The [18F]2-fluoro-1,3-thiazolyl moiety - An easily-accessible structural motif for prospective molecular imaging radiotracers

Article abstract of DOI:10.1016/j.tetlet.2010.09.037

2-Fluoro-1,3-thiazoles were rapidly and efficiently labeled with no-carrier-added fluorine-18 (t_1/2 = 109.7 min) by treatment of readily prepared 2-halo precursors with cyclotron-produced [¹⁸F] fluoride ion. The [¹⁸F]2-fluoro-1,3-thiazolyl moiety constitutes a new and easily-labeled structural motif for prospective molecular imaging radiotracers.

Full text of DOI:10.1016/j.tetlet.2010.09.037

Tetrahedron Letters 51 (2010) 6034–6036
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The [18F]2-fluoro-1,3-thiazolyl moiety—an easily-accessible structural motif
for prospective molecular imaging radiotracers
⇑
Fabrice G. Siméon , Matthew T. Wendahl, Victor W. Pike
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Rm. B3 C346A, 10 Center Drive, Bethesda, MD 20892-1003, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2010
Revised 9 September 2010
Accepted 13 September 2010
Available online 17 September 2010
2-Fluoro-1,3-thiazoles were rapidly and efficiently labeled with no-carrier-added fluorine-18
(t1/2 = 109.7 min) by treatment of readily prepared 2-halo precursors with cyclotron-produced [18F]fluoride
ion. The [18F]2-fluoro-1,3-thiazolyl moiety constitutes a new and easily-labeled structural motif for pro-
spective molecular imaging radiotracers.
Published by Elsevier Ltd.
Keywords:
Radiofluorination
1,3-Thiazole
Microwave-assisted synthesis
Interest in the efficient synthesis of new fluoro compounds as
potential drugs and imaging agents is growing dramatically.1 Fluo-
rinated drugs include antibiotics, sedatives, antidepressants and
anti-tumor agents.1,2 Moreover, methods for introducing fluorine-
18 (t1/2 = 109.7 min) into organic molecules have become increas-
ingly important for the development of radiotracers for positron
emission tomography (PET),3 a sensitive and powerful technique
for molecular imaging in animal and human subjects in vivo, and
hence for clinical research and diagnosis.4 For the development
of PET radiotracers, the preferred source of fluorine-18 is [18F]fluo-
ride ion, obtained from the 18O(p,n)18F reaction on 18O-enriched
water.5 This production method is very high yielding and impor-
tantly gives the [18F]fluoride ion at a very high ‘no-carrier-added’
(NCA) specific radioactivity. High specific radioactivity (typically
1,3-Thiazole can be regarded as isosteric with benzene and
pyridine.10 Replacement of a phenyl or pyridinyl group with a
1,3-thiazolyl groupmaythereforeleadtoanimproveddrugorrecep-
tor ligand. A striking example occurs among diarylacetylene-type
metabotropic glutamate sub-typereceptor5 (mGluR5)ligands. Here
pairing of a substituted 1,3-thiazolyl group with a substituted phe-
nyl group in the diarylacetylene provides ligands with similar or
higher potency than the pairing of other aryl groups.11 Such 1,3-thi-
azoles appear susceptible to metabolism by oxidative ring
opening.12 However, one report suggests that fluorination of a 1,3-
thiazolyl group might lead to better resistance to metabolism
in vivo.13 We hypothesized that the 2-position in 1,3-thiazoles
would be an attractive site for facile incorporation of fluorine-18
from [18F]fluoride ion and moreover might deliver a relatively met-
abolically stable [18F]2-fluoro-1,3-thiazolyl structural motif.
>1 Ci/lmol) is often mandatory for the safety and efficacy of PET
radiotracers.6
In order to establish reaction conditions for the preparation of
The introduction of fluoride ion or [18F]fluoride ion at an alkyl
carbon is usually straightforward.6 Fluoroalkanes are however gen-
erally more susceptible to metabolic defluorination in vivo than
fluoroarenes.7 Therefore, the latter are often more desirable targets
in the development of drugs and of 18F-labeled imaging agents.
[
18F]2-fluorothiazoles, we first sought a simple method to prepare
reference 2-fluorothiazoles. Among the few methods reported for
preparing such fluoro compounds, including fluoro-de-diazonia-
tion14 or nucleophilic substitution,15,16 nucleophilic substitution
with fluoride ion in 2-halo-1,3-thiazoles16 appeared attractive
since the precursor halo compounds were quite accessible.
2-Bromo-1,3-thiazole (1) was submitted to fluorination with
potassium fluoride and an equimolar amount of the cryptand,
KryptofixÒ 2.2.2 (K 2.2.2) or the crown ether 18-crown-6, in various
solvents (DMSO, MeCN or DMF) under microwave irradiation. We
found that fluorination was almost quantitative after irradiation
for 10 min at 150 °C (35 W) in DMSO. The conversion of 2-bromo-
1,3-benzothiazole (2) into the corresponding 2-fluoro derivative
(8) also proceeded in very high yield under these conditions
(Table 1).
[
18F]Fluoride ion may be incorporated readily into electron-deficient
benzenes6 and also into pyridines6,8 at their 2- and 4-positions by
aromatic nucleophilic substitution reactions, and at all positions in
electron-rich or electron-poor benzenes and pyridines by reaction
with diaryliodonium salts.9 Fast efficient methods for utilizing
[
18F]fluoride ion in the fluorination of other arenes, especially other
heteroarenes, have however been little explored.
⇑
Corresponding author.
E-mail address: simeonf@mail.nih.gov (F.G. Siméon).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.09.037

F. G. Siméon et al. / Tetrahedron Letters 51 (2010) 6034–6036
6035
Table 1
Table 2
Yields of 2-fluorothiazoles produced under microwave irradiation
RCYs of [18F]2-fluoro-thiazoles from NCA [18F]fluoride ion
18F-
K+-K 2.2.2
S
S
N
S
N
S
N
KF
18F
X
X
F
K 2.2.2
DMSO
N
R
R
R
R
MW, 130 oC
10 min
7_10
1_7
1_6
[
18F]7_10
Precursor
Reaction conditions
[
18F]Fluoro-
RCYa
Precursor
Fluoro-product
Yielda (%)
product
R
X
R
X
1
1
H
H
Br DMSO, 150 °C, 30 min
Br DMSO, MW (130 °C,
10 min)
[
[
18F]7
18F]7
29
81
1
2
H
Br
7
8
95
89
Br
Cl
2
2
2
2
2
2
2
Br MeCN, 80 °C, 30 min
Br MeCN, 150 °C, 30 min
Br DMF, 80 °C, 30 min
Br DMF, 150 °C, 30 min
Br DMSO, 80 °C, 30 min
Br DMSO, 150 °C, 30 min
[
[
[
[
[
[
[
18F]8
18F]8
18F]8
18F]8
18F]8
18F]8
18F]8
19
19
21
24
26
35
47
3
4
9
9
78
72
Br
5
6
I
9
9
N
N
Br
10
55
DMSO, MW (150 °C,
10 min)
Br
a
Yield for isolated and analytically pure compound.
DMSO, MW (130 °C,
8 min)
3
4
5
4
Cl
[
[
[
[
18F]9
18F]9
18F]9
18F]9
14.5
14
We decided to test the generality of these microwave conditions
for the rapid high-yield preparation of other 2-fluoro-thiazole deriv-
atives. First we prepared the 2-chloro-, 2-bromo- and 2-iodo-1,3-
thiazolyl compounds, 3–5,17 as simple analogs of a potent mGluR5
ligand, namely 3-[(2-methyl-1,3-thiazol-4-yl)-ethynyl]-pyridine.18
These halo compounds were subjected to fluorination under the
most effective conditions found for 2. The target fluoro derivative 9
was successfully isolated in high yield from the chloro (3) and bromo
(4) precursors (Table 1). The yield of 9 from the iodo precursor 5 was
however low (Table 1).
DMSO, MW (130 °C,
8 min)
Br
DMSO, MW (130 °C,
8 min)
I
2.0
45
DMSO, MW (130 °C,
10 min)
We also prepared the 2-bromo and N-Me derivative (6) of the
powerful antibiotic, thiabendazole, as a precursor for fluorination
(Scheme 1). Previous work has shown that thiabendazole retains
high fungicidal and bactericidal activity after 2-halogenation19
(halo = Cl or Br) of the thiazolyl group or N-methylation20 of the
imidazolyl ring. Fluorination of 6 in DMSO for 10 min with micro-
Br
N
N
DMSO, MW (130 °C,
10 min)
6
7
Br
[
[
18F]10
18F]7
23
26
H
F
MeCN, 110 °C, 35 min
a
Isolated decay-corrected radiochemical yield from starting [18F]fluoride ion.
S
S
NaH, MeI
DMF
N
N
NH
wave heating at 130 °C gave N-methyl-2-fluorothiabendazole (10)
in good yield (Scheme 1; Table 1).
N
N
N
The apparent rapidity and effectiveness of the fluorination of
2-halo-1,3-thiazoles with potassium fluoride under microwave irra-
diation encouraged us to explore the preparation of [18F]2-fluoro-
1,3-thiazoles with cyclotron-produced NCA [18F]fluoride ion under
thermal or microwave heating conditions (Table 2). We found that
treatment of a low amount of the 2-fluorothiazole 7 (1.1 mg;
1.0 mmol) with [18F]fluoride ion in the presence of K+-K 2.2.2 in ace-
11
12
1) BuLi, Me3SnCl
2) Br2
S
S
KF, K 2.2.2
F
Br
DMSO, MW, 130 oC, 10 min
tonitrile (500 l
L) at 110 °C produced carrier-added [18F]7 in 26% de-
N
N
N
N
cay-corrected radiochemical yield (RCY) within 35 min (Table 2).
N
N
Similartreatmentof the2-bromocompound1 in DMSOwith NCA
[
18F]fluorideionat150 °Cfor30 mingave[18F]7in29%RCY(Table2).
10
6
Use of microwave heating (10 min at 40–90 W; 130 °C) dramatically
increased the RCY of [18F]7 to 81%. Similarly, under thermal heating
Scheme 1. Synthesis of N-methyl-2-fluoro-thiabendazole (10).

6036
F. G. Siméon et al. / Tetrahedron Letters 51 (2010) 6034–6036
conditions, theRCYof[18F]8 increasedwithtemperaturebetween80
and 150 °C, and with solvent polarity, among acetonitrile, DMF or
DMSO. Thus, at 80 °C in DMSO, [18F]8 was obtained in only 26%
RCY. A higher RCY of [18F]8 (35%) was obtained in DMSO at 150 °C
for 30 min. Under inert atmosphere in DMSO with brief microwave
heating (90 W, 150 °C, 10 min), [18F]8 was obtained in 47% RCY,
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.09.037.
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Acknowledgment
This work was supported by the Intramural Research Program
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Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data for new compounds 9–10, and representative radio-HPLC
chromatograms for compounds [18F]7–[18F]10) associated with