Convergent18F-labeling and evaluation of N-benzyl-phenethylamines as 5-HT2Areceptor PET ligands

Article abstract of DOI:10.1016/j.bmc.2016.08.056

Positron emission tomography (PET) investigations of the 5-HT_2Areceptor (5-HT_2AR) system can be used as a research tool in diseases such as depression, Alzheimer's disease and schizophrenia. We have previously developed a¹¹C-labeled agonist PET ligand ([¹¹C]Cimbi-36), and the aim of this study was to identify a¹⁸F-labeled analogue of this PET-ligand. Thus, we developed a convergent radiochemical approach giving easy access to 5 different¹⁸F-labeled ligands structurally related to Cimbi-36 from a common¹⁸F-labeled intermediate. After intravenous injection, all ligands entered the pig brain. However, since within-scan intervention with ketanserin, a known orthosteric 5-HT_2Areceptor antagonist, did not result in significant blocking, the radioligands seem unsuitable for neuroimaging of the 5-HT_2AR in vivo.

Full text of DOI:10.1016/j.bmc.2016.08.056

Bioorganic & Medicinal Chemistry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Convergent 18F-labeling and evaluation of N-benzyl-
phenethylamines as 5-HT2A receptor PET ligands
Ida Nymann Petersen a, Jonas Villadsen b, Hanne Demant Hansen b, Anders A. Jensen a, Szabolcs Lehel c,
Nic Gillings c, Matthias M. Herth a,c, Gitte M. Knudsen b, Jesper L. Kristensen a,
⇑
a Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 København Ø, Denmark
b Center for Integrated Molecular Brain Imaging (CIMBI), Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark
c Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
Positron emission tomography (PET) investigations of the 5-HT2A receptor (5-HT2AR) system can be used
as a research tool in diseases such as depression, Alzheimer’s disease and schizophrenia. We have previ-
ously developed a 11C-labeled agonist PET ligand ([11C]Cimbi-36), and the aim of this study was to iden-
tify a 18F-labeled analogue of this PET-ligand. Thus, we developed a convergent radiochemical approach
giving easy access to 5 different 18F-labeled ligands structurally related to Cimbi-36 from a common 18F-
labeled intermediate. After intravenous injection, all ligands entered the pig brain. However, since
within-scan intervention with ketanserin, a known orthosteric 5-HT2A receptor antagonist, did not result
in significant blocking, the radioligands seem unsuitable for neuroimaging of the 5-HT2AR in vivo.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 30 June 2016
Revised 22 August 2016
Accepted 27 August 2016
Available online xxxx
Keywords:
18F-labeling
PET
Serotonin
5-HT2A receptor agonist
1. Introduction
Cimbi-36. 18F has several advantages compared to 11C for PET
studies: the isotope has a longer physical half-life, it can produce
The serotonin 2A receptor (5-HT2AR) is involved in the regula-
tion of several brain functions, such as appetite, emotion, body
temperature and the sleep/wake cycle, and important for numer-
ous diseases, for example depression, Alzheimer’s and schizophre-
nia.1,2 Positron Emission Tomography (PET) imaging is a sensitive
and non-invasive in vivo imaging tool. PET imaging can be used
images with higher resolution, and it is possible to transport 18F-
labeled radioligands to other facilities. Towards that goal, we
recently reported an attempt to develop a 18F-labeled version of
[
11C]Cimbi-36 via substitution of all three possible methoxy groups
with a [18F]FCH2CH2O-group.12 Unfortunately, these ligands were
unable to penetrate the blood brain barrier to any major extent.
In the present study, we introduced a 18F at another position in
the Cimbi-36 molecule hoping that this structural modification
neither would be detrimental to the compounds ability to enter
the brain nor to its binding affinity to the 5-HT2AR. The position
of the fluorine was also selected to allow us to introduce 18F in a
convergent manner from a common 18F-labeled intermediate. In
the development of [11C]Cimbi-36 we observed that subtle modifi-
cations to the 4-positon in the molecule had dramatic effects on
brain uptake and PET-ligand kinetics10 as well as their pharmaco-
logical profile.13 Therefore we wanted to be able to screen ligands
with various 4-substituents and targeted the ligands shown in
Figure 1. Halogenated analogues 2–4 were selected as direct ana-
logues of previously screened 11C-labeled analogues of Cimbi-36
possessing the best overall profiles with respect to affinity for 5-
HT2AR and ability to cross the blood–brain-barrier, whereas 5
and 6 were included as the introduction of the NO2 and CN groups
with their different physiochemical characteristics was expected to
for diagnosis, therapy planning and monitoring,3 and 5-HT2A
R
antagonist PET-ligands such as [18F]Altanserin and [11C]MDL-
10097 are routinely used in a clinical setting.4–7 Recently, an effort
has been made to expand the toolbox of PET ligands applicable for
quantification of 5-HT2AR levels in the human brain. Antagonist
radioligands bind to the global population of receptors, whereas
an agonist radioligand should be able to image only the population
of functional receptors, i.e., those mediating neurotransmitter
signaling.8,9
To address this shortcoming of the available PET-ligands in the
5-HT2AR field, we have previously developed an agonist PET-ligand,
[
11C]Cimbi-36, for this receptor.10,11 Herein, we detail some of our
efforts towards the development of a 18F-labeled version of
⇑
Corresponding author. Tel.: +45 35336487.
E-mail address: jesper.kristensen@sund.ku.dk (J.L. Kristensen).
http://dx.doi.org/10.1016/j.bmc.2016.08.056
0968-0896/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Petersen, I. N.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.08.056

2
I. N. Petersen et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
F
and 5-HT2C compared with a range of different CNS targets—as is
the case for 1, see Supporting information for details.
O
O
O
O
2:
X = Br
3: X = I
4:
H
N
H
N
X = Cl
The functional properties of 2 at the h5-HT2A and the h5-HT2C
receptors were determined at HEK293 cell lines stably expressing
the two receptors in a fluorescence-based Ca2+ imaging assay using
O
O
5: X = NO2
6: X = CN
Br
X
1
Cimbi-36 (
)
Fluo-4 as dye (Table 2).15 In good agreement with their 5-HT2A
R
Figure 1. Structure of Cimbi-36 (1) and targeted derivatives amenable for
18F-labeling (2–6).
binding affinities, 2 exhibited 7-fold lower agonist potency at the
receptor than 1, and its potency at 5-HT2CR was even lower (100-
fold) compared to that of 1, and thus 2 exhibited 15-fold functional
selectivity between the receptors in this assay. Interestingly, the
introduction of the fluorine into 1 converted it from a full agonist
into a partial agonist at 5-HT2CR, whereas the intrinsic activities
of 1 and 2 as 5-HT2AR agonists were comparable.
exert more pronounced effects on the behavior of the prospective
PET ligands.
2. Results and discussion
All in all, these data suggested that the introduction of a fluorine
into this position of Cimbi-36 is tolerated, and based on their
respective in vitro binding properties we proceeded to develop a
radiochemical route to 18F-labeled versions of analogs 2–6.
Compounds 2–6 were synthesized via reductive amination with
4-fluoro-2-methoxybenzaldehyde and the appropriately substi-
tuted phenethylamines, see Supporting information for details.
The binding affinities of the six ligands at the human 5-HT2A
(h5-HT2A) and 5-HT2C (h5-HT2C) receptors were determined using
membranes from tsA201 cells transiently expressing the two
receptors in a [3H]Cimbi-36 competition binding assay as previ-
ously described.12
The addition of a fluorine onto Cimbi-36 (1) to give 2 decreased
the binding affinities to both h5-HT2AR and h5-HT2CR with ꢀ16-
fold, and thus the 2A/2C selectivity ratio of 2 was similar to that
of 1 (Table 1). Substitution of the bromine in 2 with an iodine
yielded an analog 3 with slightly improved binding affinities to
both h5-HT2AR and h5-HT2CR, although these binding affinities
were ꢀ7-lower than those exhibited by Cimbi-36 at the two recep-
tors (Table 1). The binding affinities exhibited by chloro-analog 4 at
the two receptors were further reduced compared to 2 and 3.
Finally, the introduction of a NO2 or a CN group in this position
resulted in analogs displaying substantially reduced binding affini-
ties at the receptors. Interestingly, although analog 6 displayed a
ꢀ500 fold lower binding affinity at h5-HT2AR than 1, the reduction
in h5-HT2CR binding affinity for this analog was considerably lar-
ger, resulting in 6 exhibiting pronounced binding selectivity for
5-HT2AR over 5-HT2CR. A broad screen of analog 2 at the NIMH Psy-
choactive Drug Screening Program14 (PDSP) showed that the com-
pound is at least two orders of magnitude selective towards 5-HT2A
We previously investigated the one-pot 11C-labeling of ben-
zaldehydes and subsequent reductive amination with 4-substi-
tuted phenethylamines to produce 11C-labeled PET-ligands from
the Cimbi-36 structural class.16 Using this approach a series of
11C-labeled compounds was produced from the same radiolabeled
intermediate. This greatly simplifies the screening of new PET-
ligands, as precursor synthesis and radiochemical development
can be reduced to a minimum. In the current study we wanted
to develop a similar setup where the 18F-labeling of an aldehyde
and subsequent reductive amination could be performed in a
one-pot reaction. 18F can generally be introduced on electron defi-
cient aromatic rings via nucleophilic substitution of a leaving
group such as halogens, a NO2-group, or ideally a trimethyl ammo-
nium salt. The synthesis of aldehyde [18F]9 (see Scheme 1) has pre-
viously been reported from the corresponding NO2-precursor,17,18
but since excess of the aldehyde would react with the phenethy-
lamine and give products with similar polarity as the desired
PET-ligands, this procedure could complicate the final purification
of the PET-ligands. Thus, we decided to target the trimethylammo-
nium salt 8 as precursor instead as it generally gives better incor-
poration yields and the polarity of the trimethylammonium
reagent is very different from the final PET-ligands due to the fixed
18F
Table 1
18F
O
O
O
O
H
N
Binding affinities of 1–6 at h5-HT2AR and h5-HT2C
R
NH2
(d)
K2i C/K2i A
+
h5-HT2A h5-HT2C
R
R
O
HCl
9
X
X
O
O
1
2
3
4
5
6
0.21 [9.68 0.09] (8)
3.3 [8.48 0.03] (3)
1.5 [8.82 0.08] (4)
7.7 [8.11 0.03] (4)
30 [7.53 0.03] (3)
120 [6.93 0.14] (3)
2.5 [8.60 0.07] (6)
39 [7.41 0.06] (4)
18 [7.74 0.08] (3)
67 [7.18 0.06] (3)
250 [6.60 0.08] (4)
ꢀ10.000 [ꢀ5.0] (3)
12
12
12
8
8
ꢀ85
(c)
[
[
18F]2
: X = Br
18F]3: X = I
F
N+
I-
[
18F]4: X = Cl
[
[
18F]5
(a), (b)
: X = NO2
18F]6
: X = CN
7
8
The affinities were determined in a competition assay using [3H]Cimbi-36 (1) as
radio ligand and membranes from tsA201 cells transiently expressing human 5-
HT2A and 5-HT2C receptors. The Ki values for the analogs are given in nM with
pKi SEM values in brackets. The number of experiments (n) is given in parenthesis
after each value.
O
O
O
O
Scheme 1. Convergent 18F-labeling of 2–6. Reaction and conditions: (a) Me2NH,
DMF, 75 °C, 86% (b) MeI, 7 days, 22% (c) [18F]/FK, K222, DMSO, 70 °C (d) NaBCNH3,
AcOH, DMSO, 130 °C.
Table 2
Functional properties of 1 and 2 at h5-HT2AR and h5-HT2C
R
EC50 [pEC50 SEM]
Rmax(%) SEM
h5-HT2AR
h5-HT2C
R
h5-HT2A
R
h5-HT2CR
1
2
9.02 0.09
8.17 0.08
9.04 0.06
7.00 0.05
83
75
3
6
99
52
7
4
Stable h5-HT2A- and h5-HT2C-HEK293 cell lines were used in the Ca2+/Fluo-4/assay. The EC50 values (given in nM with pEC50 SEM values) and Rmax SEM values (given in %
of the maximal response evoked by 5-HT at the receptor) are based on 3 independent experiments.
Please cite this article in press as: Petersen, I. N.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.08.056

I. N. Petersen et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
3
positive charge. The synthesis of the aldehyde precursor; 4-formyl-
3-methoxy-N,N,N-trimethylbenzenaminium iodide was accom-
The pigs were scanned with a high resolution research tomog-
raphy (HRRT) scanner (Siemens AG). The 18F-labeled radio ligands
exhibited good brain uptake and reversible binding, see Figure 2.
The highest uptake was observed in thalamus, followed by high
neocortical uptake, moderate striatal and low cerebellar uptake,
except for the high thalamus uptake this distribution is in accor-
dance with the known 5-HT2AR distribution in the pig brain.6,10
We speculate that the thalamic uptake is due to off-target binding
to a target not included in the broad PDSP-screening of 2. [18F]6
shows very high uptake in bone tissue, and by the end of the scan
the great majority of activity stems from the skull. This could be a
result of defluorination of the PET-ligand, as bone tissue is known
to take up fluoride ions.21 Thus, it is possible that cortical uptake in
the later frames of the scan is overestimated due to spill-over of
radioactivity from the skull.
plished in two steps: addition of dimethylamine to
7 gave
4-(dimethylamino)-2-methoxybenzaldehyde in 86% yield which
subsequently was quaternized by stirring it in neat MeI for a week
at room temperature. This caused the desired trimethylammonium
precursor 8 to precipitate which was isolated by filtration in 22%
yield. Attempts to shorten the reaction time by heating of the reac-
tion mixture caused decomposition.
The labeling of the aldehyde was performed in DMSO at 70 °C
for 10 min giving consistent high incorporation yields (between
75% and 90%) as determined by TLC and HPLC analysis. In compar-
ison, it is necessary to heat the corresponding NO2-precursor to
140 °C in order to obtain similar yields of [18F]9.18 With the
required 18F-labeled aldehyde in hand we set out to identify condi-
tions that would allow us to couple it with the selected phenethy-
lamines. Initially the condition used for the reductive amination of
the 11C-labeled aldehydes and similar procedures reported ear-
lier16,19 were investigated but this led to poor yields of the desired
radioligands. Thus, several parameters were optimized, and it was
found that increasing the amount of K222 and K2CO3 in the first step
(in an attempt to reduce the amount of 18F sticking to the reaction
vial), increasing the reaction time and changing the solvent to
DMSO improved the radiochemical yield—but problems with
reproducibility persisted. Careful scrutiny of several parameters
revealed that the quality of the NaCNBH3 used in the reduction
of the imine is of crucial importance for the success of the reaction.
Purification of NaCNBH3 as previously described20 and storing/
handling it under dry conditions at all times led to consistently
higher radiochemical yields. With these conditions we were able
to produce 1.5–7 GBq of the final product in less than 1 h from a
10 min irradiation in a fully automated radiosynthesis system.
When attempting to displace the 18F-labeled radioligands from
the 5-HT2AR with a within-scan challenge with the known orthos-
teric 5-HT2AR antagonist ketanserin, we did not see any significant
decrease in binding for any of the radioligands. Apart from [18F]3,
injection of ketanserin was followed by an increase in plasma
radioactivity. This likely represents displacement of the radioli-
gand from peripheral 5-HT2AR sites into blood, which then leads
to an increased input to the brain. This confirms that the ligands
exhibit specific 5-HT2AR binding in vivo, and thus we speculate
that the lack of displacement in the brain could be due to the
majority of the radioactivity in the brain representing off-target
binding. Lack of displacement could also be caused by a self-block-
ing effect, i.e., not fulfilling the tracer principle of only having a
occupancy of 5–10% with the PET-ligand itself. The specific activi-
ties of the 18F-labeled ligands were between 9 and 177 GBq/
lmol.
To assess whether low specific activity was the reason for the
observed lack of displacement, we decided to evaluate [11C]2
Figure 2. Time activity curves (TACs) from PET-experiments in pigs with overlay of metabolite-corrected plasma radioactivity for the [18F]2–6 in cortex, cerebellum and
plasma. The arrows represent the time points for the administration of a ketanserin challenge. The sagittal image shows the distribution of [18F]2 in the pig brain.
Please cite this article in press as: Petersen, I. N.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.08.056

4
I. N. Petersen et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
Acknowledgments
F
F
O
Boc
N
The authors thank the Lundbeck Foundation and the Novo Nor-
disk Foundation for funding and the technical staff at the PET and
cyclotron unit for assistance.
OH
Br
Br
(1) [11C]MeOTf
(2) TFA
O
O
A. Supplementary data
H
N
Supplementary data (full experimental detail, description of the
assays, radiochemistry and animal procedures) associated with
this article can be found, in the online version, at http://dx.doi.
org/10.1016/j.bmc.2016.08.056.
O
H311C
2
C]
11
O
[
Figure 3. Radiosynthesis of [11C]2 and TACs with overlay of metabolite-corrected
plasma radioactivity for [11C]2 in cortex and cerebellum. The dotted lines represent
a separate experiment in which a blocking dose of ketanserin (3 mg/kg + 1 mg/kg/h)
was administered prior [11C]2.
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thereby ensuring high specific activity (P500 GBq/l
mol). The 11C-
labeling was performed in analogy to the labeling of [11C]1 from
the corresponding precursor, see Figure 3.
In vivo evaluation of [11C]2 in a pig confirmed the data from the
experiments with [18F]2; the binding in the cortical areas could not
be blocked by pretreatment with ketanserin. Quantifying the bind-
ing of [11C]2 with full arterial input modeling (data not shown)
revealed no decrease in distribution volumes across the investi-
gated regions. The observed increased uptake and distribution vol-
ume of the block scan with [11C]2, as well as the slight increase in
binding for [18F]5 and [18F]6 after ketanserin administration, is
thus interpreted as displacement of radioligand from peripheral
5-HT2AR sites leading to increase in radioligand concentration in
the blood and brain compartments. This leads us to conclude that
neither low specific activity nor the within-scan challenge
approach seems to be the reason to the lack of displacement. Thus,
decorating the Cimbi-36 scaffold with a single fluorine in the
selected position (going from 1 to 2) renders the ligands unsuitable
for in vivo imaging of the 5-HT2AR.
3. Conclusion
We successfully 18F-labeled five new 5-HT2AR agonist radioli-
gands from a common 18F-labeled benzaldehyde intermediate.
The radio synthesis of this previously reported benzaldehyde was
optimized using a trimethylammonium precursor, with the follow-
ing improvements: The introduction of 18F can be performed at
lower temperature due to the higher reactivity of the precursor
and the final purification is facilitated by the presence of a fixed
positive charged in the precursor—simplifying chromatographic
purification. Medium to high brain uptake of these 18F-labeled
ligands was seen in pigs, but none of the tested radioligands could
be displaced by ketanserin indicating that they are not suitable for
neuroimaging of the 5-HT2AR.
Please cite this article in press as: Petersen, I. N.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.08.056