Synthesis and evaluation of [O-methyl-11C]4-[3-[4-(2- methoxyphenyl)- piperazin-1-yl]propoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5- dione as a 5-HT1A receptor agonist PET ligand

Article abstract of DOI:10.1002/jlcr.1475

4-[3-[4-(2-Methoxyphenyl)piperazin-1-yl]propoxy]-4-aza-tricyclo[5.2.1.02,6] dec-8-ene-3,5-dione (4), a potent and selective 5-HT_1A agonist, was labeled by ¹¹C-methylation of the corresponding desmethyl analogue 3 with ¹¹C-methyl triflate. The precursor molecule 3 was synthesized from commercially available endo-N-hydroxy-5-norbornene-2,3-dicarboximide in two steps with an overall yield of 40%. Radiosynthesis of ¹¹C-4 was achieved in 35 min in 20 ± 5% yield (n = 6) at the end of synthesis with a specific activity of 2600 ± 250 Ci/mmol. In vivo positron emission tomography (PET) studies in baboon revealed rapid uptake of the tracer into the brain. However, lack of specific binding indicates that ¹¹C-4 is not useful as a 5-HT_1A agonist PET ligand for clinical studies. Copyright

Full text of DOI:10.1002/jlcr.1475

Research Article
Received 1 June 2007,
Revised 10 October 2007,
Accepted 12 October 2007
Published online 1 February 2008 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1475
Synthesis and evaluation of [O-methyl-11C]4-
[3-[4-(2-methoxyphenyl)- piperazin-1-
yl]propoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-
ene-3,5-dione as a 5-HT1A receptor agonist
PET ligand
Vattoly J. Majo,a Ramin V. Parsey,a,b Jaya Prabhakaran,a J. John Mann,a,b
Ã
and J. S. Dileep Kumara,c
4-[3-[4-(2-Methoxyphenyl)piperazin-1-yl]propoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (4), a potent and selective
5-HT1A agonist, was labeled by 11C-methylation of the corresponding desmethyl analogue 3 with 11C-methyl triflate. The
precursor molecule 3 was synthesized from commercially available endo-N-hydroxy-5-norbornene-2,3-dicarboximide in two
steps with an overall yield of 40%. Radiosynthesis of 11C-4 was achieved in 35 min in 20 5% yield (n = 6) at the end of
synthesis with a specific activity of 2600 250 Ci/mmol. In vivo positron emission tomography (PET) studies in baboon
revealed rapid uptake of the tracer into the brain. However, lack of specific binding indicates that 11C-4 is not useful as a 5-
HT1A agonist PET ligand for clinical studies.
Keywords: radiotracer; carbon-11; positron emission tomography; 5-HT1A; agonist
specific binding in preliminary in vivo studies in baboon.15
However, the lack of favorable kinetics of this ligand prompted
Introduction
The serotonin 1A receptor (5-HT1AR) belongs to the superfamily of
G-protein-coupled receptors and is negatively coupled to adenylyl
cyclase.1 Preclinical and clinical studies suggest that 5-HT1AR is
involved in the pathophysiology and treatment of major
neuropsychiatric disorders, including depression, schizophrenia
and anxiety.2–4 Brain 5-HT1ARs are located as autoreceptors in the
raphe nuclei and postsynaptically in the terminal fields in many
brain regions including limbic regions, prefrontal and entorhinal
cortices.5,6 Positron emission tomography (PET) allows measure-
ment of 5-HT1AR binding in living human brain, and the antagonist
radiotracers such as [11C]WAY-100635 and [18F]MPPF are the most
commonly used 5-HT1A ligands for in vivo studies.7,8 However,
antagonist ligands bind both to the high-affinity (HA) and low-
affinity conformation of 5-HT1AR with equal affinity.9 In contrast, an
agonist ligand would provide a functional measure of the 5-HT1AR
by preferentially binding to the HA state of the receptor which is
coupled to G-protein.10 Moreover, a sensitive agonist radioligand is
expected to provide a better tool for (i) the estimation of
occupancy of agonist drugs at the 5-HT1AR; (ii) the estimation of
the intrasynaptic levels of endogenous serotonin; and (iii) imaging
rapid desensitization (internalization) of 5-HT1A autoreceptors after
the administration of a selective serotonin reuptake inhibitor as a
measure of its treatment efficacy.11–13 In spite of efforts by several
groups, no successful 5-HT1A agonist radioligand is currently
available for in vivo PET imaging in human.14,15 We have recently
shown that 11C-MPT, a 5-HT1A agonist PET ligand, demonstrates
us to evaluate 4-[3-[4-(2-methoxyphenyl)piperazin-1-yl]prop-
oxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (4), a potent and
selective 5-HT1A agonist.
Results and discussion
4-[3-[4-(2-Methoxyphenyl)piperazin-1-yl]propoxy]-4-aza-tricyclo
[5.2.1.02,6]dec-8-ene-3,5-dione (4) is a selective HA 5-HT1AR
ligand (Ki 5 0.021 nM).16 The syntheses of the standard (4) and
precursor (3) for radiolabeling were achieved by the sequence of
reactions demonstrated in Scheme 1.
The commercially available endo-N-hydroxy-5-norbornene-
2,3-dicarboximide (1) was tethered with 3-chloropropyl moiety
by treatment with 1-bromo-3-chloropropane to afford com-
pound 2 in 83% yield. The chloride 2 was then refluxed with
aDepartment of Psychiatry, Columbia University College of Physicians and
Surgeons, New York, NY 10032, USA
bDepartment of Molecular Imaging and Neuropathology, New York State
Psychiatric Institute (NYSPI) , New York, NY 10032, USA
cDepartment of Radiology, Columbia University of Physicians and Surgeons,
New York, NY 10032, USA
*Correspondence to: J. S. Dileep Kumar, Department of Psychiatry, Columbia
University College of Physicians and Surgeons, New York, NY 10032, USA.
E-mail: dk2038@columbia.edu,dkumar@neuron.cpmc.columbia.edu
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V. J. Majo et al.
sodium iodide (NaI) in acetonitrile and coupled with 2- required for the radiosynthesis was 35 min from the end of
(piperazinyl)phenol (2) in the presence of excess K2CO3 to bombardment (EOB). The chemical identity of 11C-4 was
obtain precursor 3 for radiolabeling in 47% yield. In an established by co-injection with an authentic sample of standard
analogous way, the standard 4 was synthesized in 52% yield 4 by analytical RP-HPLC on two different columns using different
by coupling the chloride 2 with 2-(methoxyphenyl)piperazine aqueous buffers. Chemical and radiochemical purities of 11C-4
hydrochloride after preactivation with NaI. To determine were found to be 95 and 98, respectively, with an average
whether 4 is an agonist, we have examined its effect upon specific activity 26007250 Ci/mmol (EOS, n 5 6). The precursor
GTP-g, and found that it is a full agonist at 5-HT1AR meaning its was not observed as an impurity in the isolated product fraction.
maximum response was comparable to serotonin (Emax 5 95%, The determination of 11C-4 partition coefficient (log Po/w) was
EC50 5 1.2 nM) (Figure 1).
performed in 1-octanol and 0.02 M phosphate buffer at a pH of
The synthesis of [O-methyl-11C]4-[3-[4-(2-methoxyphenyl) 7.4 by the modified procedure of Wilson et al.17 and was found
piperazin-1-yl]propoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-
dione (11C-4) was achieved from the corresponding desmethyl
to be 2.8.
Global inspection of the PET imaging studies of 11C-4 in
precursor 3 (Scheme 2). The precursor 3 was dissolved in baboon revealed that the tracer penetrates the blood brain
acetone and subjected to radiomethylation using 11C-MeOTf in barrier (BBB) rapidly, but the distribution of radioactivity is
the presence of aqueous sodium hydroxide to provide 11C-4. homogenous across the brain. The time–activity curves (TACs) of
The radiolabeled product was isolated by reverse phase high- the distribution of radioactivity in 5-HT1AR-rich regions of
performance liquid chromatography (RP-HPLC) with an average interest demonstrated that initial rapid uptake is followed by
yield of 2075% (encl of synthesis, EOS, n 5 6). The average time fast clearance of the radioactivity (Figure 2). The maximum
Scheme 1
Figure 1. Effect of 5-HT1AR concentration on the stimulation of [35S]GTPgS binding in CHO cells. Values are expressed as a percentage above basal which is
the binding of [35S]GTPgS in the absence of agonists. Data points are means of duplicate determinations from representative experiments repeated on at
least three independent occasions with similar results. This figure is available in colour online at www.interscience.wiley.com/journal/jlcr.
J. Label Compd. Radiopharm 2008, 51 132–136
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V. J. Majo et al.
Scheme 2
uptake is 2–3 min after injection across all brain regions of then converted to 11C-methyl triflate at 2001C by passing
interest. Highest cerebellum to target ratios are observed at through a glass column impregnated with silver triflate.18
16 min after the administration of 11C-4 and are 1.6, 1.5, 1.45, Melting points were determined on a Fisher Scientific Melting
1.33 and 1.1 for hippocampus, anterior cingulate, cingulate and point apparatus. High-resolution mass spectra were acquired
prefrontal cortex, respectively. The cerebellum to target ratios under fast atom bombardment (FAB1) mode using a JKS-HX
are ꢀ1 in all regions within 45 min after injection. Metabolite 11UHF/HX110 HF Tandem Mass Spectrometer. The 1H NMR
analysis was performed by RC-HPLC (Phenomenex, Prodigy spectra of all the compounds were recorded on a Bruker PPX
ODS(3) 4.6 Â 250 mm, 10 mm, mobile phase: acetonitrile/25 mM 300 or 400 MHz spectrometers. The spectra were recorded in
disodium hydrogen phosphate solution 50:50, flow rate: 2 mL/ CDCl3 or CD3OD and chemical shift (d) data for the proton
min, retention time: 6–7 min). Metabolite studies in baboon resonances were reported in parts per million (ppm) relative to
show that 11C-4 undergoes rapid metabolism to give polar internal standard TMS. Thin-layer chromatography was per-
metabolites at 2–3 min and the unmetabolized 11C-4 comprised formed using Silica Gel 60 F254 plates from EM Science and
8674% of total plasma radioactivity at 2 min after injection and visualized by UV light. Flash column chromatography was
2871% after 60 min. The amount of 11C-4 unbound to proteins carried out using silica gel 60 (Fisher Scientific, 230–400 mesh).
in plasma (free fraction) is 5074% (n 5 6), and 3173% (n 5 6) Analytical HPLC was performed using a Phenomenex Prodigy
for baboon and human plasma, respectively. Despite the reverse phase column (ODS 4.6 Â 250 mm, 5 mm) eluted with
excellent in vitro profile, the cause of in vivo failure of 11C-4 is acetonitrile:aqueous buffer (25 mM Na2HPO4 solution) and
not clear. Even though compound 4 shows 50% free fraction in Waters mBondapak RP-HPLC column (4.6 Â 300 mm, 10 mm)
baboon plasma, self-blocking by the carrier can be ruled out eluted with acetonitrile:aqueous buffer (0.1 M ammonium
taking into account the low injected mass (0.0470.001 mg/kg formate solution). Semipreparative HPLC was performed using
baboon weight) and high specific activity (26007250 Ci/mmol). a Phenomenex Prodigy ODS (10 Â 250 mm, 10 mm) reverse
The possibility of compound 4 as a p-glycoprotein (p-gp) phase column eluted with an acetonitrile:aqueous buffer
substrate is more likely to contribute to the low retention of (25 mM Na2HPO4 solution) mobile phase mixture. For detection
radiotracer in brain.
of radiolabeled compounds, g-ray detector (Bioscan Flow-Count
fitted with NaI detector) was used in series with
a
the UV detector (Waters Model 996 set at 254 nm). Data
acquisition for both the analytical and preparative systems
was accomplished using a Waters Empower Chromatography
System. Metabolite analyses were performed using Phenomenex
Experimental section
General Methods
All commercial reagents and solvents were used without further Prodigy reverse phase column (ODS 4.6 Â 250 mm, 10 mm)
purification unless otherwise specified. 11C-Methyl iodide was eluted with acetonitrile:aqueous buffer (25 mM Na2HPO4 solu-
synthesized using the reaction of 11C-carbon dioxide with tion). The free fractions and metabolites weremeasured using
lithium aluminum hydride, followed by hydroiodic acid and was Packard Instruments Gamma Counter (Model E5005).
Figure 2. Time–activity curves of the distribution of radioactivity in baboon brain after the injection of 11C-4 (ACN, anterior cingulate; CER, cerebellum;
CIN, cingulate; HIP, hippocampus; PFC, prefrontal cortex).
www.jlcr.org
Copyright r 2008 John Wiley & Sons, Ltd.
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V. J. Majo et al.
piperazine); 3.08 (brs, 4H, 2CH2 piperazine); 3.18 (m, 2H); 3.43 (s,
2H); 3.86 (s, 3H, –OCH3); 4.04 (t, 2H, O–CH2, J 5 6.4 Hz); 6.17 (s,
2H); 6.85 (d, 1H, Ar–H, J 5 7.6 Hz); 6.89–6.94 (m, 2H, ArH);
6.96–7.02 (m, 1H, ArH). HRMS Calculated for C23H30N3O4 (MH1):
412.2236; Found: 412.2252.
4-(3-Chloropropoxy)-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-
dione (2)
Following the procedure of Fiorino et al.,16 commercially
available endo-N-hydroxy-5-norbornene-2,3-dicarboximide (1)
(3.22 g, 18 mmol) was treated with 1-bromo-3-chloropropane
(2.83 g, 18 mmol) in ethanol (50 mL) in the presence of sodium
hydroxide (0.72 g, 18 mmol). The reaction mixture was heated at
701C for 24 h. After the completion of the reaction, the mixture
was processed and the product was purified by column
chromatography (hexane:ethyl acetate 70:30 (v/v) to yield the
product as a colorless solid (3.8 g, 83%).
M.p.: 581C, 1H NMR (400 MHz, CDCl3) d: 1.52 (t, 1H, J 5 9.2),
1.77 (dt, 1H, J 5 8.8, 1.6 Hz), 2.10 (pentet, 2H, J 5 6.0 Hz), 3.19
(dd, 2H, J 5 1.6, 2.8 Hz), 3.44 (s, 2H), 3.74 (t, 2H, J 5 6.4 Hz), 4.11
(t, 2H, J 5 5.8), 6.16 (d, 2H, J 5 1.6 Hz), HRMS calculated for
C12H15ClNO3 (MH1): 256.0740, Found: 256.0751.
Radiosynthesis of [O-Methyl-11C]4-[3-[4-(2-methoxyphenyl)-
piperazin-1-yl]propoxy]-4-aza-tricyclo-[5.2.1.02,6]dec-8-ene-
3,5-dione (11C-4)
Precursor 3 (1.0 mg) was dissolved in 400mL of acetone in a
capped 1 mL reactivial. Aqueous NaOH (10 mL, 5 M) was then
added to the solution and the reaction mixture was vortexed. 11C-
methyl triflate was transported by a stream of argon (20–30mL/
min) into the reactivial over a period of 5min at room
temperature. At the end of the trapping, the reaction mixture
was diluted with the mobile phase and directly injected into a
semipreparative RP-HPLC (Phenomenex C18, 10 Â 250 mm, 10 mm)
and eluted with acetonitrile:25 mM aqueous disodium hydrogen
phosphate solution (35:65) at a flow rate of 10 mL/min. The
precursor appeared at 2–3 min during the semipreparative HPLC
analysis. The product fraction with a retention time of 13–14 min
based on g-detector was collected, diluted with 100 mL of
deionized water, and passed through a classic C-18 Sep-paks
cartridge. Reconstitution of the product in 1 mL of absolute
ethanol afforded 11C-4 in 2075% yield (EOS, n 56). A portion of
the ethanol solution was analyzed by analytical HPLC (Phenom-
enex, Prodigy ODS(3) 4.6 Â 250 mm, 5 mm mobile phase: acetoni-
trile/25 mM disodium hydrogen phosphate solution 40:60, flow
rate: 2mL/min, retention time: 9.1 min) to determine the specific
activity and radiochemical purity. The chemical and radiochemical
purities of 11C-4 were reconfirmed by RP-HPLC (Waters mBondapak
4.6 Â 300 mm, 10 mm, mobile phase, 50:50 acetonitrile/0.1 M
ammonium formate flow rate: 2 mL/min, retention time 5 5.8 -
min). The ethanol solution was then diluted with 9 mL of saline
and passed through a sterile filter.
4-[3-[4-(2-Hydroxyphenyl)piperazin-1-yl]propoxy]-4-aza-tri-
cyclo[5.2.1.02,6]dec-8-ene-3,5-dione (3)
A mixture of 4-(3-chloropropoxy)-4-aza-tricyclo-[5.2.1.02,6]dec-8-
ene-3,5-dione (2) ( 767 mg, 3 mmol) and NaI (749mg, 5mmol) in
acetonitrile (10mL) was stirred under reflux for 30min. Then, 2-
(piperazin-1-yl)phenol (2.7 g, 15 mmol) and anhydrous K2CO3
(830 mg, 6 mmol) were added. The reaction mixture was stirred
under reflux for 48 h. After cooling, the mixture was filtered to
remove unreacted K2CO3 and concentrated to dryness, and the
residue was dissolved in water (50 mL). The solution was extracted
with EtOAc (3 Â 50mL). The combined organic layers were dried
over anhydrous MgSO4 and the solvent was removed under
vacuum. The crude mixtures were purified by silica gel column
chromatography using chloroform/methanol 96:4 (v/v) as the
eluent. The crude products were triturated with chloroform:diethyl
ether to yield the product as a colorless solid (556 mg, 47%).
M.p.: 151–1521C. 1H NMR (400 MHz, CDCl3) d: 1.51 (d, 1H,
J 5 8.8 Hz); 1.77 (m, 1H); 1.88 (pentet, 2H, –CH2–, J 5 7.2 Hz); 2.59
(t, 2H, N1–CH2, J 5 7.4 Hz); 2.63 (brs, 4H, 2CH2 piperazine); 2.89 (t,
4H, 2CH2 piperazine, J 5 4.8 Hz); 3.19 (m, 2H); 3.44 (s, 2H); 4.05 (t,
2H, O–CH2, J 5 6.4 Hz); 6.17 (d, 2H, J 5 1.6 Hz); 6.86 (dt, 1H, Ar–H,
J 5 7.6, 1.6 Hz); 6.94 (dd, 1H, Ar–H, J 5 8.0, 1.6 Hz); 7.06 (dt, 1H,
Ar–H, J 5 7.6, 1.6 Hz); 7.16 (dd, 1H, Ar–H, J 5 7.6, 1.6 Hz). HRMS
Calculated for C22H28N3O4(MH1): 398.2080; Found: 398.2092.
Agonist Stimulated [35S]GTPgS Binding of 4
The experiments were carried out as described previously with
some modification.19 Chinese hamster ovary cell expressing 5-
HT1A receptor (CHO-h5-HT1A) membranes (30 mg) were pre-
incubated with compound 4 for 5 min at room temperature with
indicated concentrations in a buffer containing 20 mM HEPES pH
7.4, 3 mM MgCl2, 100 mM NaCl and 3 mM GDP in a final volume
of 0.5 mL. [35S]GTPgS (0.1 nM; 1250 Ci/mmol Perkin Elmer Life
Science, Boston, MA) was added and the incubation was
continued for 60 min at room temperature. Experiments were
terminated by rapid filtration through Whatman GF/B filters
followed by three washes with ice-cold 20 mM HEPES buffer, pH
7.4, using a cell harvester (Brandel, M-24R, Gaithersburg, MD).
Bound radioactivity was determined by liquid scintillation
spectrometry (Beckman, LS9000).
4-[3-[4-(2-Methoxyphenyl)piperazin-1-yl]propoxy]-4-aza-tri-
cyclo[5.2.1.02,6]dec-8-ene-3,5-dione (4)
The title compound was prepared from 4-(3-chloropropoxy)-4-
aza-tricyclo-[5.2.1.02,6]dec-8-ene-3,5-dione (2) and 2-methoxy-
phenylpiperazine hydrochloride (3.4 g, 15 mmol) by following
the procedure of Fiorino et al.16 The reaction mixture was
stirred under reflux for 24 h. After cooling, the mixture was
filtered to remove excess K2CO3, and concentrated to dryness.
The residue was dissolved in water (50 mL) and the solution was
repeatedly extracted with EtOAc. The combined organic layers
were dried over anhydrous MgSO4 and the solvent was removed
PET Studies in Baboons
under vacuum. The crude mixture was purified by silica gel PET studies were performed in two male baboons with an ECAT
column chromatography using chloroform/methanol 97:3 (v/v) EXACT HR1 scanner (CPS/Knoxville, TN). For each scanning
as the eluent and was recrystallized fromdiethyl ether to yield session, the fasted animal was immobilized with ketamine
the desired product as a colorless solid (640 mg, 52%).
(10 mg/kg, im) and anesthetized with 1.5–2.0% isoflurane via an
M.p.: 1231C. 1H NMR (400 MHz, CDCl3) d: 1.50 (d, 1H, endotracheal tube. Core temperature was kept constant at 371C
J 5 9.2 Hz); 1.76 (d, 1H, J 5 7.2 Hz); 1.88 (pentet, 2H, –CH2–, with a heated water blanket. An intravenous infusion line with
J 5 7.2 Hz); 2.57 (t, 2H, N1–CH2, J 5 7.2 Hz); 2.65 (brs, 4H, 2CH2 0.9% NaCl was maintained during the experiment and used for
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V. J. Majo et al.
hydration and radiotracer injection. An arterial line was placed
for obtaining arterial samples for the input function. The head
was positioned at centre of the field of view, and a 10 min
transmission scan was performed before the tracer injection. For
each scan, 571 mCi (SA 5 26007250 Ci/mmol) of 11C-4 was
injected as an i.v. bolus and emission data were collected for
120 min in 3-D mode. Blood samples were taken every 10 s for
the first 2 min, using an automatic system, and thereafter
manually for a total of 34 samples over 2 h. For metabolites
analyses, the plasma was separated from cellular elements, and
the radiolabeled species in the plasma were analyzed by RP-
HPLC at 2, 6, 12, 30, 60 and 90 min after radioactivity injection as
previously described.15
The PET data were reconstructed with attenuation correction
using the transmission data, and scatter correction was done
using model-based scatter correction.20 The reconstructionfilter
and estimated image filter were Shepp 0.5, the axial (Z) filter was
all pass 0.4, and the zoom factor was 4.0. The final image
resolution at the center of the field of view was5.1 mm FWHM.21
A T1-weighted magnetic resonance image (MRI) of the animal’s
head was acquired on a GE 1.5-T Signa Advantage system.
Regions of interests (ROIs) were drawn on the MRI using the
MEDX software (Sensor Systems, Inc., Sterling, VA). ROIs included
cerebellum, hippocampus, prefrontalcortex, occipital cortex and
cingulate. The PET data were co-registered to the MRI using the
software AIR,22 andTACs were generated for each ROI.
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Conclusion
The radiosynthesis of 11C-4, a 5-HT1AR agonist was achieved in
35 min from EOB using [11C]methyl triflate in 20% yield at EOS,
and with an average specific activity ꢀ26007250 Ci/mmol. PET
study of 11C-4 in baboon showed that the tracer penetrated the
BBB. However, rapid washout of the radioactivity was observed
without any specific uptake in the 5-HT1AR-rich regions. Despite
the HA and selectivity based on in vitro studies, demonstration
that it is a full agonist and rapid BBB permeability, our in vivo
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Acknowledgement
This work was supported by research grant from National
Institutes of Health (R21 MH077161).
www.jlcr.org
Copyright r 2008 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2008, 51 132–136