Investigation of an F-18 oxytocin receptor selective ligand via PET imaging

Article abstract of DOI:10.1016/j.bmcl.2013.07.045

The compound 1-(1-(2-(2-(2-fluoroethoxy)-4-(piperidin-4-yloxy)phenyl) acetyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (1) was synthesized and positively evaluated in vitro for high potency and selectivity with human oxytocin receptors. The positron emitting analogue, [F-18]1, was synthesized and investigated in vivo via PET imaging using rat and cynomolgus monkey models. PET imaging studies in female Sprague-Dawley rats suggested [F-18]1 reached the brain and accumulated in various regions of the brain, but washed out too rapidly for adequate quantification and localization. In vivo PET imaging studies in a male cynomolgus monkey suggested [F-18]1 had limited brain penetration while specific uptake of radioactivity significantly accumulated within the vasculature of the cerebral ventricles in areas representative of the choroid plexus.

Full text of DOI:10.1016/j.bmcl.2013.07.045

Bioorganic & Medicinal Chemistry Letters 23 (2013) 5415–5420
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Investigation of an F-18 oxytocin receptor selective ligand via PET
imaging
a,
Aaron L. Smith a,b, Sara M. Freeman b, Ronald J. Voll a, Larry J. Young b, , Mark M. Goodman
⇑
⇑
a Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA 30329, United States
b Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Atlanta, GA 30322, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The compound 1-(1-(2-(2-(2-fluoroethoxy)-4-(piperidin-4-yloxy)phenyl)acetyl)piperidin-4-yl)-3,4-dihy-
droquinolin-2(1H)-one (1) was synthesized and positively evaluated in vitro for high potency and selec-
tivity with human oxytocin receptors. The positron emitting analogue, [F-18]1, was synthesized and
investigated in vivo via PET imaging using rat and cynomolgus monkey models. PET imaging studies in
female Sprague–Dawley rats suggested [F-18]1 reached the brain and accumulated in various regions
of the brain, but washed out too rapidly for adequate quantification and localization. In vivo PET imaging
studies in a male cynomolgus monkey suggested [F-18]1 had limited brain penetration while specific
uptake of radioactivity significantly accumulated within the vasculature of the cerebral ventricles in
areas representative of the choroid plexus.
Received 15 May 2013
Revised 12 July 2013
Accepted 22 July 2013
Available online 30 July 2013
Keywords:
Oxytocin
Oxytocin receptor
Receptor imaging
Fluorine-18
Ó 2013 Published by Elsevier Ltd.
PET imaging
Cerebral ventricles
Choroid plexus
Alpha-1 adrenergic receptor
Adrenergic receptor
Oxytocin was the first endocrine system hormone to be synthe-
sized in the laboratory, and has been studied extensively for its role
in the induction of labor and the milk ejection reflex.1 More re-
cently, research foci have been directed toward the role of oxytocin
and the oxytocin receptor (OTR) in the regulation of psychosocial
behavior.2–10 In addition to being implicated in modulating mater-
nal nurturing and mother–infant bonding, pair bonding, social rec-
ognition, increased eye-to-eye contact, trust and empathy, the
oxytocin system has also been investigated in relation to disorders
characterized by disruption in social behavior, including autism
spectrum disorders.11–17 While the bulk of the research conducted
with the oxytocin system in humans has been limited to experi-
mental paradigms involving administration of oxytocin followed
by behavior monitoring, methodologies implemented for investi-
gating OTR within the brain have been limited to post-mortem
receptor autoradiography, in situ hybridization, and gene associa-
tion studies.12,13,18–21 The development of a methodology permit-
ting the quantification of OTR in the living brain would represent
a significant advance in this area of research. Our goal is to develop
a positron-emitting small molecule with high affinity and selectiv-
ity for the human and primate OTR to enable non-invasive correla-
tions between neural OTR densities and behavior via in vivo
positron emission tomography (PET). In addition to this goal, we
are simultaneously seeking to discover new candidate pharmaceu-
ticals which may prove useful in reaching OTR specifically within
the brain or the periphery for the purpose of potentially alleviating
and/or investigating symptoms associated with social behavior
disorders. We report here the synthesis, radiosynthesis, and PET
imaging evaluation of one of our lead candidate compounds meet-
ing these criteria.
We have recently reported progress in the development of OTR
selective ligands bearing radioactive isotopes with some bearing
structural similarity to the lead candidate described here.22,23
These molecules were found to either not penetrate the blood–
brain barrier or have high affinity for the p-glycoprotein pump
which prevented their retention within the brain. We concluded
that the lack of a hydrogen bond donor may have been the cause
for lack of brain penetration or retention. Therefore, we proceeded
to modify the structure by eliminating the methyl sulfonyl group of
our former lead candidate, 2, to generate a compound bearing a
free amine to act as a hydrogen bond donor, 1 (Fig. 1). The syn-
thetic route was derived from a precursor in our previously re-
ported synthetic pathway, 3, and is outlined in Scheme 122 The
free amine of 3 was protected using di-tert-butyl dicarbonate to
generate 4. The phenol position of 4 was then alkylated using
⇑
Corresponding authors. Tel.: +1 (404) 727 8272; fax: +1 (404) 727 8070 (L.J.Y.).
Tel.: +1 (404) 727 9366; fax: +1 (404) 712 5689 (M.M.G.).
E-mail addresses: lyoun03@emory.edu (L.J. Young), mgoodma@emory.edu
(M.M. Goodman).
0960-894X/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmcl.2013.07.045

5416
A. L. Smith et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5415–5420
O
F
the binding affinity of 1 for the V1aR slightly increased, the binding
affinity for the V2R decreased significantly in comparison to 2, thus
making it slightly more selective overall. Further in vitro binding
assays were also performed on 88 other human G-protein coupled
receptors (GPCR) in a screen to determine if 1 had affinity for these
other receptors. Table 2 contains the results of the screen in which
7 other GPCR had modest to mild affinity for 1, none of which
would be expected to display significant uptake during a PET scan.
The most notable binding affinity was found in the alpha-1A
subtype of the adrenergic receptor and the 6 subtype of the
5-hydroxytryptophan receptor (5-HT6) having a Ki values of
82 nM and 187 nM, respectively. Although these Ki values for the
non-target receptors are not believed to be optimal for PET
imaging, they would present an issue if 1 was to be considered
for pharmaceutical development.
N
O
N
NH
O
O
F
1
O
N
O
O
N
S
N
O
O
O
2
Having good binding affinity and selectivity, the F-18 analogue
Figure 1. Structures of OTR selective compounds 1 and 2.
O
O
N
N
OH
OH
O
a
N
N
NH
N
O
O
HCl
O
O
O
O
3
4
O
F
O
F
N
N
O
O
b
c
N
N
NH
N
O
HCl
O
O
O
O
5
1
Scheme 1. Synthetic route to obtain the target molecule 1. Reagents and conditions: (a) Boc2O, dioxane, 1 N NaOH, rt, 48%; (b) 1-bromo-2-fluoroethane, Cs2CO3, DMF, rt, 97%,
(c) (1) 2 M HCl in ether, rt, 96%. Further reaction details and characterizations are provided in the Supplementary data.
1-bromo-2-fluoroethane to provide the fluoroethoxy moiety of 5. A
deprotection using 2 M HCl in ether then resulted in the target
molecule, 1, as a hydrochloride salt. Further synthetic details and
characterizations are provided in the Supplementary data.
To determine if the structural modification resulted in any loss
of biological properties, 1 was subjected to in vitro competitive
binding assays using cell lines expressing human oxytocin and all
known vasopressin receptor subtypes (V1aR, V1bR, and V2R). The
results of these assays are displayed in Table 1 with data for 2 ob-
tained from our previously reported study.22 These data indicate
the removal of the methyl sulfonyl group actually resulted in a
slight improvement of the biological properties. Having a Ki value
of 15 nM for the OTR, 1 matched the binding affinity of 2. While
of 1 was generated for further investigation. The synthetic route to
18F]1 is outlined in Scheme 2. The Boc-protected amine 4 was
[
alkylated with ethane-1,2-diyl bis(4-methylbenzenesulfonate) to
generate our tosylate precursor 6. Radiolabeling was then con-
ducted in a CTI-Seimens Chemistry process Control Unit (CPCU)
to perform SN2 substitution using the cryptand ligated K22218F fol-
lowed by removal of the Boc-protecting group with 1 M HCl. The
crude radioactive mixture was eluted from the CPCU unit with a
7 ml solution of ethanol:water:triethylamine (50:50:0.1). Solid
phase extraction was then performed to remove excess acid prior
to HPLC purification. The extracted mixture was then purified via
HPLC and concentrated into a dose form (15 ml solution of 10%
ethanol in saline) via solid phase extraction and passed through
1 and 0.2 lm filters using high argon pressure. A dose would nor-
mally be prepared in 120 min from the start of synthesis and result
in approximately 19% uncorrected yields of [18F]1 with a specific
Table 1
activity greater than 10 Ci/lmol. Radiochemical purity was greater
than 99.9%. A representative analytical HPLC graph is shown in Fig-
In vitro Ki (nM) determinations of 1–2 from competition assays with human OTR and
vasopressin receptors (3 subtypes)a
ure 2.
Compound
OTR
V1aR
V1bR
V2R
To gauge the probability of brain penetration, the log P7.4 was
determined to be 1.57 using previously reported methods. This
lipophilicity measurement is within the range of 1–3 estimated
to be the calculated optimal range for penetration of the blood
brain barrier.24 To evaluate brain penetration in vivo, PET studies
were first performed using female 180–200 g Sprague–Dawley rats
(n = 4) in the same manner as our previously reported study.22,25
Figure 3 contains representative time activity curves generated
2
1
16
15
8700
5600
>10,000
>10,000
1800
8700
For experimental details please refer to the PDSP web site http://pdsp.med.unc.edu/
and click on ‘Binding Assay’ or ‘Functional Assay’ on the menu bar.
a
Ki Values were generously provided by the National Institute of Mental Health’s
Psychoactive Drug Screening Program, contract # HHSN-271-2008-00025-C (NIMH
PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of
North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda
MD, USA.

A. L. Smith et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5415–5420
5417
Table 2
In vitro Ki (nM) determinations of 1 from competition assays with the human muscarinic acetylcholine receptor (M4), the 1B, 2B, B, and 6 subtypes of the 5-hydroxytryptophan
receptors (5-HT), the alpha 1A adrenergic receptor, and dopamine D3 receptora
Receptor
M4
5-HT1B
700
5-HT2B
500
5-HTB
1270
5-HT6
190
Adrenergic alpha 1A
80
Dopamine D3
6790
Ki (nm)
1270
For experimental details please refer to the PDSP web site http://pdsp.med.unc.edu/ and click on ‘Binding Assay’ or ‘Functional Assay’ on the menu bar.
a
Ki Values were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, contract # HHSN-271-2008-00025-C (NIMH
PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA.
O
O
OTs
O
N
N
OH
O
O
O
a
N
N
N
O
N
O
O
O
O
6
7
O
18F
N
O
b
N
NH
O
O
[18F]1
Scheme 2. Synthetic route for obtaining [18F]1. Reagents and conditions: (a) ethane-1,2-diyl bis(4-methylbenzenesulfonate), Cs2CO3, DMF, rt, 55%; (b) (1) K22218F, CH3CN,
110 °C, 15 min; (2) 1 N HCl, 110 °C, 10 min, 19% (uncorrected). Further reaction details and characterizations are provided in the Supplementary data.
from [18F]1 distribution which compares the muscle tissue uptake
with whole brain uptake. As can be seen in the graph, there is a
burst of activity into the brain at the beginning of the scan which
clears after 20 min post injection. Therefore, the first 20 min of
the scan were summed to analyze brain uptake. Figure 4 contains
representative images of [18F]1 over the first 20 min time span post
injection. Uptake appears to be located at areas in and around the
cerebral ventricles. However, it is difficult to make a conclusive
determination of the exact areas of uptake in the rat due to the size
of the subject, small areas of OTR binding in the rat brain, limits of
resolution of the PET scanner, and limited time of retained uptake.
To further evaluate [18F]1 in a model which would better repre-
sent a human and should be large enough to detect regions of OTR
binding with a PET scanner, PET imaging was conducted using
the brain which synthesizes and recycles cerebrospinal fluid
(CSF). The time activity curves of the standard uptake values
(SUV) for the ventricular lining, the whole brain, and the muscle
tissue obtained from the baseline scan are shown in Figure 6a.
The graph suggests significant amounts of [18F]1 reach the brain
during the first 500 s of the scan, but as can seen by the concentra-
tion of [18F]1 in the ventricular lining during the same timeframe,
it could be deduced to account for the bulk of brain activity de-
tected. Therefore, no significant accumulation of the ligand was de-
tected in any sites within the brain. Thus, it could be deduced that
[
18F]1 did not penetrate the extracellular space of the brain, and
only reached the vasculature and the choroid plexus. As can be
seen in Figure 5d which sums up the first 15 min of the scan, there
is uptake observed at the middle cerebral artery in the sulcus of the
outer region of the cerebral cortex near the insula. This may ex-
plain the increase in whole brain uptake during the first 500 s of
the scan, although we cannot rule out accumulation in the CSF of
this region. The time activity curve of the choroid plexus/ventricu-
lar lining in Figure 5a clearly demonstrates that [18F]1 binds
strongly in this area. Although there have been reports of vasopres-
sin 1a and alpha-1A adrenergic receptors in this region, there are
have been no reports of OTR in the choroid plexus.26
[
18F]1 in a cynomolgus monkey model. Three types of studies were
performed to evaluate the tracer and its distribution within the
brain, a baseline scan in which only the tracer was injected, a
blocking scan (5 mg/kg of the cold standard was administered 30
min prior to the tracer), and a chase scan (5 mg/kg of cold standard
was administered 45 min after the tracer). These procedures were
performed on a subject anesthetized with Telazol (3 mg/kg; i.m.)
and maintained on a 1–2% isoflurane in pure oxygen mixture while
intubated and placed on a ventilator throughout the imaging pro-
cedure. A 15 min transmission scan was performed using a germa-
nium-68 point source to provide attenuation correction.
Approximately 5 mCi of [18F]1 was then administered at the start
of the emission scan and scanning continued for 2 h. For blocking
and chase studies, 5 mg/kg of 1 was administered 30 min prior to
To verify if the observed [18F]1 uptake was due to binding to a
saturable protein on the cerebral ventricles, blocking and chase
scans were performed in which 5 mg/kg of the cold standard, 1,
was administered 30 min prior to [18F]1 (blocking) or 45 min post
injection of [18F]1 (chase). The comparable time–activity curves are
shown in Figure 6b and c, respectively. The blocking study resulted
in an increase of overall brain activity, primarily in the region of
the choroid plexus. The images obtained were nearly identical to
those obtained from the baseline scan and are not shown. The ob-
served increase of [18F]1 after blocking is thought to be due to the
blocking of peripheral OTR and perhaps the mild affinity 1 has for
the alpha-1 adrenergic receptor (there is a vast distribution of
these type of receptors in the periphery). Once the majority of
[
18F]1 injection or 45 min after [18F]1 injection, respectively, via a
slow bolus injection.
Figure 5a–c contains images obtained from the sum of the 2 h
baseline scan and arrows indicate the uptake found primarily in
the ventricles within the brain. One possible site of radiotracer
binding within the ventricles is the choroid plexus, which is a
highly vascularized network of structures within the ventricles of

5418
A. L. Smith et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5415–5420
Figure 2. Two representative analytical HPLC chromatograms (dose and dose co-injected with cold standard) as obtained from a Waters Breeze HPLC system equipped with a
Bioscan radiation detector and Novapak 4
m C-18 column (3.9 Â 150 mm). The chromatograms are showing graphs at 254 nm (top graph), 280 nm (middle graph) and
detected radiation on the SAT/IN channel (bottom graph) by elution with a solution of methanol:water:triethylamine (70:30:0.1).
l
the chase study, the uptake within the choroid plexus was com-
pletely removed after administration of 1 by the end of the remain-
ing hour and 15 min of scan time. When the summed images from
the final 30 min of both the baseline and chase scans are directly
compared (Fig. 7), it is clearly evident [18F]1 is completely removed
by the addition of 1. These results suggest that 1 has some type of
affinity equilibrium within the choroid plexus that shifts when
additional amounts of 1 are administered. It should be noted that
previously investigated PET imaging studies using pharmaceutical
derivatives, including our studies with a completely different OTR
selective molecule, have shown to have uptake in the choroid
plexus region; the phenomenon is not unique to 1.23,27,28
In summary, a very selective OTR ligand, 1, has been investi-
gated in vitro with receptor binding assays and in vivo via synthe-
sis of its positron emitting analogue, [18F]1, and PET. Brain
penetration of [18F]1 may be present in the rat, but appears to be
limited to the choroid plexus area in both the cynomolgus maca-
que and the rat. In the cynomolgus monkey, brain penetration ap-
pears to be negligible except for specific uptake within the choroid
plexus. Neither PET scan suggested [18F]1 will be useful for detect-
ing OTR in vivo. It is possible that the densities of OTR in the cyno-
molgus monkey model are not high enough to afford a signal via
PET using a biomarker with a Ki affinity greater than 1 nM, or that
they even do not exist. Indeed, to date, inconclusive results have
been reported regarding specific OTR binding in the rhesus maca-
que brain29 (Young, LJ and Freeman, SM unpublished data). By con-
trast, we and others have confirmed that the common marmoset
Figure 3. Baseline time–activity curves of the muscle tissue and brain generated
from [18F]1 in a female Sprague Dawley rat model.
these receptors are blocked in the periphery, it allowed more tracer
to become available in the blood, thus increasing the overall activ-
ity concentrations in the choroid plexus and vasculature. The
inability of 1 to block the uptake of [18F]1 in the choroid plexus
would suggest that the uptake is not specific to a saturable protein.
However, the chase study afforded completely opposite results. In

A. L. Smith et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5415–5420
5419
Figure 4. Representative images of 280 l
Ci of [18F]1 during the first 20 min of a PET scan with arrows pointing to the choroid plexus area in each image and the crosshairs of
the sagittal image designating the slice locations of the coronal and transverse slices. (a) Transverse slice. (b) Sagittal slice. (c) Coronal slice.
Figure 5. Images a–c were obtained from the sum of a 2 h scan of 5.5 mCi [18F]1 in a cynomolgus monkey model with arrows indicating uptake in the choroid plexus. (a)
Transverse view at the lateral ventricle. (b) Coronal view at the lateral ventricle and inferior horn of lateral ventricle. (c) Saggital view at the lateral ventricle. Image d was
obtained from a sum of the first 15 min of the scan with arrows indicating [18F]1 at the middle cerebral artery within a sulcus of the outer cerebral cortex of the brain near the
insula.
Figure 6. Time–activity curves of [18F]1 in the whole brain, choroid plexus, and muscle tissue of a cynomolgus monkey during (a) baseline scan (b) blocking study with 5 mg/
kg of 1 administered 30 min prior to 5 mCi of [18F]1 (c) chase study with 5 mg/kg of 1 administered 2700 s after [18F]1.
has high densities of OTR in the nucleus accumbens.19 Therefore,
we will be conducting future investigations utilizing the common
marmoset as the model system. We will continue to perform struc-
ture/activity studies with derivatives of this candidate compound
to increase brain penetrance, increase affinity for OTR will main-
taining selectivity, and eliminate binding to the cerebral ventricles.

5420
A. L. Smith et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5415–5420
Figure 7. Images from 5 mCi of [18F]1 in a cynomolgus monkey model during the sum of the last 30 min of a 2 h baseline scan (blue) and the last 30 min of a chase study in
which 5 mg/kg of 1 was administered 45 min after injection of 5 mCi of [18F]1 (red). The images demonstrate the removal of activity from the choroid plexus after
administration of 1.
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We thank Larry Williams, Mel Camp and Eugene Malveaux for
their contributions to the rodent studies. We thank the Yerkes Na-
tional Primate Imaging Suite staff for their aid in performing non-
human primate scans. We thank the NIMH PDSP directed by Bryan
L. Roth M.D, Ph.D at the University of North Carolina at Chapel Hill
and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA for
their contributions of the human cell line studies. This research
was funded by the National Institute of Mental Health through
grant 5 R21 MH090776. We also acknowledge NIH MH064692
(L.J.Y.) and the National Center for Research Resources P51RR165
(currently P51OD11132) to YNPRC.
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