Development of [123I]IPEB and [123I]IMPEB as SPECT Radioligands for Metabotropic Glutamate Receptor Subtype 5

Article abstract of DOI:10.1021/ml500007z

mGlu₅ play an important role in physiology and pathology to various central nervous system (CNS) diseases. Several positron emission tomography (PET) radiotracers have been developed to explore the role of mGlu₅ in brain disorders. H

Full text of DOI:10.1021/ml500007z

Letter
pubs.acs.org/acsmedchemlett
Development of [123I]IPEB and [123I]IMPEB as SPECT Radioligands for
Metabotropic Glutamate Receptor Subtype 5
Kun-Eek Kil, Aijun Zhu, Zhaoda Zhang, Ji-Kyung Choi, Sreekanth Kura, Chunyu Gong,
and Anna-Liisa Brownell*
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown,
Massachusetts 02129, United States
S
* Supporting Information
ABSTRACT: mGlu5 play an important role in physiology and pathology to various central nervous system (CNS) diseases.
Several positron emission tomography (PET) radiotracers have been developed to explore the role of mGlu5 in brain disorders.
However, there are no single photon emission computed tomography (SPECT) radioligands for mGlu5. Here we report
development of [123I]IPEB ([123I]1) and [123I]IMPEB ([123I]2) as mGlu5 radioligands for SPECT. [123I]1 and [123I]2 were
produced by copper(I) mediated aromatic halide displacement reactions. The SPECT imaging using mouse models
demonstrated that [123I]1 readily entered the brain and accumulated specifically in mGlu5-rich regions of the brain such as
striatum and hippocampus. However, in comparison to the corresponding PET tracer [18F]FPEB, [123I]1 showed faster washout
from the brain. The binding ratios of the striatum and the hippocampus compared to the cerebellum for [123I]1 and [18F]FPEB
were similar despite unfavorable pharmacokinetics of [123I]1. Further structural optimization of 1 may lead to more viable
SPECT radiotracers for the imaging of mGlu5.
KEYWORDS: metabotropic glutamate receptor subtype 5 (mGlu5), negative allosteric modulator (NAM),
single photon emission computed tomography (SPECT), in vivo imaging, [123I]IPEB, [123I]IMPEB
for CNS diseases by imaging receptor distribution, concen-
lutamate is the most abundant excitatory neurotransmit-
Gter in vertebrates, which acts on two main types of tration, functions in normal and pathological states, and
occupancy of potential drug candidate in the brain. Since the
first selective mGlu5 antagonist was identified in 1999,13 a large
number of potent, subtype selective, and structurally diverse
NAMs have been described.14 Many mGlu5 PET tracers have
been reported, in which 3-[18F]fluoro-5-(pyridin-2-ylethynyl)-
benzonitrile ([18F]FPEB),15,16 [11C]ABP688,17 and [11C]-
SP20318 have been translated into human studies (Figure
membrane receptors: ionotropic glutamate receptors and
metabotropic glutamate receptors (mGluRs).1,2 mGluRs belong
to family C of G-protein-coupled receptors (GPCRs).3 To date,
eight mGluR subtypes have been identified that are subdivided
into three groups based on sequences, preferred signal
transduction mechanisms, and pharmacology.4 Of eight
subtypes of mGluRs, mGlu5 is a member of group I mGluRs
along with mGlu1, and it is mainly expressed postsynaptically.5
In contrast to group II and group III mGluRs, which stimulate
inhibitory cyclic adenosine monophosphate pathways via Gαi/o
subunit of G protein, group I mGluRs interact with Gαq subunit
of G-protein to stimulate downstream effectors and tyrosine
kinases, such as phospholipase C-β, mitogen-activated protein
kinase, and phosphoinositide 3 kinase.5,6 In recent years,
negative allosteric modulators (NAMs) of mGlu5 that bind to
the transmembrane domains have been developed for their
therapeutic potential in a variety of central nervous system
(CNS) disorders including pain,7 Parkinson’s disease (PD),8
drug abuse,9 fragile X syndrome,10 epilepsy,11 and anxiety.12
However, positron emission tomography (PET) has played
an important role in the development of potential therapeutics
1a).19−21 We have developed several PET radioligands for
16,22
mGlu5
and investigated interplay of glutamatergic and
dopaminergic system in rat model of PD by in vivo imaging of
modulation of mGlu5 expression and dopamine transporter and
D2 receptor function during degeneration.23 The PET imaging
of mGlu5 showed a relationship between glutamatergic system
and neuroinflammation.24
In spite of such accomplishments in PET imaging, the effort
to develop single photon emission computed tomography
(SPECT) radioligands for mGlu5 has been almost negligible.
Received: January 6, 2014
Accepted: April 6, 2014
Published: April 6, 2014
© 2014 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
putamen) in rat.31 With the criteria of Bmax/KD ≫ 1, a tracer
with an affinity <5 nM, and preferably <2 nM, is desired.15,30
For achieving low nonspecific binding as well as good blood−
brain barrier (BBB) penetration, which is often related to
lipophilicity, a logD7.4 value between 1 and 3 is preferred.30
Although the cLogP values of 1 and 2 are higher than 3, the
experimental value (logD7.4 = 2.30) of 2 is well below its
calculated value (cLogP = 4.33). Therefore, we anticipate that 1
will exhibit appropriate lipophilicity for brain imaging
application since the cLogP (3.84) of 1 is lower than that of
2. It has also been suggested that compounds with effective
BBB penetration preferably have a polar surface area (tPSA) of
<60, and molecular weight under 450.32 Compounds 1 and 2
definitely meet these requirements. Here we report the
syntheses and preliminary evaluation of [123I]IPEB ([123I]1)
and [123I]IMPEB ([123I]2) for imaging mGlu5.
Scheme 1 shows the syntheses of nonradioactive reference
compounds 1 and 2, precursors 5a and 5b, and radioactive
Figure 1. (a) Examples of the published mGlu5 PET ligands.15−18,29
(b) Molecular properties of SPECT radioligand [123I]YP428, iodo-
compounds IPEB (1) and IMPEB (2).
Scheme 1. Syntheses of Nonradioactive Compounds (1 and
2) and Radioligands ([123I]1 and [123I]2); RCYs Are Decay
Corrected
To date, only one mGluR5 SPECT agent ([123I]YP428; Figure
1b) was reported at the fifth ISR meeting in 2004 for studying
cocaine addiction.25 In comparison to PET radionuclides,
SPECT radionuclide such as iodine-123 (t1/2 = 13.2 h) has
relatively longer half-life and can be bought commercially, thus
offering more flexibility in tracer synthesis, lower cost, and
better access to the technique.26,27 Technical advancements in
the field have also dramatically improved the spatial resolution
for SPECT measurements.28 Therefore, a reliable SPECT
radioligand for mGlu5 would make a big impact on biomedical
research of glutamate neurotransmitter and the development of
potential therapeutics for CNS diseases.
There are additional challenges for the incorporation of an
iodine-123 atom into mGlu5 ligands since it could add
significant lipophilicity to the parent molecule, therefore
increasing the risk of nonspecific binding. [123I]YP428 can be
considered as a derivative of the PET tracer, 3-([11C]methoxy)-
5-((2-methyl-1,3-thiazol-4-ylethynyl)pyridine ([11C]M-MTEP)
(Figure 1a),29 in which its methoxy group is replaced by an
iodine. Although they have good in vitro properties, both
products [123I]1 and [123I]2. Compounds 5a and 5b were
obtained by Sonogashira coupling reaction between 3,5-
dibromobenzonitrile (4) and 2-ethynylpyridine derivative (3a
or 3b), respectively. The bromo-compounds, 5a and 5b, were
converted into tributylstannyl derivatives (6a and 6b,
respectively) using bis(tributyltin) and tetrakis-
(triphenylphosphine)palladium(0). The tributylstannyl groups
in 6a and 6b were iodinated to give nonradioactive compounds
1 and 2, respectively. The iodine-123 labeling was first
attempted under the oxidative condition mediated by chlor-
amine T using tributylstannyl derivatives 6a and 6b,
respectively. However, this labeling reaction ended up with
predominantly the radioactive side products. Desired radio-
active products, [123I]1 and [123I]2, were produced less than
20% radiochemical yield (RCY) (Supporting Information C).
On the contrary, in the syntheses of nonradioactive compounds
using the similar condition, 1 and 2 were major products,
respectively. The radiolabeling reactions were then carried out
using the bromo-precursor 5a or 5b under the reductive
condition mediated by copper(I) catalyst to displace bromine
with iodine-123. The reaction produced [123I]1 and [123I]2 with
45% and 23% decay-corrected RCY, respectively. The specific
activity of [123I]1 was 182.8 GBq/μmol. Figure 2a,b displays the
HPLC profile of radiolabeling reactions of [123I]1 and [123I]2,
respectively. As Figure 2a shows, the bromo-precursors 5a and
the radioactive products [123I]1 were well separated by using
HPLC equipped with Zorbax Eclipse XDB-Phenyl semi-
[
123I]YP428 and [11C]M-MTEP show fast washout in the brain.
Optimal SPECT radioligands should have reasonable slow
washout to allow flawless image quality. It is advantageous to
design and develop SPECT agents based on promising mGlu5
PET tracers, which have shown not only good in vitro
properties but also excellent in vivo results. We and other
research groups have demonstrated previously that [18F]FPEB
(Figure 1a) is a superior PET tracer for mGlu5.15,16 It has fast
uptake and slow washout in mGlu5 abundant brain regions such
as striatum and hippocampus and fast washout in mGlu5
deficient region such as cerebellum. Because [18F]FPEB
shows excellent properties as a PET radiotracer, we like to
develop the iodine-123 labeled compounds based on the
structure of [18F]FPEB. It is also known that the compounds 3-
iodo-5-(pyridin-2-ylethynyl)benzonitrile (IPEB (1)) and 3-
iodo-5-((6-methylpyridin-2-yl)ethynyl)benzonitrile (IMPEB
(2)) (Figure 1b) have shown good inhibitory activity against
mGlu5, in which the IC50 are 0.66 and 0.71 nM, respectively.30
The required affinity for a radiotracer is related to the receptor
concentration. It is reported that Bmax values for mGlu5 are
ranging from 21 nM (hypothalamus) to 83 nM (caudate/
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ACS Medicinal Chemistry Letters
Letter
Figure 2. HPLC chromatographs of radiolabeling reactions of (a)
[
123I]1 and (b) [123I]2.
Figure 3. SPECT images with [123I]1 and PET images with [18F]FPEB
show the accumulation of the labeled ligands on striatal and
hippocampal level in the mouse brain. The slice thickness in the
SPECT images is 0.76 mm, while it is 0.62 mm in PET imaging. The
injected radioactivity was 13.5 MBq for SPECT study and 1.5 MBq for
PET study demonstrating the significant difference in detection
sensitivity between SPECT and PET imaging. The images provide
almost equal contrast (target to background ratio).
preparative column (250 × 10 mm, 5 μm, Agilent) eluting with
a solution of 0.1 M ammonium formate aqueous solution:
CH3CN (55:45) at a flow rate of 4 mL/min. The similar
separation was also achieved between 5b and [123I]2 by using
Gemini NX-C18 semipreparative column (250 × 10 mm, 5 μm,
Phenomenex) eluting with a solution of 0.1 M ammonium
formate aqueous solution: CH3CN (45:55) at a flow rate of 4
mL/min (Figure 2b).
After purification, the combined radioactive aliquots were
checked for radiochemical purities and coinjected with
corresponding nonradioactive standards by using HPLC
equipped with Alltima C18 analytical column (150 × 4.6 mm,
5 μm, Grace) eluting with a solution of 0.1 M ammonium
formate aqueous solution: CH3CN (40:60 for [123I]1 and 35:65
for [123I]2). Both of the radioactive aliquots display over 98%
radiochemical purities, and coinjection of the radioactive
aliquots with nonradioactive standard (1 or 2) confirmed that
the isolated radioactive species are authentic radioactive
products (see Supporting Information D).
Because [123I]1 was obtained in higher yield and may have
lower lipophilicity than [123I]2, we selected it for preliminary
evaluation in mouse studies. Around 11.5−15.5 MBq of [123I]1
in 10% ethanol saline solution was administered by tail vein
injection. The images of mouse brain were acquired by a 4-head
SPECT camera (Triumph II, Trifoil Imaging Inc.), in which 90
deg rotation divided to 16 projections with 30 s frame time.
Figure 3 illustrates the SPECT images of mouse brain using
Figure 4. TACs of (a) [123I]1 and (b) [18F]FPEB in a mouse model
show different pharmacokinetics. [123I]1 has fast washout in all brain
areas, while [18F]FPEB is almost in the steady state in striatum and
hippocampus having washout from cerebellum. However, the binding
ratios to cerebellum of (c) [123I]1 and (d) [18F]FPEB indicate similar
trends for these two PET and SPECT tracers.
[
123I]1 and PET images using [18F]FPEB, which show
accumulation of [123I]1 (SPECT study) and [18F]FPEB (PET
study) in a mouse brain at the coronal striatal and hippocampal
level. Both studies show activity distribution at the time interval
4−20 min after administration of the radioligand in the
anesthetized mice. Those images demonstrated that [123I]1
readily crossed BBB, and its major accumulation was observed
in hippocampus and striatum, the regions that were reported to
have the most abundant mGlu5 expression along with olfactory
bulb, lateral septum, and cortex.33,34
iodine induces different pharmacokinetic property, which
results in the decreased retention time in the brain. The results
indicate that incorporation of iodine-123 impact physicochem-
ical and pharmacological properties, which may include affinity,
lipophilicity, and selectivity. First, although IPEB (1) has shown
good inhibitory activity (IC50 = 0.66 nM)30 against mGlu5, its
affinity may not be as good as that of [18F]FPEB (Ki = 0.20
nM)15 since the IC50 value is not always correlated closely to
the affinity value.35 Second, [123I]1 may have higher lip-
ophilicity than [18F]FPEB, therefore increasing the risk of
nonspecific binding. Finally, the selectivity to other receptors
such as mGlu1 may be different from [18F]FPEB. These
properties will be studied to understand the exact reasons that
cause the fast washout of [123I]1 and to get insight for designing
Time−activity curves (TACs) of (a) [123I]1 and (b)
[18F]FPEB in a mouse model were generated from SPECT
and PET data for striatum, hippocampus, and cerebellum
(Figure 4a,b). TACs of [123I]1 show fast uptake and washout
from brain within the first 20 min of SPECT scanning, while
the corresponding PET ligand [18F]FPEB has fast uptake but
slow washout from striatum and hippocampus and fast washout
from cerebellum, which gave consistent results with previous
study with rats.16 Thus, the structural change from fluorine to
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ACS Medicinal Chemistry Letters
Letter
a suitable SPECT radioligand for mGlu5. However, when TACs
of striatum and hippocampus were divided by TACs of
cerebellum to derive binding ratio, the graphical trends for
AUTHOR INFORMATION
■
Corresponding Author
*(A.-L.B.) E-mail: abrownell@mgh.harvard.edu.
[
123I]1 and [18F]FPEB were similar to each other (Figure 4c,d).
Specificity of [123I]1 was investigated by preinjection of 3-
Funding
Funding was provided by NIBIB-R01EB012864 and NIMH-
R01MH91684 to A.-L.B. Authors would like to acknowledge
supporting grants for the instrumentation 1S10RR029495-01,
1S10RR026666-01, and 1S10RR023452-01.
((2-methyl-4-thiazolyl)ethynyl)pyridine hydrochloride (MTEP·
HCl) (a NAM of mGlu5; 10 mg/kg i.v. 2 min before
radioactivity injection) as a blocking agent for mGlu5. The
SPECT images obtained during 24 min after injection of
radioactivity were summed, and the images obtained in the
baseline study were compared to the data from the blocking
study. Blocking with MTEP·HCl reduced accumulation of
Notes
The authors declare no competing financial interest.
[
123I]1 by 31% in the whole brain, 34% in the hippocampus,
ACKNOWLEDGMENTS
■
and 42% in the striatum (Figure 5). Thus, this study indicates
that [123I]1 has specific binding to mGlu5.
Authors are grateful to Mr. Bryan McIntosh and Ms. Joann
Zhang from TriFoil Imaging for the maintenance and operation
of Triumph-II PET-SPECT-CT Preclinical Imaging System.
ABBREVIATIONS
■
mGlu5, metabotropic glutamate receptor subtype 5; mGluR,
metabotropic glutamate receptor; NAM, negative allosteric
modulator; CNS, central nervous system; PD, Parkinson’s
disease; BBB, blood−brain barrier; SPECT, single photon
emission computed tomography; PET, positron emission
tomography; [18F]FPEB, 3-[18F]fluoro-5-(pyridin-2-ylethynyl)-
benzonitrile; [11C]M-MTEP, 3-([11C]methoxy)-5-((2-methyl-
1,3-thiazol-4-ylethynyl)pyridine; [123I]IPEB, 3-[123I]iodo-5-
(pyridin-2-ylethynyl)benzonitrile; [123I]IMPEB, 3-[123I]iodo-5-
((6-methylpyridin-2-yl)ethynyl)benzonitrile; MTEP·HCl, 3-
((2-methyl-4-thiazolyl)ethynyl)pyridine hydrochloride; tPSA,
polar surface area; RCY, radiochemical yield; TAC, time−
activity curve
Figure 5. Injection of MTEP·HCl (10 mg/kg i.v. 2 min before
radioactivity) reduced accumulation of [123I]1 by 31% in the whole
brain, 34% in the hippocampus, and 42% in the striatum indicating
similar specificity as reported previously for [18F]FPEB.16 Cumulative
accumulation is presented at the time interval 0−24 min.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed procedure and molecular property of chemistry,
radiochemistry, imaging experiments, and supporting data.
1
Spectra of H NMR and 13C NMR are also provided. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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