Synthesis, radiofluorination, and preliminary evaluation of the potential 5-HT2A receptor agonists [18F]Cimbi-92 and [18F]Cimbi-150

Article abstract of DOI:10.1002/jlcr.3557

An agonist PET tracer is of key interest for the imaging of the 5-HT_2A receptor, as exemplified by the previously reported success of [¹¹C]Cimbi-36. Fluorine-18 holds several advantages over carbon-11, making it the radionuclide of choice for clinical purposes. In this respect, an ¹⁸F-labelled agonist 5-HT_2A receptor (5-HT_2AR) tracer is highly sought after. Herein, we report a 2-step, 1-pot labelling methodology of 2 tracer candidates. Both ligands display high in vitro affinities for the 5-HT_2AR. The compounds were synthesised from easily accessible labelling precursors, and radiolabelled in acceptable radiochemical yields, sufficient for in vivo studies in domestic pigs. PET images partially conformed to the expected brain distribution of the 5-HT_2AR; a notable exception however being significant uptake in the striatum and thalamus. Additionally, a within-scan displacement challenge with a 5-HT_2AR antagonist was unsuccessful, indicating that the tracers cannot be considered optimal for neuroimaging of the 5-HT_2AR.

Full text of DOI:10.1002/jlcr.3557

Received: 30 June 2017
DOI: 10.1002/jlcr.3557
Revised: 22 August 2017
Accepted: 23 August 2017
R E S E A R C H A R T I C L E
Synthesis, radiofluorination, and preliminary evaluation of
the potential 5‐HT2A receptor agonists [18F]Cimbi‐92 and
[18F]Cimbi‐150
Fraser Graeme Edgar1 | Hanne D. Hansen2 | Sebastian Leth‐Petersen1 | Anders Ettrup2 |
Jesper L. Kristensen1 | Gitte M. Knudsen2,4 | Matthias M. Herth1,2,3
1 Department of Drug Design and
An agonist PET tracer is of key interest for the imaging of the 5‐HT2A receptor,
Pharmacology, University of Copenhagen,
as exemplified by the previously reported success of [11C]Cimbi‐36. Fluorine‐18
Copenhagen, Denmark
2 Neurobiology Research Unit and Center
holds several advantages over carbon‐11, making it the radionuclide of choice
for clinical purposes. In this respect, an 18F‐labelled agonist 5‐HT2A receptor
for Integrated Molecular Brain Imaging,
Copenhagen, Denmark
3 Department of Clinical Physiology,
Nuclear Medicine and PET, Copenhagen,
Denmark
4 University of Copenhagen, Copenhagen,
Denmark
(5‐HT2AR) tracer is highly sought after. Herein, we report a 2‐step, 1‐pot label-
ling methodology of 2 tracer candidates. Both ligands display high in vitro
affinities for the 5‐HT2AR. The compounds were synthesised from easily acces-
sible labelling precursors, and radiolabelled in acceptable radiochemical yields,
sufficient for in vivo studies in domestic pigs. PET images partially conformed
to the expected brain distribution of the 5‐HT2AR; a notable exception however
being significant uptake in the striatum and thalamus. Additionally, a within‐
scan displacement challenge with a 5‐HT2AR antagonist was unsuccessful, indi-
cating that the tracers cannot be considered optimal for neuroimaging of the 5‐
HT2AR.
Correspondence
Matthias M. Herth, Department of Clinical
Physiology, Nuclear Medicine and PET,
Blegdamsvej 9, 2100 Copenhagen,
Denmark.
Email: matthias.herth@sund.ku.dk
KEYWORDS
[
18F]Cimbi‐150, [18F]Cimbi‐92, 5‐HT2A antagonist, PET, radiofluorination, reductive amination
1 | INTRODUCTION
Among its many applications, it allows for receptor dis-
tribution characterisation, receptor quantification, and
The serotonin‐2A receptor (5‐HT2AR) has been identified
to be involved in the pathophysiology of psychiatric
disorders, including schizophrenia and depression.1,2
Pharmacological intervention with 5‐HT2AR acting com-
pounds suggests that the receptor could be a target for
several different purposes, eg, hypnotics such as trazo-
done requiring 5‐HT2AR antagonism for therapeutic
action.3-7 Additionally, the 5‐HT2AR is a key target
for second‐generation neuroleptics, with drugs (eg
clozapine) again relying on the antagonism of the
receptor.8 Positron emission tomography (PET) is a
powerful tool for molecular imaging allowing in vivo
studies and visualisation of human physiology.9
determination of receptor occupancy of small molecule
ligands.10 Several 5‐HT2AR tracers have been developed,
including (R)‐[18F]MH.MZ, [18F]altanserin, and [11C]
MDL 100907 (Figure 1); however, they are all
antagonists.11,12,19,20
According to the extended ternary complex model
hypothesis, antagonists bind to receptors in both their
inactive and active states, therefore allowing the quanti-
fication of the full receptor population.14,21,22 By con-
trast, agonist tracers should only bind to the active
receptor pool and may thus provide additional informa-
tion regarding neurotransmission.23 In this respect, ago-
nists should be more sensitive to endogenous serotonin,
J Label Compd Radiopharm. 2017;1–6.
wileyonlinelibrary.com/journal/jlcr
Copyright © 2017 John Wiley & Sons, Ltd.
1

2
EDGAR ET AL.
OH
O
OH O
18F
O
O11CH3
N
N
F
F
(R)-[18F]MH.MZ
[
11C]MDL-100907
Ki (5-HT2AR): 0.21 nM
Ki (5-HT2AR): 0.72 nM
18F
O
O
Br
O11CH3
N
H
O
O
N
N
S
N
H
11C]Cimbi-36
[
18F]Altanserin
[
FIGURE 1 Successfully applied 5‐
HT2AR PET ligands11-18
Ki (5-HT2AR): 0.13 nM
Ki (5-HT2AR): 0.21 nM
and as a consequence agonists could serve as a tool to
quantify endogenous serotonin concentrations within
the synaptic cleft.24,25 Furthermore, agonist tracers
should provide a better estimate of receptor occupancy
levels of receptor activating therapeutic drugs.26 Access
to a 5‐HT2AR agonist PET tracer could provide insights
into therapeutic mechanism of action, the effects on neu-
robiology and potentially help determine effective doses
of similar drugs. Currently, [11C]Cimbi‐36 is the only
validated 5‐HT2AR agonist PET tracer in the human
brain (Figure 1).27,28 However, for clinical applications,
the PET radionuclide fluorine‐18 has several advantages
over carbon‐11: (1) its longer half‐life of 109.8 minutes
allows for range of distribution, thus marketability, (2)
the lower β+‐energy of fluorine‐18 allows for higher
resolution, and (3) higher radioactivity amounts can be
produced.11,29 Accordingly, an 18F‐labelled agonist 5‐
HT2AR PET tracer would be beneficial, and there have
been several unsuccessful attempts to develop such a
tracer.13,14,30
The aim of this study is to extend these efforts, and
18F‐label recently developed and promising 5‐HT2A
R
agonist ligands.18 Cimbi‐92 and Cimbi‐150 show a similar
selectivity profile as Cimbi‐36,27 and they can be labelled
using a similar labelling strategy that we have recently
published (Figure 2).9,13,14,20 Despite some affinity for
the 5‐HT2B receptor, Cimbi‐92 and Cimbi‐150 appeared
to be a suitable candidate to develop an 18F‐labelled
Cimbi‐36 derivative for 5‐HT2AR PET imaging. This is
due to the 5‐HT2B receptors only being present in low
O
(A)
OTf
N
[
18F]/FK, K222
,
DMSO
O
O
O
O
X
18F
X
NaBCNH3, AcOH
DMSO
+
N
H
NH2
18F
O
2-[18F]FBA
X = Br
X = C2H5
[
18F]Cimbi-92
[
X = Br
X = C2H5 2C-E
2C-B
18F]Cimbi-150
(B)
Affinity data [nM]
5-HT1A
5-HT6
>10000 n.d.
5-HT2C
5-HT1e
5-HT7
5-HT2A 5-HT2B
FIGURE 2 A, synthesis strategy for 18F‐
label Cimbi‐92 and [18F]Cimbi‐150; B,
selectivity profile of Cimbi‐36, Cimbi‐92,
and Cimbi‐15027
CimbiI-36
Cimbi-92
Cimbi-150
0.8
2.7
2.4
0.5
5.9
20
1.7
1255
826
4720
2088
n.d.
18.6
26.1
1245
n.d.
378
742
n.d.

EDGAR ET AL.
3
abundance in relevant brain regions for the imaging of
Subsequent PET scans of [18F]Cimbi‐92 and [18F]
Cimbi‐150 were performed in Danish Landrace pigs. Both
ligands exhibited good brain uptake and reversible
binding (Figure 3). For both compounds, the highest
uptake was observed in striatum and thalamus, followed
by neocortical, and low cerebellar uptake. High striatal
and thalamic uptake are not in accordance with the
known 5‐HT2AR distribution in the pig brain.27 The
binding pattern could be explained by off‐target binding
not included in our initial selectivity screen. To test
whether this is the case, a displacement study with the
known 5‐HT2AR antagonist ketanserin was conducted.
The experimental setup used within this study has
previously been successfully applied in the same animal
model for [11C]Cimbi‐36 or [18F]MH.MZ.28,34 The dis-
placement study was performed after 90 minutes. No sig-
nificant decrease in binding was seen (Figure 3) showing
that neither [18F]Cimbi‐92 or [18F]Cimbi‐150 shows
displaceable 5‐HT2AR binding, at least not in a within‐
scan displacement study. This observation is incompatible
with the features of suitable 5‐HT2AR PET tracers.
the 5‐HT2AR, for example in cortical structures.31-33
2 | RESULTS AND DISCUSSION
[18F]Cimbi‐92 was successfully radiolabelled in a 2‐step
reaction sequence. First 2‐[18F]fluorobenzaldehyde was
labelled and subsequently reacted with 2C‐B (Figure 2).
A n.d.c. RCY of 1.7% resulting in 311 54 MBq (n = 3)
was isolated in a total synthesis time of 75 minutes.
Radio‐chemical purity was found to be >97% and chemi-
cal purity was determined to be >99%. A molar activity
of 78 23 GBq/μmol (n = 3) was obtained. [18F]Cimbi‐
150 was synthesised using the same labelling strategy.
2C‐E was alkylated using 2‐[18F]fluorobenzaldehyde in a
n.d.c. RCY of 4%. The total synthesis time was 75 minutes
and 456 54 MBq (n = 3) was isolated. Radiochemical
purity was found to be >98%, and chemical purity was
determined to be >99%.
A
molar activity of
358 41 GBq/μmol (n = 3) could be obtained.
[
18F]Cimbi-92
[
18F]Cimbi-150
3
2
1
0
3
2
1
0
Cortex
Cerebellum
Striatum
Thalamus
0
30
60
90
120
150
0
30
60
90
120
150
Time (min)
Time (min)
FIGURE 3 Time‐activity curves (TACs) from PET‐experiments in pigs for [18F]Cimbi‐92 and [18F]Cimbi‐150 in cortex, cerebellum,
striatum, and thalamus (upper line). The arrows represent the time points for the administration of a ketanserin challenge. Representative
summed baseline images for [18F]Cimbi‐92 and [18F]Cimbi‐150 (lower line); images are averaged from 0 to 90 minutes
O
N
O
O
F
MeOTf
DCM
Me2NH, K2CO3,
EtOH:DMF
OTf
SCHEME 1 Synthesis of labelling
precursor14,37
NH2

4
EDGAR ET AL.
water and 0.6‐mL methanol) from the anion exchange
resin. The resulting mixture was then concentrated to
dryness by azeotropic drying at 90°C with
acetonitrile under a helium‐stream for 20 minutes to give
no‐carrier‐added (n.c.a) [18F]KF‐K222 complex as a
yellow residue. A solution of 2‐trimethylammonium‐
benzaldehyde triflate (6 mg, 19 μmol) dissolved in DMSO
(0.5 mL) was added to the dried [18F]KF‐K222 complex,
and subsequently heated to 70°C for 10 minutes to yield
[18F]2‐fluorobenzaldehyde. Thereafter, the respective
phenylethylamine (8 mg, 21.7/25.2 μmol) and NaCNBH3
(10 mg, 15.9 mmol) dissolved together in DMSO (0.5 mL)
and AcOH (4 μL) were added, and subsequently heated
to 130°C for 10 minutes. Afterwards, the reaction mixture
was purified via semi‐preparative HPLC (Luna 5 μm
C18(2) 100 Å, 250 × 10.00 mm; acetonitrile/phosphoric
acid in water (0.1%) 50/50, flow rate: 6 mL/min; RT of
[18F]2‐fluorobenzaldehyde: 5 minutes, RT of [18F]Cimbi‐
92: 13 minutes, RT of [18F]Cimbi‐150: 15 minutes). The
fraction (6 mL) containing the product was collected into
200‐mL water and then passed through a Sep‐Pak C18
column. The column was afterwards washed with an
additional 10‐mL water and eluted with EtOH.
Following elution of the product, it was subsequently
filtered through a sterile filter and collected into a 20‐mL
vial containing sodium phosphate‐buffered saline (9 mL,
100 mM, pH 7), giving a 15‐mL solution of the final
product with a pH of approximately 7. The final solution
was visually inspected for clarity, absences of colour and
particles. Chemical and radiochemical purities were also
assessed by analytical HPLC analysis (Luna 5 μm C18(2)
100 Å, 150 × 4.6 mm; MeCN/citrate buffer (25mM,
pH 4.61) 60/40, flow rate: 1.5 mL/min; RT of [18F]2‐
fluorobenzaldehyde: 3.2 minutes, RT of [18F]Cimbi‐92:
5.5 minutes, RT of [18F]Cimbi‐150: 5.7 minutes, RT of
2C‐B: 1.1 minutes, RT of 2C‐E: 1.3 minutes).
3 | CONCLUSION
[18F]Cimbi‐92 and [18F]Cimbi‐150 could successfully be
labelled using
a
1‐pot, 2‐step labelling strategy.
Subsequent evaluation of both structures revealed brain
penetration, but an unexpected binding profile that is
only partly in line with the known 5‐HT2AR distribution
in the pig brain. A displacement study with a known 5‐
HT2AR antagonist failed for both ligands. Thus, none of
the radioligands can be considered suitable for 5‐HT2A
R
PET neuroimaging. In conclusion, further fluorine‐based
analogues of the lead Cimbi‐36 structure must be devel-
oped in order to identify future promising candidates.
4 | MATERIALS AND METHODS
4.1 | Chemicals and reagents
Standard chemicals were purchased from Sigma‐Aldrich,
and all chemicals were used as received. Ketanserin was
purchased from Tocris Bioscience, and Sep‐Pak C18
columns (Sep‐Pak Light) were purchased from (Waters
AccellPlus). NMR was conducted on a Bucher 400‐MHz
NMR spectrometer. Purity was determined by HPLC
using a ThermoScientific UltiMate 3000.
4.2 | Reference compound synthesis
The Cimbi‐92 and Cimbi‐150 reference compounds and
precursors were synthesised as previously described.18,35,36
4.3 | Precursor synthesis
The labelling precursor was synthesised as previously
described.37 In short, 2‐aminobenzaldhyde was synthe-
sised from 2‐fluorobenzaldehyde and subsequently
reacted with methyl triflate (Scheme 1).14,37
4.5 | Animal procedure
Two female Danish Landrace pigs (weight, 19.4 2 kg;
4.4 | Radiolabelling of [18F]Cimbi‐92 and
[18F]Cimbi‐150
8
weeks) were used for in vivo PET imaging.
Tranquillization, anaesthesia, monitoring, and euthanasia
of animals were performed as previously described.14 All
animal procedures were approved by the Danish Council
for Animal Ethics (journal no. 2012‐15‐2934‐00156).
[18F]Fluoride was produced via the 18O(p, n)18F‐reaction
on a CTI Siemens Eclipse cyclotron (Rigshospitalet,
Denmark), in which 18O‐enriched water was irradiated
with 11‐MeV protons. The aqueous [18F]fluoride solution
was passed through an anion exchange resin (Sep‐Pak
Waters Acell Plus QMA Cartridge), which was washed
with ethanol (10 mL) and water (20 mL) and then dried
with air prior to use. Afterwards, the trapped [18F]fluoride
was eluted with a Kryptofix222/K2CO3 solution (19 mg K222
(4,7,13,16,21,24‐hexaoxa‐1,10‐diazabicyclo[8.8.8] hexa‐
cosane, 6.6‐mg potassium carbonate dissolved in 0.1‐mL
4.6 | PET scanning protocol and
metabolism study
[18F]Cimbi‐92 was given as an intravenous (iv) bolus
injection, with an injected dose of 223 MBq. The pigs were
subsequently scanned for 150 minutes in list‐mode with a
high resolution research tomography (HRRT) scanner

EDGAR ET AL.
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(Siemens AG, Munich, Germany), where scanning started
at the time of injection (0 minutes). Ninety minutes after
the injection of [18F]Cimbi‐92, ketanserin was given iv
as a within‐scan challenge bolus (5.0 mg/kg). Ketanserin
was dissolved in 3‐mL DMSO and subsequently diluted
with saline to a 10% DMSO solution. Radiochemical
purity and specific activity of the injected product were
measured with HPLC.
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4.7 | PET quantification and modelling
List‐mode PET data (150 minutes) were reconstructed into
58 dynamic frames of increasing length (6 × 10, 6 × 20,
6 × 30, 6 × 60, 4 × 120, 14× 300, 8 × 150, and 8 × 300 -
seconds). Images consisted of 207 planes of 256 × 256
voxels of 1.22 × 1.22 × 1.22 mm. A summed picture of all
counts in the 90‐minute scan was reconstructed for each
pig and used for co‐registration to a standardised MRI‐
based atlas of the Danish Landrace pig brain, similar to
that previously published.38,39 The time‐activity curves
(TACs) were calculated for the following volumes of
interest (VOIs): cerebellum, cortex, hippocampus, lateral
and medial thalamus, caudate nucleus, and putamen.
Striatum is defined as the mean radioactivity in caudate
nucleus and putamen. The activity in thalamus is
calculated as the mean radioactivity in the lateral and
medial thalamus. Radioactivity in all VOIs was calculated
as the average of radioactive concentration (Bq/mL) in the
left and right sides. Outcome measure in the time‐activity
curves (TACs) was calculated as radioactive concentration
in VOI (in kBq/mL) normalised to the injected dose
corrected for animal weight (in kBq/kg), yielding
standardised uptake values (g/mL).
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15O, and 13N radiolabels for positron emission tomography.
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ORCID
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How to cite this article: Edgar FG, Hansen HD,
Leth‐Petersen S, et al. Synthesis, radiofluorination,
and preliminary evaluation of the potential 5‐HT2A
receptor agonists [18F]Cimbi‐92 and [18F]Cimbi‐
150. J Label Compd Radiopharm. 2017;1–6. https://
doi.org/10.1002/jlcr.3557
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