Syntheses of 2-amino and 2-halothiazole derivatives as high-affinity metabotropic glutamate receptor subtype 5 ligands and potential radioligands for in vivo imaging

Article abstract of DOI:10.1021/jm101430m

The structure of the potent selective mGlu5 ligand, SP203 (1, 3-fluoro-5-[[2-(fluoromethyr)thiazol-4-yl]ethynyl]benzonitrile), was modified by replacing the 2-fluoromethyl substituent with an amino or halo substituent and by variation of substituents in the distal aromatic ring to provide a series of new high-affinity mGlu5 ligands. In this series, among the most potent ligands obtained, the 2-chloro-thiazoles 7a and 7b and the 2-fluorothiazole 10b showed subnanomolar mGlu₅ affinity. 10b also displayed >10000-fold selectivity over all other metabotropic receptor subtypes plus a wide range of other receptors and binding sites. The 2-fluorothiazoles 10a and 10b were labeled using [¹⁸F]fluoride ion (t_1/2 = 109.7 minin moderately high radiochemical yield to provide potential radioligands that may resist troublesome radiodefluorination during the imaging of brain mGlu ₅ with position emission tomography. The iodo compound 9b has nanomolar affinity for mGlu₅ and may also serve as a lead to a potential ¹²³I-labeled ligand for imaging brain mGlu₅ with single photon emission computed tomography.

Full text of DOI:10.1021/jm101430m

J. Med. Chem. 2011, 54, 901–908 901
DOI: 10.1021/jm101430m
Syntheses of 2-Amino and 2-Halothiazole Derivatives as High-Affinity Metabotropic Glutamate
Receptor Subtype 5 Ligands and Potential Radioligands for in Vivo Imaging
ꢀ
Fabrice G. Simeon,* Matthew T. Wendahl, and Victor W. Pike
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3C346A,
10 Center Drive, Bethesda, Maryland 20892-1003, United States
Received November 8, 2010
The structure of the potent selective mGlu5 ligand, SP203 (1, 3-fluoro-5-[[2-(fluoromethyl)thiazol-4-
yl]ethynyl]benzonitrile), was modified by replacing the 2-fluoromethyl substituent with an amino or
halo substituent and by variation of substituents in the distal aromatic ring to provide a series of new
high-affinity mGlu5 ligands. In this series, among the most potent ligands obtained, the 2-chloro-
thiazoles 7a and 7b and the 2-fluorothiazole 10b showed subnanomolar mGlu5 affinity. 10b also
displayed >10000-fold selectivity over all other metabotropic receptor subtypes plus a wide range of
other receptors and binding sites. The 2-fluorothiazoles 10a and 10b were labeled using [18F]fluoride ion
(t1/2 = 109.7 min) in moderately high radiochemical yield to provide potential radioligands that may
resist troublesome radiodefluorination during the imaging of brain mGlu5 with position emission
tomography. The iodo compound 9b has nanomolar affinity for mGlu5 and may also serve as a lead to a
potential 123I-labeled ligand for imaging brain mGlu5 with single photon emission computed tomo-
graphy.
Introduction
role in drug-related behaviors, particularly drug abuse,11 drug
addiction,12 and alcohol withdrawal.13 Hence, mGlu5 antago-
nists may turn out to be useful therapeutics for a variety of
central nervous system disorders.
Glutamate, the predominant excitatoryneurotransmitter in
the central nervous system, promotes fast-synaptic transmis-
sion and synaptic plasticity by activating any one of three ion
channel ionotropic glutamate receptors, namely NMDA,a
AMPA, or kainate receptors.1 Glutamate also has a modula-
tory influence on neuronal excitability by activating metabo-
tropic glutamate receptors (mGluRs), which are members of
the G protein-coupled seven-membrane-domain class of
receptors.2 Eight mGluR subtypes have been identified and
classified according to their sequence homology, signal trans-
duction, and pharmacology.3 Among these subtypes, the
metabotropic glutamate receptor subtype 5 (mGlu5) plays key
roles in a variety of normal brain functions and is also
putatively involved in several neuropsychiatric disorders. Acti-
vation of mGlu5 stimulates phospholipase C, and this results in
phosphoinositide hydrolysis and an increase in intracellular
Ca2þ levels.3,4
We previously reported the discovery of a very potent and
highly selective ligand for mGlu5, which we dubbed SP203 (1,
3-fluoro-5-[[2-(fluoromethyl)thiazol-4-yl]ethynyl] benzonitrile;
Chart 1).14 [18F]1, which has a fluorine-18 (t1/2 = 109.7 min)
label in the 2-fluoromethyl position, is an effective radioligand
for imaging brain mGlu5 receptors in human subjects in vivo
without major complications arising from radiometabolites.15
Only a low amount of radioactivity appears in the skeleton
and that radioactivity is associated with marrow rather than
bone, thereby showing this radioactivity is not present as
[18F]fluoride ion and that metabolic radiodefluorination is
virtually absent.16 [18F]1 is significantly easier to prepare than
previous 18F-labeled mGlu5 radioligands, such as the structurally
related [18F]3-fluoro-5-[(2-methyl-1,3-thiazole-4-yl)ethynyl]-
benzonitrile ([18F]F-MTEB,17 [18F]2; Chart 1), and has broad
potential utility, ranging from receptor occupancy studies pre-
ceding drug clinical trials to studies of mGlu5 receptor expression
in neuropsychiatric patients.
Modulation of mGlu5 receptors has potential for the treat-
ment of schizophrenia,5 fragile X syndrome,6 and Alzheimer’s
disease.7 Further evidence supports the use of antagonists
or modulators of mGlu5 in the treatment of anxiety,8
depression,9 and pain.10 mGlu5 may also play an important
In rat and in monkey, [18F]1 also shows acceptable brain
entry and a sizable receptor-specific signal.14 However, unlike
in human subjects, radiodefluorination occurs,18 leading to
steady accumulation of fluorine-18 in bones and skull. This
radioactivity confounds measurement of rat or monkey brain
mGlu5 receptors with this radioligand and positron emission
tomography (PET).
Although metabolic defluorination often occurs from an
aliphatic carbon,19 this is relatively rare from an aryl carbon.
The thiazole moiety is strongly aromatic. We therefore consid-
ered that a 2-fluoro-thiazole moiety might resist defluorination
*To whom correspondence should be addressed. Phone: 301-451-
3907. Fax: 301-480-5112. E-mail: simeonf@mail.nih.gov.
a Abbreviations: AMPA, R-amino-3-hydroxyl-5-methyl-4-isoxazole-
propionate; DCM, dichloromethane; F-PEB, 3-fluoro-5-[2-methyl-1,3-
thiazol-4-yl)ethynyl]benzonitrile; mGlu, metabotropic glutamate; mGluR,
metabotropic glutamate receptor; M-MTEB, 3-methyl-5-[(2-methyl-1,3-thia-
zol-4-yl)ethynyl]benzonitrile; MPEP, 2-methyl-6-(phenylethynyl)pyridine;
NCA, decay-corrected radiochemical yield; NMDA, N-methyl-D-aspar-
tate; PET, positron emission tomography; RCY, decay-corrected radio-
chemical yields; SPECT, single photon emission computed tomography.
r
2011 American Chemical Society
Published on Web 01/05/2011
pubs.acs.org/jmc

902 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 3
Simeꢀon et al.
in vivo, unlike the 2-fluoromethylthiazole moiety of 1 when in
monkey or rat. One report suggests that fluorination on a
thiazole ring might increase stability toward ring metabolism.20
Here we report the synthesis of a series of compounds
related to 1 in which the 2-fluoromethylthiazole moiety in 1
was replaced with a halogen, including fluorine, or with an
amino group. The substitution pattern in the distal phenyl
ring was also varied. We report the affinities of these new
ligands toward mGlu5 receptors. Finally, we describe the
labeling of some of the novel 2-fluorothiazoles to produce
candidate 18F-labeled PET mGlu5 radioligands.
(cLogD = 3.31). These values are within the range usually
considered desirable for a prospective brain imaging agent.21
In accord with this guideline, [18F]1, in rodents and primates,
shows good penetration of the blood-brain barrier, has high
peak uptake in brain, and shows relatively low nonspecific
binding.14
Chemistry
The 2-amino compounds (6a-d, Scheme 1) were prepared
bySonogashiracross-couplingofthe aminothiazole4 withthe
appropriate haloarenes. Yields were low from bromoarenes
(<30%) but moderate to high from iodoarenes (60 to ∼90%).
Therefore, iodoarenes were used in all coupling reactions. The
amines 6a-d were then halogenated regioselectively22 with
CuX (X = Cl, Br, I) in the presence of n-butyl nitrite to give
the 2-chloro (7a-d), 2-bromo (8a-d), and 2-iodo derivatives
(9a-d) (Table 1). Yields increased with halogen size. Thus,
yields for chlorination were low and typically in the range
15-25%. Yields for bromination and iodination were usually
over 50% (Table 1).
Because the 2-chloro derivatives 7a-d could only be ob-
tained in small amounts and their purifications were tedious,
we decided to explore an alternative synthesis to improve their
yields. We considered that the use of the 2-chlorothiazole
synthon 5 (Scheme 1) in a Sonogashira cross-coupling reac-
tion might lead to higher yields. Synthon 5 was prepared by
reaction of the easily accessible compound 4 with CuCl and
n-butyl nitrite and submitted to Sonogoshira cross-coupling.
Yields of the 2-chloro compounds 7a-d from cross-coupling
reactions with 5 were greatly improved (48-67%). The
purifications of the 2-chloro products were also easier than
those for the amino compounds 6a-d. Noticeably, during the
cross-coupling reactions, no coupling was observed at posi-
tion 2 of the 2-chloro-thiazole acetylene 5.
Results and Discussion
Our primary goal was to produce high-affinity mGlu5
ligands that would be suitable for development as 18F-labeled
ligands for imaging brain mGlu5 in animals without being
susceptible to troublesome radiodefluorination. We consid-
ered that this aim might be achieved by modifying [18F]1 so
that the fluorine-18 atom was directly bound to the thiazole
ring at the 2-position. Computation indicated that this mod-
ification, the replacement of a fluoromethyl group with a
single fluorine atom, would not greatly alter lipophilicity. For
example, the cLogD value of the 2-fluoro compound 10b is
3.58 and similar to that of the 2-fluoromethyl analogue 1
Chart 1. Structures of Some mGlu5 Ligands and Derived PET
Radioligands
With the 2-chloro, 2-bromo, and 2-iodo compounds avail-
able, we aimed to prepare the corresponding 2-fluorothia-
zoles. The use of electrophilic reagents, either Accufluor23 or
Selectfluor,24 gave almost negligible yields (1-5%) of the
desired fluorinated products. Therefore, we next investigated
direct nucleophilic substitution in the halo precursors with
potassium fluoride. We recently reported a procedure for the
rapid fluorination of 2-chloro and 2-bromothiazole deriva-
tives under microwave irradiation,25 and we looked to apply
Scheme 1a
a Reagents and conditions: (i) CuCl, n-BuNO2; 30-67%; (ii) PdPPh4, ArI, Et3N, TBA, DME, 62-89%; (iii) CuX, n-BuNO2 (X = Br or I), 32-83%.
See Table 1 for identity of R1 and R2.

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 3 903
Scheme 2a
Table 1. Ligand Yields, Lipophilicities, and mGlu5 Affinities
entry
X
R1
R2
CN
yield (%)
cLogDa
Ki (nM)b
0.03614
1
FCH2
Me
NH2
NH2
NH2
NH2
Cl
F
NA
NA
71
3.66 (2.18)14
3.42
2.52
2
F
CN
CN
CN
0.08 ( 0.0217
0.90 ( 0.19
0.25 ( 0.04
5.90 ( 0.95
18.6 ( 0.38
0.27 ( 0.04
0.40 ( 0.09
3.10 ( 0.46
8.10 ( 1.36
3.70 ( 0.25
0.95 ( 0.10
3.30 ( 0.53
22.3 ( 0.50
4.20 ( 0.50
1.30 ( 0.23
23.3 ( 3.53
132.9 ( 2.54
1.60 ( 0.11*
0.28 ( 0.05*
3.90 ( 0.56
22.7 ( 0.28
122 ( 3.3
6a
6b
6c
H
F
62
3.06
2.49
H
H
H
F
CH2CN 86
6d
7a
7b
7c
OMe
CN
CN
CH2CN 67c
89
2.72
2.88
56c
64c
Cl
Cl
3.41
2.99
H
H
H
F
a Reagents and conditions: (i) KF, K 2.2.2 DMSO or MeCN, MW 130 °C,
10 min, 24-78%; (ii) KF-AgF, DMSO, MW, 130 °C, 8 min, 62%. See
Table 1 for identities of R1 and R2.
7d
8a
8b
8c
Cl
OMe
CN
CN
48c
32d
48
3.44
3.38
Br
Br
Br
Br
I
3.95
3.48
H
H
H
F
CH2CN 61
([3H]2-methyl-6-phenylethynyl)pyridine as reference radioli-
gand. The majority of the prepared 2-halo-thiazoles exhibited
high affinity, with Ki values in the nanomolar range. In
general, the 2-iodo compounds had lower affinity than their
bromo, chloro, or fluoro analogues. Unexpectedly, the amino
compound intermediates 6a-d also exhibited high to very
high affinity for mGlu5. The substituent pattern in the distal
aryl group strongly influenced affinity for mGlu5. Thus, the
combination of fluoro and nitrile substituentsin metaposition
to the alkynyl group, as also exists in 1, generally gave the
highest affinity among each subset of 2-substituted thiazoles.
Removal of the meta-fluoro substituent generally had little
effect. A single meta cyanomethyl or methoxy group reduced
affinity appreciably, especially a methoxy group.
The high-affinity 2-fluoro ligand 10b was screened for
affinity at other mGluR subtypes (mGlu1, mGlu2, mGlu4,
mGlu6, mGlu7, and mGlu8) and a panel of other brain
receptors, binding sites, and ion channels as listed under the
Experimental Section. In all cases, the affinity of 10b was
found to be >10000 nM. Therefore, replacement of the 2-fluoro-
methyl group in 1 with a fluoro substituent retained excellent
mGlu5 selectivity. Such excellent selectivity is highly desirable in
a prospective PET radioligand.
Currently, no effective radioligand exists for imaging brain
mGlu5 with single photon emission computed tomography
(SPECT). Interestingly, the iodo compounds 9a and 9b show
mGlu5 affinity in the nanomolar range and are possibly suitable
for labeling with iodine-123 to provide candidate radioligands
for imaging brain mGlu5 with single photon emission computed
tomography (SPECT). The highest affinity iodinated ligand 9b
has affinity that almost matches that of PET radioligands, such
as [11C]M-MTEB ([11C]3-methyl-5-[(2-methyl-1,3-thiazol-
4-yl)ethynyl] benzonitrile) and [18F]F-PEB ([18F]3-fluoro-5-[2-
methyl-1,3-thiazol-4-yl)ethynyl] benzonitrile), that have been
shown to give strong receptor-specific signals in monkeys.17 The
computed lipophilicity of 9b appears quite high for a prospective
SPECT radioligand. However, this computed value, and also
those for the other ligands, may be considerably overestimated
because the true value for ligand 1 is much lower than that for its
computed value (Table 1).
8d
9a
9b
9c
OMe
CN
CN
59
83
71
3.86
3.56
I
4.21
3.63
I
H
H
H
F
CH2CN 62
50
9d
10a
10b
10c
10d
10e
I
OMe
CN
CN
3.96
24, 75e 3.12
35, 72e 3.58
F
F
F
H
H
H
CH2CN 43, 78 e 3.18
F
OMe
H
33, 65e 3.56
46, 78f 3.38
F
a cLogD values were calculated with Pallas 3.7.1.1 software (Compu-
Drug Chemistry Ltd), except for the value in parentheses which is a
measured value. b Values were determined in triplicate from rat brain
homogenates, except those marked * (n = 6). c Obtained by coupling
from compound 5. d Value reported in ref 22. e From the 2-bromo and
2-chloro-thiazoles, respectively (each treated with KF in DMSO at 130 °C).
f From the 2-bromo- and 2-chloro-thiazoles, respectively.25
this method to obtain the target 2-fluoro ligands. By treating
bromides 8a-d with a potassium fluoride-Kryptofix 2.2.2 (K
2.2.2) complex in DMSO under microwave irradiation (30 W,
130 °C, 8-15 min), the respective 2-fluoro compounds 10a-d
were obtained in useful 24-43% yields (Table 1).
When the 2-chloro-precursors 7a-d were treated similarly
(KF-K 2.2.2, DMSO, MW, 130 °C, 10-15 min), the fluorina-
tion yields were dramatically improved, reaching 78% in the
case of 10c. By contrast, only negligible product was detected
when the iodo precursor 9a was submitted to nucleophilic
fluorination (yield, < 5%). These results accord with our
previous observations on leaving group ability in the nucelo-
philic fluorination of simpler 2-halo-thiazoles.25
For the synthesis of 10a, wealsoexperimentedwiththeuseofa
KF-AgF with the bromo precursor 8a under microwave irradia-
tion (Scheme 2). After 8 min of irradiation, the yield of 10a
reached 62%, as measured with HPLC. However, this fluorina-
tion method was less reproducible and we also observed the
reduction of DMSO into the irritant and volatile dimethyl sulfide.
The 2-chloro and 2-bromo-(4-phenylacetylene)thiazoles 7e
and 8e were also subjected to fluorination with KF in DMSO,
as reported previously, to give the fluoro derivative 10e in 78
and 46% yields, respectively.25
Pharmacology
Radiochemistry
The affinity of each new ligand for rat brain tissue
mGlu5 was determined in a binding assay with [3H]MPEP
We previously reported reaction conditions for the prepara-
tion of [18F]2-fluorothiazole derivatives with cyclotron-produced

904 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 3
Simeꢀon et al.
Scheme 3a
a Reagents and conditions: (i) [18F]FK, K 2.2.2., DMSO or MeCN, MW, 130 °C, 10 min, 26% RCY; (ii) [18F]FK, K 2.2.2., MeCN, MW, 110 °C,
10 min, 26-48% RCY.
no-carrier-added (NCA) [18F]fluoride ion under thermal and
microwave heating conditions.25 We established that simple
2-chlorothiazole structures label efficiently with [18F]fluoride
ion in the presence of Kþ-K 2.2.2 in DMSO or MeCN. The
radiochemical yield was slightly higher for 2-chlorothiazoles
than for 2-bromothiazoles. These conditions were applied suc-
cessfully for the radiosynthesis of [18F]10a from the chloro
compound 7a. Thus, at 130 °C in DMSO under inert atmosphere
and with brief microwave heating (90 W, 150 °C, 10 min),
[18F]10a was obtained in 36% decay-corrected radiochemical
yields (RCY) and with a measured specific activity of 2.1 Ci/μmol
at the end of synthesis.
Because of its high affinity, we then selected 10b as the
major target for labeling with fluorine-18. The chloro com-
pound 7b was selected as precursor for radiofluorination. The
conversion of 7b into [18F]10b was initially attempted using
the reaction conditions mentioned above. Reaction for 10 min
at 130 °C gave decay-corrected RCYs of 26% (Scheme 3).
Unexpectedly, under these conditions, some exchange of the
aryl fluoro group with [18F]fluoride ion was also observed and
[18F]7b was detected as a byproduct of radiofluorination.
Typically, with the use of anhydrous DMSO at 130 °C, the
ratio of [18F]10b to [18F]7b was 45:55. The use of anhydrous
acetonitrile under similar conditions (K 2.2.2-K2CO3; MW,
130 °C) switched the major labeled product to [18F]10b
([18F]10b:[18F]7b; 82:18). In acetonitrile, when the tempera-
ture of reaction was lowered to 110 °C and the incorporation
of [18F]fluoride ion was up to 48%, with the ratio of [18F]10b
to [18F]7b being 92:8.
be feasible to provide new candidate radioligands, [18F]10a and
[18F]10b, for mGlu5 imaging with PET. A candidate, 9b, for
development as a SPECT radioligand for imaging brain mGlu5,
was also identified.
Experimental Section
Materials and General Methods. 5-Amino-3-fluorobenzoni-
trile was obtained from Oakwood Products, Inc. All other
reagents and solvents were obtained from Sigma-Aldrich in
the highest purity available (g98%) and were used as purchased.
All reactions were performed under argon atmosphere unless
otherwise indicated. 4-((Trimethylsilyl)ethynyl)thiazol-2-amine
(4),26 3-((2-fluorothiazol-4-yl)ethynyl) benzonitrile (10b),25 and
2-fluoro-4-(phenylethynyl)thiazole (10e)25 were prepared as
described previously. Thin layer chromatography (TLC) was
performed with silica gel layers (type 60 F254; 400-630 mesh)
with compounds visualized under UV light (λ = 254 nm).
Column chromatography was performed on silica gel with
hexane-EtOAc mixtures as eluents. Constituent proportions
in chromatographic mobile phases are expressed by volume.
Separation of compounds with HPLC was performed on a Luna
column (10 μm, 250 mm ꢀ 10 mm, Phenomenex, Torrance, CA)
eluted with H2O-MeCN. The purities of all new compounds
were determined by HPLC on a Luna C18 column (5 μm,
250 mm ꢀ 4.6 mm, Phenomenex) eluted isocratically with
H2O-MeCN and were greater than 95%. All HPLC eluates
were monitored for absorbance at 254 nm. Yields were recorded
for chromatographically pure materials (g98%).
The 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra of
all compounds were acquired in CDCl3 using the chemical shift
of residual deuterated solvent as internal standard; chemical
shifts (δ) for the proton and carbon resonance are reported in
parts per million (ppm) downfield from TMS (δ = 0). The
following abbreviations were used to describe peak splitting
patterns when appropriate: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, dd = double of doublet. 19F-NMR
(376.5 MHz) spectra were acquired in CDCl3 in the presence of
CFCl3 as internal standard (δ = 0). Mass spectra were acquired
with either a GC-MS instrument equipped with a capillary
RTX-5 ms column (30 m ꢀ 0.25 mm; flow rate, 1 mL/min;
carrier gas, He) or by LC-MS. LC-MS analyses were performed
on a LCQ Deca MS instrument interfaced with a Surveyor
HPLC pump and autosampler (Thermo Fisher Scientific,
Waltham, MA). High-resolution mass spectra were acquired
with ESI.
The radioligands were easily purified by HPLC in high
chemical purity (>95%) and high radiochemical purity
(>99%). The specific activity of the target compound
[18F]10b, was 0.5 Ci/μmol at the end of synthesis (about 150
min from the end of radionuclide production) and somewhat
lower than for [18F]10a, probably because of the 18F for F
exchange occurring in precursor 7b. Nonetheless, this new
radioligand now merits further evaluation with PET in ani-
mals to assess its resistance to radiodefluorination and effi-
cacy for imaging brain mGlu5.
Conclusions
Several new 2-amino and 2-halo-thiazole-4-(alkynylbenzenes)
were synthesized, and they showed moderate to high affinity as
ligands at mGlu5 in rat brain tissue. The labeling of some of the
2-fluorothiazole derivatives with [18F]fluoride ion was shown to
3-Fluoro-5-iodobenzonitrile (3). 3-Amino-5-fluorobenzoni-
trile (2.72 g, 20 mmol) was treated with n-butyl nitrite (3.09 g,
35.6 mmol) and CuI (5.71 g, 30 mmol) in MeCN (30 mL) at
80 °C. The mixture was refluxed for 20 min, and allowed to cool

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 3 905
to rt. Then the solvent was evaporated off. The residue was
suspended in water (20 mL) and extracted twice with DCM (2 ꢀ
25 mL). The organic layers were combined, washed with
brine (15 mL), dried over MgSO4, and evaporated to dryness
under vacuum. Chromatography of the residue on silica gel
(hexane-EtOAc; 90:10, v/v) gave 3 as yellow crystals (2.32 g;
159.5, 133.3, 129.6, 124.4, 123.8, 116.5, 115.5, 113.5, 88.3, 83.9,
55.5. HRMS (ESIþ): calcd for C12H11N2OS 231.0585, found
231.0592. HPLC purity: 97.22%.
3-((2-Chlorothiazol)-4-yl)ethynyl)benzonitrile (7a). Compound 5
(431 mg, 2.0 mmol), 3-iodobenzonitrile (650 mg, 2.85 mmol),
CuI (25 mg, 0.12 mmol), Pd(PPh3)4 (74 mg, 0.7 mmol), and Et3N
(1.2 mL) were added to dimethylethylene glycol (10 mL) under
argon. Argon was bubbled into the resulting dark solution while it
was heated to 80 °C. A solution of TBAF (1.0 M) in THF (2.5 mL)
was added via syringe over 25 min. The reaction mixture was stirred
at 80 °C. After 15 min, TLC showed no starting material present.
The reaction mixture was then cooled to rt and evaporated to
dryness. The residue was dissolved in EtOAc (25 mL) and then
washed with water (2 ꢀ 40 mL) and brine (1 ꢀ 40 mL). The
combined organic fractions were dried over MgSO4 and evaporated
to dryness in vacuo. Chromatography of the residue on silica gel
(hexane-EtOAc, 85:15, v/v) gave 7a as a brown solid (274 mg;
56%); mp 118-120 °C. 1H NMR: δ 7.81 (t, J = 1.4 Hz, 1H), 7.75
(dt, J1 = 7.88 Hz, J2 = 1.34 Hz, 1H), 7.65 (dt, J1 = 7.84 Hz, J2 =
1.33 Hz, 1H), 7.58 (s, 1H), 7.49 (t, J = 7.86 Hz, 1H). 13C NMR: δ
138.1, 136.6, 135.2, 133.2, 132.7, 129.9, 126.1, 123.7, 117.1, 114.4,
87.5, 84.8. HRMS (ESIþ): calcd for C12H679BrN2S 244.9936,
found 244.9940. HPLC purity: 99.11%.
3-((2-Chlorothiazol)-4-yl)ethynyl)-5-fluorobenzonitrile (7b).
This compound was prepared from 5 and 3-fluoro-5-iodoben-
zonitrile with the method and chromatography described for 7a
and gave 7b as a yellow powder (335 mg; yield, 64%); mp
120-121 °C. 1H NMR: δ 7.62 (s, 1H), 7.49 (s, 1H), 7.46
(m, 1H), 7.36 (m, 1H). 13C NMR: δ 161.9 (d, J = 251.85 Hz),
152.3, 135.1, 131.2 (d, J = 3.56 Hz), 125.9, 123.2 (d, J = 23.07
Hz), 119.5 (d, J = 24.80 Hz), 116.7, 114.4 (d, J = 10.22 Hz),
85.9, 84.6. 19F-NMR: δ -109.12 (s, 1F). HRMS (ESIþ): calcd
for C12H5ClFN2S 262.9841, found 262.9844. HPLC purity:
98.75%.
1
yield, 47%); mp 29-30 °C. H NMR: δ 7.80 (s, 1H) 7.71 (m,
1H), 7.36 (m, 1H). 13C NMR: δ 161.6 (d, J = 256.03 Hz), 136.7
(d, J = 3.8 Hz), 129.1 (d, J = 23.20 Hz), 118.7 (d, J = 24.34 Hz),
115.9 (d, J = 3.23 Hz), 115.3 (d, J = 9.59 Hz), 93.9 (d, J =
8.23 Hz). 19F-NMR: δ -107.54 (s, 1F). GC-MS m/z: 247.94
[M þ H] þ
.
2-Chloro-4-((trimethylsilyl)ethynyl)thiazole (5). 4-(Trimethyl-
silyl)ethynyl)thiazol-2-amine (4; 2.25 g, 11.48 mmol) and CuCl
(2.85 g, 28.78 mmol) were dissolved in MeCN (25 mL) at rt.
n-Butyl nitrite (1.6 mL, 13.7 mmol) was added with stirring, and
the solution was heated to 75 °C. TLC showed the reaction to be
complete after 45 min. The reaction mixture was then evapo-
rated to dryness under vacuum. The residue was dissolved in
ethyl acetate (20 mL) and washed with ammonia solution (0.1M;
2 ꢀ 50 mL). The organic layer was dried over MgSO4 and
evaporated to dryness under vacuum. Chromatography of the
residue on silica gel (hexane-EtOAc; 95:5, v/v) gave 5 as a white
powder (750 mg; yield, 30%); mp 67-68 °C. 1H NMR: δ 7.34
(s, 1H), 0.25 (s, 9H). 13C NMR: δ 151.1, 136.7, 125.2, 97.4, 96.3,
0.0. HRMS (ESIþ): calcd for C8H11NClSSi 207.0070, found
207.0067. HPLC purity: 98.45%.
3-[(2-Aminothiazol)-4-ethynyl]benzonitrile (6a). Compound 4
(375 mg, 1.91 mmol), 3-iodobenzonitrile (650 mg, 2.85 mmol),
CuI (25 mg, 0.12 mmol), Pd(PPh3)4 (74 mg, 0.7 mmol), and
Et3N(1.2 mL) were added to dimethylethylene glycol (10 mL)
under argon. Argon was bubbled into the resulting dark solu-
tion while it was heated to 80 °C. A solution of TBAF (1.0 M) in
THF (2.5 mL) was then added via syringe over 25 min. The
reaction mixture was heated at 80 °C until TLC showed no
starting material present (15 min) and then cooled to rt and
evaporated to dryness. The residue was dissolved in EtOAc
(25 mL) and then washed with water (2 ꢀ 40 mL) and brine
(1 ꢀ 40 mL). The combined organic fractions were dried over
MgSO4 and evaporated to dryness in vacuo. Chromatography
of the residue on silica gel (hexane-EtOAc, 70:30, v/v) gave 6a
(230 mg; yield, 54%) as a brown solid; mp 154-155 °C. 1HNMR:δ
7.52 (m, 2H), 7.33 (m, 2H), 6.78 (s, 1H). 13C NMR: δ 166.6, 133.1,
131.7, 128.5, 128.3, 122.6, 113.15, 88.1, 83.9. HRMS (ESIþ): calcd
for C11H9N2S 201.0486, found 201.0485. HPLC purity: 99.75%.
3-[(2-Aminothiazol)-4-ethynyl]-5-fluorobenzonitrile (6b). This
compound was prepared from 4 and 3-fluoro-5-iodobenzoni-
trile with the method and chromatography described for 6a and
gave 6b as a brown powder (288 mg; yield, 62%); mp 209-
210 °C. 1H NMR: δ 7.64 (m, 1H), 7.59 (s, 1H), 7.55 (m, 1H), 7.44
(m, 1H). 13C NMR:δ166.5 (d, J = 256.10 Hz), 160.7, 152.3, 135.1,
131.2 (d, J = 3.56 Hz), 125.9, 123.1 (d, J = 22.86 Hz), 118.9 (d,
J = 24.76 Hz), 116.7, 115.3 (d, J = 10.10 Hz), 85.9, 84.6. 19F-
NMR: δ -109.18 (s, 1F). HRMS (ESIþ): calcd for C11H9N2S
244.0345, found 244.0334. HPLC purity: 97.32%.
2-(3-((2-Aminothiazol-4-yl)ethynyl)acetonitrile (6c). This com-
pound was prepared from 4 and 2-(3-iodophenyl)acetonitrile with
the method and chromatography described for 6a and gave 6c as a
brown powder (395 mg; yield, 86%); mp 154-156 °C. 1H NMR: δ
7.47 (m, 2H), 7.30 (t, J = 7.80 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H),
6.82 (s, 1H), 3.75 (s, 2H). 13C NMR: δ 166.7, 159.5, 133.3 (2 C),
129.6, 124.4, 123.8, 116.5, 115.5, 113.5, 88.3, 83.9, 22.4. HRMS
(ESIþ): calcd for C12H7FN3S 240.0591, found 240.0595. HPLC
purity: 96.40%.
4-(3-Methoxyphenyl)ethynyl(thiazol)-2-amine (6d). This com-
pound was prepared from 4 and 1-iodo-3-methoxybenzene with
the method and chromatography described for 6a and gave 6d as
a yellow powder (392 mg; yield, 89%); mp 94-95 °C. 1H NMR:
δ 7.24 (t, J = 7.64 Hz, 1H), 7.12 (d, J = 7.60 Hz, 1H), 7.05 (s,
1H), 6.89 (m, 1H), 6.78 (s, 1H), 3.80 (s, 3H). 13C NMR: δ 166.8,
2-(3-((2-Chlorothiazol)-4-yl)ethynyl)-phenyl)acetonitrile (7c).
This compound was prepared from 5 and 2-(3-iodophenyl)-
acetonitrile with the method and chromatography described for
7a and gave 7c as a beige powder (346 mg; yield, 67%); mp
1
108-110 °C. H NMR: δ 7.52 (m, 1H), 7.50 (m, 1H), 7.43 (s,
1H), 7.36 (m, 2H), 3.75 (s, 2H). 13C NMR: δ 150.7, 135.0, 130.4,
130.1, 129.3, 128.3, 127.4, 123.5, 122.0, 116.3, 87.6, 82.2, 22.4.
HRMS (ESIþ): calcd for C13H8ClN2S 259.0097, found
259.0098. HPLC purity: 98.62%.
2-Chloro-4-((3-methoxyphenyl)ethynyl)thiazole (7d). This com-
pound was prepared from 5 and 1-iodo-3-methoxybenzene with
the method and chromatography described for 7a and gave 7d as
a light-yellow powder (238 mg; yield, 48%); mp 88 °C. 1H NMR:
δ 7.39 (s, 1H), 7.26 (t, J = 7.96 Hz, 1H), 7.15 (m, 1H), 7.07 (m,
1H), 6.93 (m, 1H), 3.81 (s, 3H). 13C NMR: δ 159.3, 151.6, 136.4,
129.5, 124.4, 124.1, 122.9, 116.5, 115.9, 89.7, 82.1, 55.3. HRMS
(ESIþ):calcd for C12H9ClNOS250.0093, found 250.0097. HPLC
purity: 99.08%.
3-((2-Bromothiazol)-4-ethynyl)-5-fluorobenzonitrile (8b). The
2-aminothiazole derivative 6b (0.245 g, 1 mmol) and CuBr (0.2 g,
1.39 mmol) were dissolved in MeCN (8 mL) at rt. n-Butyl nitrite
(162 μL, 1.39 mmol) was added with stirring, and the solution
was heated to 60 °C. The reaction was complete after 15 min, as
monitored by TLC. The reaction mixture was then evaporated
to dryness in vacuo. The residue was dissolved in EtOAc (20 mL)
and washed with ammonia solution (0.1 M; 2 ꢀ 50 mL). The
organic layer was dried over MgSO4 and evaporated to dryness
in vacuo. Chromatography of the residue on silica gel
(hexane-EtOAc; 97:3, v/v) gave 8b (150 mg; yield, 48%); mp
139-140 °C. 1H NMR: δ 7.62 (t, J1 = 1.28 Hz, 1H), 7.54 (s, 1H),
7.47 (ddd, J1 = 8.72 Hz, J2 = 1.36 Hz, J2 = 1.12 Hz, 1H), 7.36
(ddd, J1 = 7.82 Hz, J2 = 1.40 Hz, J2 = 1.12 Hz, 1H). 13C NMR:
δ 161.9 (d, J = 251.71 Hz),136.6, 136.3 (d, J = 32.20 Hz), 131.2
(d, J = 3.56 Hz), 127.6, 125.7 (d, J = 10.08 Hz), 123.2 (d, J =
23.50 Hz), 119.5 (d, J = 24.57 Hz), 116.7, 114.4 (d, J = 10.20
Hz), 86.2 (J = 3.45 Hz), 85.3. 19F-NMR: δ -108.7 (s, 1F).

906 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 3
Simeꢀon et al.
HRMS (ESIþ) calcd for C12H5BrFN2S 306.9335, found
306.9338. HPLC purity: 98.45%.
1H), 7.48 (t, J= 8.0 Hz, 1H) 7.18 (d, J2 = 1.6 Hz, 1H). 13CNMR:δ
169.1 (d, J = 285.7 Hz), 135.8, 135.0, 132.2, 130.0 (d, J = 19.2 Hz),
129.4, 123.6, 119.7 (d, J = 5.03 Hz), 117.8, 113.1, 86.6, 84.9. 19F-
NMR: δ -77.7 (s, 1F). HRMS (ESIþ): calcd for C12H6FN2S
229.0231, found 229.0236. HPLC purity: 99.85%.
3-((2-Fluorothiazol-4-yl)ethynyl)-5-fluorobenzonitrile (10b). The
method described for 10a was applied to 7b and gave 10b as a white
powder (65 mg; yield, 72%); mp 128-130 °C. 1H NMR: δ 7.81 (t,
J=1.4Hz, 1H), 7.75(dt, J1 =7.88Hz, J2 = 1.34 Hz, 1H), 7.65 (dt,
J1 = 7.84 Hz, J2 = 1.33 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H) 7.18 (d,
J2 = 1.6 Hz, 1H). 13C NMR: δ 169.2 (d, J = 286.0 Hz), 161.9 (d,
J = 251.7 Hz), 131.2 (d, J = 3.5 Hz), 129.6 (d, J = 19.1 Hz), 125.7
(d, J = 9.7 Hz), 123.2 (d, J = 22.8 Hz), 120.5 (d, J = 4.9 Hz), 119.5
(d, J= 24.8 Hz), 115.4, 114.4 (d, J= 10.2 Hz), 86.6, 84.9 (d, J=3.6
Hz). 19F-NMR: δ -109.02 (s, 1F), -77.2 (s, 1F). HRMS (ESIþ):
calcd for C12H5F2N2S 247.0142, found 247.0133. HPLC purity:
100.00%.
2-(3-((2-Fluorothiazol-4-yl)ethynyl)phenyl)acetonitrile (10c). The
method described for 10a was applied to 7c and gave 10c as a beige
powder (68 mg; yield, 78%); mp 106-108 °C. 1H NMR: δ 7.52 (m,
2H), 7.47 (s, 1H), 7.35 (m, 2H), 3.76 (s, 2H). 13C NMR: δ 170.1 (d,
J = 285.1 Hz), 137.9, 136.1, 131.5 (d, J = 30.1 Hz), 131.4, 130.5,
129.5, 128.7, 126.4, 123.3, 117.5, 89.2, 83.2, 23.6. 19F-NMR:
δ -78.05 (s, 1F). HRMS (ESIþ): calcd for C13H8FN2S 243.0389,
found 243.0383. HPLC purity: 98.85%.
2-Fluoro-4-((3-methoxyphenyl)ethynyl)thiazole (10d). The meth-
od described for 10a was applied to 7d and gave 10d as a white
crystals (70 mg; yield 65%); mp 64-66 °C. 1H NMR: δ 7.26 (t, 1H,
J = 7.94 Hz), 7.12 (dt, 1H, J = 7.96 Hz, J = 1.20 Hz), 7.10 (s, 1H),
7.06 (dd, 1H, J= 2.6 Hz, J= 1.40 Hz), 6.92 (ddd, 1H, J= 8.32Hz,
J = 2.60 Hz), 3.81 (s, 3H). 13C NMR: δ 169.2 (d, J = 284.80 Hz),
159.5, 130.9 (d, J = 18.87 Hz), 129.7, 124.6, 123.1 (1C), 118.6 (d,
J = 4.70 Hz), 116.7, 116.0, 89.4, 82.7, 55.5. 19F-NMR: δ -78.23 (s,
1F). HRMS (ESIþ): calcd for C12H9FNOS 234.0389, found
234.0383. HPLC purity: 98.95%.
2-(3-((2-Bromothiazol-4-yl)ethynyl)phenyl)acetonitrile (8c). This
compound was prepared from the 2-aminothiazole derivative 6c
with the method described for 8b. Chromatography (hexane-
EtOAc, 95:5, v/v) gave 8c as a white powder (185 mg; yield,
1
61%); mp 110-111 °C. H NMR δ 7.51 (m, 2H), 7.47 (s, 1H),
7.37 (m, 2H), 3.76 (s, 2H). 13C NMR δ 137.9, 136.1, 131.7, 131.4,
130.5, 129.5, 128.7, 126.4, 123.3, 117.5, 89.2, 83.2, 23.6. HRMS
(ESIþ): calcd for C13H8BrN2S 302.9592, found 302.9587. HPLC
purity: 98.08%.
2-Bromo-4-((3-methoxyphenyl)ethynyl)thiazole (8d). This com-
pound was prepared from the amino-thiazole derivative 6d with the
method and chromatography described for 8c and gave 8d as a
white powder (175 mg; yield, 59%); mp 98 °C. 1H NMR: δ 7.44 (s,
1H), 7.25 (t, J = 8.01 Hz, 1H), 7.14 (m, 1H), 7.08 (m, 1H), 6.92 (m,
1H), 3.81 (s, 3H). 13C NMR: δ 159.5, 138.2, 135.9, 129.7, 126.0,
124.5, 123.1, 116.7, 116.1, 90.2, 82.0, 55.5. HRMS (ESIþ): calcd for
C12H9BrNOS 293.9588, found 293.9594. HPLC purity: 97.91%.
3-[(2-Iodothiazol)-4-ethynyl]-benzonitrile (9a). This compound
was prepared from 6a with the method described for 8b but with
CuI in place of CuBr. Chromatography (hexane-EtOAc, 95:5, v/v
gave 9a as a beige powder (280 mg; yield 83%); mp 118-120 °C. 1H
NMR: δ 7.81 (t, J = 1.4 Hz, 1H), 7.76 (dt, J1 = 7.60 Hz, J2 = 1.32
Hz, 1H), 7.65 (dt, J1 = 7.64 Hz, J2 = 1.32 Hz, 1H), 7.53 (s, 1H),
7.49 (t, J = 8.00 Hz, 1H). 13C NMR: δ 138.1, 136.6, 135.2, 133.2,
132.7, 129.9, 126.1, 123.7, 117.1, 114.4, 87.5, 84.8. HRMS (ESIþ):
calcd for C12H6IN2S 336.9296, found 336.9307. HPLC purity:
98.25%.
3-((2-Iodothiazol)-4-ethynyl)-5-fluorobenzonitrile (9b). This com-
pound was prepared from 6b with the method described for 9a.
Chromatography (hexane-EtOAc, 90:10, v/v) gave 9b as a light-
yellow powder (250 mg; yield 71%); mp 158-160 °C. 1H NMR: δ
7.62 (s, 1H), 7.56 (s, 1H), 7.47 (m, 1H), 7.36 (m, 1H). 13C NMR: δ
161.9 (d, J = 251.76 Hz), 138.5, 131.2 (d, J = 3.51 Hz), 130.1, 125.8
(d, J = 10.01 Hz), 123.2 (d, J = 22.95 Hz), 119.4 (d, J = 24.76 Hz),
116.7 (d, J = 3.05 Hz), 114.4 (d, J = 10.18 Hz), 100.7, 86.5 (d, J =
3.31 Hz), 85.0. 19F-NMR: δ -108.7 (s, 1F). HRMS (ESIþ): calcd
for C12H5FIN2S 354.9202, found 354.9192. HPLC purity: 99.05%.
2-(3-((2-Iodothiazol-4-yl)ethynyl)phenyl)acetonitrile (9c). This
compound was prepared from 6c with the method described for 9b.
Chromatography (hexane-EtOAc, 90:10, v/v) gave 9c as a beige
powder (215 mg; yield 62%); mp 120-122 °C. 1H NMR: δ 7.52 (m,
2H), 7.50 (s, 1H), 7.37 (m, 2H), 3.76 (s, 2H). 13C NMR: δ 139.7,
131.7, 131.4, 130.5, 129.5, 128.9, 128.6, 123.3, 117.5, 100.3, 89.5,
82.8, 23.6. HRMS (ESIþ): calcd for C13H8IN2S 350.9453, found
350.9443. HPLC purity: 97.77%.
mGlu5 Binding Assay and Pharmacological Screen. The pre-
pared ligands were assayed for binding to rat brain mGlu5
receptors by the National Institute of Mental Health (NIMH)
Psychoactive Drug Screening Program (PDSP) in an assay using
[3H]MPEP (1.0 nM) as radioligand.
The high-affinity ligand 10b was also screened by the PDSP
for binding to a wide variety of receptor and binding sites
(5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT2A, 5-HT2B, 5-HT2C
5-HT3, 5-HT5A, 5-HT6,7, R1A, R1B, R1D, R2A, R2B, R2C, β1-3
BZP rat brain site, D1-5, DAT, DOR, GABAA, KOR, H1-4
,
,
,
M1-5, mGlu1, mGlu2, mGlu4, mGlu6, mGlu8, MOR, NET,
NMDA PCP site, SERT, σ1-2). Full details of the assays used
by the PDSP may be found at their Web site (http://pdsp.med.
unc.edu/indexR.html).
2-Iodo-4-((3-methoxyphenyl)ethynyl)thiazole (9d). This com-
pound was prepared from 6d with the method described for
9a. Chromatography (hexane-EtOAc, 90:10, v/v) gave 9d as a
pale-yellow (170 mg; yield 50%); mp 106-108 °C. 1H NMR: δ
7.46 (s, 1H), 7.26 (t, J = 7.95 Hz, 1H), 7.15 (dt, J1 = 7.6 Hz, J2 =
1.16 Hz,1H), 7.08 (m, 1H), 6.92 (m, 1H), 3.81 (s, 3H). 13C NMR:
δ 159.3, 139.9, 129.5, 128.2, 124.4, 123.0, 116.5, 115.8, 99.9, 90.3,
81.4, 55.3. HRMS (ESIþ): calcd for C12H9INOS 341.9450,
found 341.9449. HPLC purity: 98.65%.
Radiochemistry. NCA [18F]fluoride ion was obtained through
the 18O(p,n)18F nuclear reaction by irradiating [18O]water
(95 atom %) for 90-120 min with a proton beam (17 MeV;
20 μA) produced with a PET trace cyclotron (GE Medical Systems,
Milwaukee, MI). Radioactivity was measured with a calibrated
ionization calibrator (Atomlab 300; Biodex Medical Systems,
Shirley, NY) and corrected for background and physical decay.
Radiochemistry was performed in a lead-shielded hot-cell for
personnel safety with a Synthia MKII Lab System apparatus
equipped with a microwave-heated reactor cavity.27 The reactor
cavity was linked via an RF coaxial cable to a controller of both
irradiation time and power placed on the outside of the hot-cell.
Reactions were performed in a V-vial (1 mL) equipped with a
screw-on cap and septum (Tuf-Bond Teflon/silicone). The septum
was pierced with a vent needle that was connected to a glass vial
(20 mL) to collect any emitted solvents and also to a charcoal trap
to retain any breakthrough of volatile radioactive species. Liquid
handling was achieved with an Aspec autoinjector/dispenser which
forms part of the Synthia apparatus. Other operations in the
radiosyntheses and purification procedures were controlled by a
Visual Chemistry-based recipe.
3-((2-Fluorothiazol-4-yl)ethynyl)benzonitrile (10a). 8a (105 mg,
0.36 mmol) was placed in a microwave vial with Kryptofix 2.2.2
(135 mg, 0.36 mmol), anhydrous KF (42 mg, 0.72 mmol), and
DMSO (1 mL). The solution was irradiated with microwaves
1
(30 W, 130 °C 10 min). Reaction was monitored with H NMR
until disappearance of the signal of the proton in C5 in the thiazole
ring. The reaction mixture was then poured into water (10 mL) and
extracted with EtOAc (3 ꢀ 25 mL). The combined organic phases
were washed with water (3 ꢀ10 mL) and then brine (10 mL). The
organic fraction was dried over MgSO4, evaporated to dryness
under vacuum, and chromatographed on silica gel (DCM-hexane,
50:50, v/v) to give 10a as an off-white powder (30 mg; yield, 24%);
mp 113-114 °C. 1HNMR:δ7.81 (t, J= 1.4 Hz, 1H), 7.75 (dt, J1 =
7.88 Hz, J2 = 1.34 Hz, 1H), 7.65 (dt, J1 = 7.84 Hz, J2 = 1.33 Hz,

Article
Cyclotron-produced [18F]fluoride ion (50-100 mCi) in 18O-
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 3 907
X. H.; McDonald, I.; Rao, S.; Washburn, M.; Varney, M. A.
3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and
highly selective metabotropic glutamate subtype 5 receptor
antagonist with anxiolytic activity. J. Med. Chem. 2003, 46,
204–206.
enriched water (350-500 μL) was dried in the V-vial in the
presence of Kryptofix 2.2.2 (13 μmol; 5 mg), K2CO3 (3.6 μmol,
0.5 mg) in MeCN-H2O (9:1 v/v, 100 μL). Microwave heating
(90 W in 3 pulses of 2 min) was applied under nitrogen gas flow
(200 mL/min) to speed up the removal of MeCN-H2O azeo-
trope. The acetonitrile (500 μL) addition and evaporation were
repeated twice. Precursor for labeling (∼1.0-1.5 mg) in MeCN
(100 μL) was then introduced into the sealed V-vial and heated
at 130 °C (50-90 W in five pulses of 2 min). The reaction mixture
was then diluted with water (0.75 mL) and injected onto a Luna
C18 column (5 μm, 250 mm ꢀ 10 mm) eluted at 4 mL/min with
MeCN-H2O with MeCN at 45% (v/v) for 2 min and then 75%
for 20 min and finally 25% for 30 min. The radioactive product
was collected andmeasuredfor the calculation ofdecay-corrected
radiochemical yield.
Measurement of Specific Radioactivity. The specific radio-
activity of [18F]10b was calculated by injecting a sample of
known radioactivity content (0.1-0.4 mCi) into a mass-cali-
brated analytical HPLC system, comprising a Luna C18 column
(5 μm, 4.6 mm ꢀ 250 mm; Phenomenex) eluted with MeCN-10
mM HCOONH4 (60:40 v/v) at 2 mL/min with eluate monitored
for absorbance at 254 nm. Specific radioactivity was calculated
as the measured mass of 10b divided by the activity of [18F]10b,
corrected for physical decay to the time of product isolation. The
specific radioactivity of [18F]10a, was measured similarly.
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Hodge, C. W.; Janak, P. H.; Messing, R. O. The mGlu5 antagonist
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ꢀ
Acknowledgment. This work was supported by the Intra-
mural Research Program of the National Institutes of Health
(NIH). We are grateful to NIH Clinical Center PET Depart-
ment for cyclotron irradiations (Chief: Dr. Peter Herscovitch).
We are also grateful to the National Institute of Mental Health’s
Psychoactive Drug Screening Program (PDSP) (contract no.
NO1MH32004) for ligand Ki determinations and receptor
screening. The NIMH PDSP is directed by Dr. Bryan L. Roth
MD, Ph.D. at the University of North Carolina at Chapel Hill
and Project Officer Jamie Driscol at NIMH, Bethesda, MD,
USA.
(14) Simeon, F. G.; Brown, A. K.; Zoghbi, S. S.; Patterson, V. M.; Innis,
R. B.; Pike, V. W. Synthesis and simple 18F-labeling of a high
affinity 2-(fluoromethyl)thiazole derivative ([18F]SP203) as a radi-
oligand for imaging brain metabotropic glutamate subtype-5 re-
ceptors with PET. J. Med. Chem. 2007, 50, 3256–3266.
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(15) Brown, A. K.; Kimura, Y.; Zoghbi, S. S.; Simeon, F. G.; Liow,
J.-S.; Kreisl, W. C.; Taku, A.; Fujita, M.; Pike, V. W.; Innis, R. B.
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