Synthesis and Evaluation of Pyridyloxypyridyl Indole Carboxamides as Potential PET Imaging Agents for 5-HT2C Receptors

Article abstract of DOI:10.1021/acsmedchemlett.7b00443

Nine pyridyloxypyridyl indole carboxamides were synthesized and displayed high affinities for 5-HT_2C receptors and high selectivity over 5-HT_2A and 5-HT_2B. Among them, 6-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]1H-indole-3-carboxamide (8) exhibits the highest 5-HT_2C binding affinity (K_i = 1.3 nM) and high selectivity over 5-HT_2A (～1000 times) and 5-HT_2B (～140 times). [¹¹C]8 was synthesized by palladium-catalyzed coupling reaction between pinacolboranate 16 and [¹¹C]CH₃I with an average radiochemical yield of 27 ± 4% (n = 8, decay-corrected from end of [¹¹C]CH₃I synthesis). MicroPET imaging studies in rhesus monkeys showed regional uptake of [¹¹C]8 in the choroid plexus, whereas the bindings in all other brain regions were low. The specific binding in the choroid plexus was confirmed by administration of a blocking dose of 0.1 mg/kg of the 5-HT_2C antagonist SB-242084.

Full text of DOI:10.1021/acsmedchemlett.7b00443

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Letter
Synthesis and Evaluation of Pyridyloxypyridyl Indole
2C
Carboxamides as Potential PET Imaging Agents for 5-HT Receptors
Fanxing Zeng, Jonathon A. Nye, Ronald J Voll, Leonard Howell, and Mark M. Goodman
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00443 • Publication Date (Web): 05 Feb 2018
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Synthesis and Evaluation of Pyridyloxypyridyl Indole Carboxamides
as Potential PET Imaging Agents for 5-HT2C Receptors
Fanxing Zeng,†, §,* Jonathon A. Nye,†, § Ronald J. Voll,†, § Leonard Howell,‡ and Mark M. Goodman†,§,‡
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†Department of Radiology and Imaging Sciences, §Center for Systems Imaging, and ‡Yerkes National Primate Research Center, Emory
University, Atlanta, Georgia 30322
Keywords: 5-HT2C receptor, carbon-11 radiolabelling, PET ligands, non-human primate imaging
ABSTRACT: Nine pyridyloxypyridyl indole carboxamides were synthesized and displayed high affinities for 5-HT2C receptors and
high selectivity over 5-HT2A and 5-HT2B. Among them, 6-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]1H-indole-3-
carboxamide (8) exhibits the highest 5-HT2C binding affinity (Ki=1.3 nM) and high selectivity over 5-HT2A (~1000 times) and 5-HT2B
(~140 times). [11C]8 was synthesized by palladium-catalyzed coupling reaction between pinacolboranate 16 and [11C]CH3I with an
average radiochemical yield of 27 ± 4% (n = 8, decay-corrected from end of [11C]CH3I synthesis). MicroPET imaging studies in
rhesus monkeys showed regional uptake of [11C]8 in the choroid plexus, whereas the bindings in all other brain regions were low.
The specific binding in the choroid plexus was confirmed by administration of a blocking dose of 0.1mg/kg of the 5-HT2C
antagonist SB-242084.
The 5-HT2C receptor (5-HT2CR), a G protein-coupled
receptor expressed by GABAergic, glutamatergic, and
dopaminergic neurons, is one of the three closely related
serotonin receptor subtypes (5-HT2A, 5-HT2B, and 5-HT2C) in
the 5-HT2 receptor family and expressed in high abundance
throughout the mammalian CNS. The choroid plexus, which is
named as the recognition site for 5-HT2CR, has the highest
density of 5-HT2CR. Other brain regions that moderately
express 5-HT2CR include frontal cortex, basal ganglia,
hippocampus, amygdala, and hypothalamus, whereas lower
density of 5-HT2CR is identified in the cerebellum.1-5 With the
availability of selective agonists and antagonists, 5-HT2CR has
been indicated as a novel pharmacotherapeutic target for the
treatment of depression, schizophrenia, anxiety, drug abuse,
obesity, and Parkinson’s disease.6-10 For example, 5-HT2CR-
selective antagonists have demonstrated to produce
antipsychotic-like effects and enhance the antidepressant-like
behavioral efficacy of selective serotonin reuptake inhibitors
in rodent studies. Moreover, a recent study demonstrated
that pretreatment with a 5-HT2CR-selective agonist reduced
the abuse-related effects of cocaine in nonhuman primates.11
Indeed, lorcaserin, a selective 5-HT2CR agonist, was approved
by the FDA in June 2012 for use in the treatment of obesity.
will enable in vivo imaging and quantification of 5-HT2CR
densities represents a significant technological advancement
in understanding both the normal function and
pathophysiology of the 5-HT2CR. Furthermore, by enabling
functional imaging studies to determine dose-receptor
occupancy, its application will provide an excellent tool to
facilitate the discovery of therapeutic agents targeting 5-
HT2CR.
Over the past decade, significant progress has been made
in the quantitative mapping serotonin receptors using
noninvasive imaging.12 Research on the serotonin subtype
receptors, 5-HT1A and 5-HT2A, has benefited from the
availability of suitable PET radioligands.13-17 In contrast, 5-
HT2CR is less well studied and the radioligands developed so
far are not ideal for in vivo brain imaging. Three agonists
[11C]WAY-16390918 (1), [11C]Vabicaserin18 (2), and [11C]10-
(azetidin-1-yl)-7-methyl-6,7,8,9-tetrahydro-5H-
pyrazolo[1’,5’:1,2]pyrimido[4,5-d]azepine19 (3) were reported
with Ki of ∼10, 3, and 75 nM for 5-HT2C, respectively. In vivo
imaging in baboons has shown that these radiotracers
penetrated the blood-brain barrier (BBB), however, they did
not display specific binding to brain regions rich in 5HT2CR. An
agonist [11C]Cimbi-3620 (4) was shown to penetrate the BBB
and had specific binding to 5HT2C receptors in the choroid
plexus of the primate brain, however, [11C]Cimbi-36 is not
selective and has a higher binding affinity, over 2-to-1, for
5HT2A (Ki=0.5 nM) vs 5HT2C (Ki=1.7 nM). This major
shortcoming necessitated blocking 5HT2a prior to
administration of [11C]Cimbi-36 to determine 5HT2C
Although the involvement of the 5-HT2CR in the
pathophysiology of neuropsychiatric disorders has long been
recognized, many results were obtained from animal models,
postmortem tissues and molecular neuroscience studies. A
direct relationship between 5-HT2CR physiology and brain
diseases has proven difficult to establish due to an inability to
accurately quantify 5-HT2CR density and functional status in
vivo. Therefore, development of a selective radioligand that
concentration.
Recently,
[18F]4-(3-
fluorophenethoxy)pyrimidine (5) was reported to exhibit
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specific binding to 5-HT2C receptors in rat brain but with a fast
washout from choroid plexus.21
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Scheme 1. Schematic synthesis approach to
pyridyloxypyridyl indole carboxamides
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Figure 1. Chemical structures of reported PET imaging agents for
5-HT2CR
In an attempt to develop potent 5-HT2CR-specific PET
imaging agents, we have chosen to investigate
pyridyloxypyridyl indole carboxamides represented by 6.
Seong et al. recently reported a series of pyridyloxypyridyl
indole carboxamides as 5-HT2CR antagonists. Among them, N-
[6-[(2-chloro-3-pyridinyl)oxy]3-pyridinyl]1H-indole-3-
In vitro competition assays were conducted by NIMH
Psychoactive Drug Screening Program (PDSP). Data in Table 1
indicate that all pyridyloxypyridyl indole carboxamides tested
displayed high affinities for 5-HT2C and high selectivity over 5-
HT2A and 5-HT2B. Replacing a chloro by a fluoro group at the
pyridine ortho-position retained the 5-HT2C potency and
selectivity as seen in compounds 6 and 7. Introduction of a
methyl group at 6-position of the indole ring increased the
affinity for 5-HT2C 3 to 5-fold and retained the lower affinity
for 5-HT2A and 5-HT2B as seen in compound 6 vs 9, and
compound 7 vs 10. Compared to compound 8, 9, 11, which
has 6-methyl substitution on the indole ring, compound 12,
13, 14 with 5-methyl, 6-chloro substitution exhibited the
similar affinity for 5-HT2C, while their selectivity over 5-HT2A
and 5-HT2B decreased, respectively. Replacing the 6-methyl
group on the indole ring of 8 with a bromo group afforded 15,
whose affinity for 5-HT2C decreased 2-fold, while the affinity
for 5-HT2A and 5-HT2B remained low. Among all the
compounds tested, compound 8 is a very attractive candidate
with 5-HT2C binding, Ki=1.3 nM, equivalent to Cimbi-36, Ki =
1.7 nM, and high selectivity over 5-HT2A (~1000 times) and 5-
HT2B (~140 times).
carboxamide (6) exhibits the highest 5-HT2CR affinity (IC50=0.5
nM) and high selectivity (>100 times) over other serotonin (5-
HT1A-5-HT7) and dopamine receptor (D2-D4) subtypes.22 In
addition, 6 exhibits a favorable lipophilicity profile with ClogP
= 2.86 and its structure enables convenient approaches for
radiochemical modifications. 6 does not have positions
available for radiolabeling, however, fluorine-18 or carbon-11
could be easily incorporated into the structure by fluorine-18
fluoride or carbon-11 methyl substitution on the ortho-
position of the pyridine ring or on the indole ring without
significant structural modification. Therefore, we synthesized
the fluorine derivative (7) and a methyl derivative (8) which
also has a methyl group on the 6-position of the indole ring,
as well as seven other related derivatives to further explore
the structure-activity relationship. After comparing their
binding affinity and selectivity at 5-HT2CR, we chose to
radiolabel compound 8 with carbon-11 and conducted
microPET imaging studies in nonhuman primates for
evaluation as a candidate PET 5-HT2CR radioligand.
Nine new pyridyloxypyridyl indole carboxamides (7-15) and
6 were synthesized in three steps according to a previously
described procedure, which includes treating substituted 3-
pyridinols with 2-chloro-5-nitropyridine using NaH in DMF,
reduction of the resulting nitropyridines with SnCl2 in a
mixture of EtOH and concentrated HCl, and coupling the
resulting pyridin-3-yl amines with the corresponding 1H-
indole-3-carboxylic acid (Scheme 1).22
Table 1
.
Binding affinities of pyridyloxypyridyl indole
carboxamides at 5-HT2 receptors (Ki, nM)a
Compound
5-HT2C
5-HT2A
5-HT2B
6
23.3±7.5
25.3±12.6
1.3±0.6
5.2±3.3
7.9±2.6
5.0±2.9
791±178
344±123
1398±230
240±80
579±160
472±167
183±61
432±120
209±68
66±9
7
8
9
10
11
1637±182
370±184
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determine the extent of brain uptake (Figure 2A and 2C). The
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15
3.4±1.6
7.9±3.7
2.0±1.1
2.6±1.2
316±163
369±123
28±15
184±108
166±38
26±12
regional uptake of [11C]8 was observed in the choroid plexus,
the region with the highest density of 5-HT2CR, whereas
retention in all other brain regions was low. Overall, [11C]8 did
not enter the brain in high amounts during the time course of
PET studies, but the contrast of binding to the choroid plexus
was excellent at greater than 10:1 compared to the
cerebellum.
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6
1487±459
338±48
aData are reported as means of three separate competitive
experiments ± standard deviation.
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8
9
Preparation of [11C]8 was successfully achieved by
palladium-catalyzed methylation of the organoboronic ester
precursor with [11C]CH3I based on Suzuki-Miyaura couping.23
As shown in Scheme 2, the pinacolboranate precursor 16 was
synthesized in a moderate yield of 49% by borylation of the
bromo compound 15 with pinacolborane in the presence of
the catalytic system of Pd(OAc)2 and a sterically hindered
phosphine ligand and Et3N as base under relatively mild
condition.24,25 [11C]8 was prepared by the coupling reaction
between 16 and [11C]CH3I using a modified procedure
developed by Suzuki et al.26 Reacting 16 (2 mg) with [11C]CH3I
at 110 oC for 5 min using palladium complex generated in situ
from Pd2(dba)3 and (o-CH3C6H4)3P (1:12) together with K2CO3
as the co-catalyst in NMP gave us a high coupling yield.
(Scheme 3)
The low brain uptake of [11C]8 does not seem to be
explained by its log P7.4 value, suggesting a factor other than
lipophilicity prevents [11C]8 from penetrating the BBB. High
plasma protein binding or involvement in active action of
efflux transporters (e.g. P-gp) at BBB may contribute to the
low brain penetration, but further studies would be needed
for validation.29
To test specific binding of [11C]8 to the choroid plexus, an in
vivo microPET blocking study (n=1) was performed with SB-
242084, a 5-HT2CR antagonist (Ki at 5-HT2CR = 3.6 nM).
Pretreating the monkey with a dose of 0.1 mg/kg 30 min prior
to injection resulted in a marked reduction of radioactivity at
the choroid plexus, suggesting that the uptake of [11C]8 in
choroid plexus reflected specific binding. (Figure 2B and 2D)
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(A)
Scheme 2. Synthesis of the pinacolboranate precursor for
radiolabeling of [11C]8
.
O
Br
B
O
O
O
B
H
Pd(OAc)2
,
H
H
N
PCy2
N
N
NH
N
NH
(Cy=cyclohexyl)
O
O
O
N
O
N
Et3N, dioxane 75 oC, 1 h
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Starting with 380-420 mCi of cyclotron produced [11C]CH3I,
typical syntheses provided 34-45 mCi (uncorrected) of [11C]8
in an average radiochemical yield of 27 ± 4% (n = 8, decay
corrected) in a total synthesis time of 45 ± 5 min end of
bombardment. Analytical HPLC demonstrated that the
radiochemical and chemical purities of [11C]8 were
consistently greater than 98%, and the specific activity was in
the range of 0.4-0.9 Ci/µmol at time of injection. The
lipophilicity of 8 was measured according to a previously
reported procedure.27 The log P7.4 value of 8 is 2.79 which is in
the optimal range (1.0-3.0) for compounds expected to
readily enter the brain.28
(B)
Scheme 3. Radiosynthesis of [11C]8.
11CH3
O
B
O
[
11C]CH3I, Pd2(dba)3, P(o-tolyl)3
K2CO3, NMP, 110 oC, 5 min
H
N
N
NH
H
N
N
NH
O
O
N
O
11
O
N
8
[
C]
16
[11C]8 was intravenously administered to rhesus monkeys
(n=3) for dynamic microPET imaging to assess in vivo regional
brain uptake. Baseline studies were initially performed to
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of the pyridine ring or on the indole ring were synthesized.
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Among them, compound 8 was identified to possess the
highest 5-HT2C binding affinity and high selectivity over 5-HT2A
and 5-HT2B. [11C]8 was successfully synthesized by palladium-
catalyzed Suzuki coupling reaction between pinacolboranate
precursor and [11C]CH3I. In vivo microPET imaging studies
demonstrated that [11C]8 displays a specific binding to 5-
HT2CR in the choroid plexus, albeit there was low overall
uptake and retention of the tracer in the monkey brain.
Structural modification is underway in order to increase BBB
penetration.
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(C)
ASSOCIATED CONTENT
Supporting Information
0.6
Cerebellum
Striatum
Thalamus
Frontal Cortex
Choroid Plexus
Procedure for the preparation of new ligands, radiolabelling, and
microPET studies. This material is available free of charge via the
internet at http://pubs.acs.org.
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0.1
0
AUTHOR INFORMATION
Corresponding Author
*To whom correspondence should be addressed. Tel: 404-727-
1365. Fax: 404-727-3488. E-mail: fzeng@emory.edu
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Author Contributions
Time [min]
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
(D)
Funding Sources
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Cerebellum
This project was funded by a grant from the National Institute of
Health (1R21MH108928)
Striatum
Thalamus
Frontal Cortex
Choroid Plexus
ACKNOWLEDGMENT
Binding affinity data was provided by the Psychoactive Drug
Screening Program as part of the National Institute of Mental
Health. We thank Dr. Jiyoung Mun for her help in radiolabelling,
and Paul Chen and Juilet Brown for their contribution in the
microPET studies.
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Figure 2. PET-MRI analysis of [11C]8 in rhesus monkey. (A)
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images at baseline. Arrows depict choroid plexus. (B) MicroPET
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Synthesis and Evaluation of Pyridyloxypyridyl Indole Carboxamides as Potential PET Imaging
Agents for 5-HT2C Receptors
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Fanxing Zeng,†, §,* Jonathon A. Nye,†, § Ronald J. Voll,†, § Leonard Howell,‡ and Mark M. Goodman†,§,‡
Baseline
With Blocking
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