
log P value of 1.4370.02 was obtained; for optimal
brain penetration the log P value should be between 2
and 3. Nevertheless, biodistribution results have shown
adequate brain uptake of the tracer in vivo.
3.3. Biodistribution results
Results of the biodistribution study for different
organs are shown in Table 1.
Uptake of the tracer in mouse brain was demon-
strated. A maximum value of 2.72% ID/g tissue in brain
was obtained 5 min post injection. The compound was
cleared out of the bloodstream quite rapidly (with less
than 1% ID/g in the blood after 3 min), and blood
activity remained lower than brain activity. This
indicates the possible usefulness of the tracer for
visualizing brain structures.
Other organs with high uptake of the tracer were the
liver, which indicates possible metabolism or degrada-
tion, and the lungs and kidneys (data not shown).
4. Conclusion
This work reported the synthesis and radiolabelling of
[123I]-(4-fluorophenyl){1-[2-(4-iodophenyl)ethyl]piperi-
din-4-yl}methanone 7a, a potential radiotracer for in
vivo visualization of the 5-HT2A receptor with SPECT,
and its biodistribution in NMRI mice. The tributyl-
stannylprecursor 6 was synthesized in an overall yield of
30%. The tracer was labelled in good yield (80%). The
specific activity was at least 55 Ci/mmol, an excellent
value for future SPECT and in vitro studies. Log P was
1.5. Although the partition coefficient was not optimal,
the tracer showed good brain uptake in mice (2.72% ID/
g tissue at 5 min p.i.). Regional biodistribution and
displacement studies in rabbit brain are further required
to demonstrate specific binding in brain regions expres-
sing 5-HT2A receptors.
Acknowledgements
We thank the FWO Belgium for financial support.
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