A practical route for synthesizing a PET ligand containing [18F]fluorobenzene using reaction of diphenyliodonium salt with [18F]F-

Article abstract of DOI:10.1016/j.tetlet.2007.10.025

The aim of this study was to develop a practical route for preparing a fluorine-18 ([¹⁸F]) labelled ligand ([¹⁸F]1) containing [¹⁸F]fluorobenzene ring by employing the reaction of diphenyliodonium salt with [¹⁸F]F^-. Diphenyliodonium tosylate (2) was synthesized from tributylphenylstannyl compound (6) with [hydroxy(tosyloxy)iodo]benzene (7). Using this method, [¹⁸F]DAA1106 ([¹⁸F]3a), a positron emission tomography ligand for imaging peripheral-type benzodiazepine receptor, was prepared.

Full text of DOI:10.1016/j.tetlet.2007.10.025

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8632–8635
A practical route for synthesizing a PET ligand containing
[18F]fluorobenzene using reaction of diphenyliodonium
salt with [18F]FÀ
Ming-Rong Zhang,* Katsushi Kumata and Kazutoshi Suzuki
Radiochemistry Section, Department of Molecular Probes, Molecular Imaging Center,
National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
Received 28 August 2007; revised 4 October 2007; accepted 5 October 2007
Available online 9 October 2007
Abstract—The aim of this study was to develop a practical route for preparing a fluorine-18 ([18F]) labelled ligand ([18F]1) contain-
ing [18F]fluorobenzene ring by employing the reaction of diphenyliodonium salt with [18F]FÀ. Diphenyliodonium tosylate (2)
was synthesized from tributylphenylstannyl compound (6) with [hydroxy(tosyloxy)iodo]benzene (7). Using this method,
[18F]DAA1106 ([18F]3a), a positron emission tomography ligand for imaging peripheral-type benzodiazepine receptor, was
prepared.
Ó 2007 Elsevier Ltd. All rights reserved.
There are two methods for introducing radioactive fluo-
rine-18 (18F) into a benzene ring to prepare a positron
emission tomography (PET) ligand containing [18F]fluoro-
benzene ring. One method is electrophilic substitution
by which a trialkylphenystannyl precursor reacts with
[18F]F2 gas to afford the desired [18F]fluorinated prod-
uct. [18F]FDOPA, a useful PET ligand for clinical inves-
tigation of dopamine receptor, has been prepared by the
reaction of a tributylphenylstannyl precursor with
[18F]F2.1 However, a significant shortcoming of this
method is the extremely low producing efficiency of
[18F]F2 recovered from the target, which thus gives the
desired product only in a low radiochemical yield
(<10%). Moreover, the specific activity of the 18F prod-
uct by this method is also extremely low (<1 mCi/lmol)
since non-radioactive F2 has to be employed to increase
the recovering efficiency of [18F]F2 from the cyclo-
tron target. Obviously, this level of specific activity,
which is 1000-fold lower than that of a common PET
[18F]ligand for brain imaging, is not enough to elucidate
a receptor with low density in the brain.
[18F]F2, this method using [18F]FÀ affords a [18F]fluo-
rinated product with higher radiochemical yield and
specific activity. For example, [18F]flumazenil2 and
[18F]altanserin,3 two useful PET ligands for imaging
the central benzodiazepine receptor and 5-HT2A recep-
tor in the brain, respectively, have been prepared by
reacting the corresponding nitrobenzene precursors with
[18F]FÀ. However, the achieving efficiency of this reac-
tion is significantly dependent upon the type and posi-
tion of the substitution group in the benzene ring. The
presence of electron-abstracting groups in the ortho or
para position of the benzene ring is an indispensable
condition. Without electron-abstracting groups such as
NO2, CN, CHO, COOMe and COOH in the ortho or
para position of the benzene ring accompanied by leav-
ing groups such as NO2, Cl, Br, I and +NMe3, the sub-
stitution reaction generally does not work well.
In this study, we determined a route for preparing a PET
ligand ([18F]1) containing [18F]fluorobenzene by apply-
ing the nucleophilic reaction of [18F]FÀ with diphenyl-
iodonium salt (2) (Scheme 1). Using this method,
we synthesized N-(2,5-dimethoxybenzyl)-N-(5-[18F]-
Another method is the nucleophilic reaction of [18F]FÀ
with a substituted phenyl precursor with SNAr reaction
mechanism. Compared with the electrophilic reaction of
fluoro-2-phenoxyphenyl)acetamide
([18F]DAA1106,
[18F]3a), a useful PET ligand for imaging peripheral-
type benzodiazepine receptor in the brain.4
*
Diphenyliodonium salt (2) had been previously reported
Corresponding author. Tel.: +81 43 206 4041; fax: +81 43 206
3261; e-mail: zhang@nirs.go.jp
as a suitable precursor for the introduction of 18F into a
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.025

M.-R. Zhang et al. / Tetrahedron Letters 48 (2007) 8632–8635
CH
8633
3
OCH
OCH
3
+
I
O
18
18
-
C
F
R
2
F
-
OTs
R
N
CH
2
R
1
R
1
O
3
18
2
[
F]1
R = H, Me, Cl, OMe
1
R = H, OMe
2
18
18
18
[
3b: R = I
3c: R = Br
3d: R = SnBu
F]DAA1106 ([ F]3a): R= F
3
Scheme 1. Synthesis of [18F]ligand ([18F]1) containing a [18F]fluorobenzene ring.
benzene ring by the nucleophilic reaction of [18F]FÀ
(Scheme 1).5–8 Due to the excellent property of phenyl-
iodonium as a leaving group, the reaction of diphenyl-
iodonium salt (2) with [18F]FÀ could proceed well to
yield [18F]fluorobenzene product ([18F]1).9–12 In parti-
cular, its ability to introduce 18F into an electron-rich
benzene ring without further activating groups thus
induced a growing interest in PET chemistry. To date,
some reports regarding the nucleophilic reaction of
[18F]FÀ with 2 have been published; however, this reac-
tion has not been successfully used to synthesize a prac-
tical PET ligand. The main reason is that the
diphenyliodonium compound 2 is difficult to prepare
starting from a precursor of the PET ligand commonly
with some functional substitution groups or with more
complicated chemical structures.
with peracetic acid (AcOOH) and then coupled with a
benzene ring in CF3COOH or CF3SO3H to yield 2 as a
triflate or trifluoroacetate (Scheme 2).13,5 However, an
iodine analogue of a PET ligand with functional substi-
tution groups is not stable for AcOOH. For example,
while trying to oxidize the iodine analogue 3b (Scheme
1) with AcOOH, the corresponding iodosobenzene di-
acetate product could not be obtained. Moreover, the
coupling of iodosobenzene diacetate with benzene in
strong acid was too severe for some functional groups.
Therefore, to apply the reaction of 2 with [18F]FÀ for
the synthesis of a PET ligand containing [18F]fluoro-
benzene, it is necessary to determine a reliable and prac-
tical route for synthesizing 2. Our present route is shown
in Scheme 2. In place of the oxidation of 5 to 4, we firstly
converted 5 to tributylphenylstannyl compound (6), an
excellent precursor also for preparing radioactive phen-
yl products labelled by 11C, 76Br and 123I. The useful-
ness of 6 guaranteed the regioselective introduction of
18F into the benzene ring. In the present study, tributyl-
phenylstannyl compound 6 with various substitution
There are several methods for synthesizing diphenyl-
iodonium salt with counter ions such as tosylate (2) as
well as acetate and triflate.13,5–7,9,12 These methods com-
monly apply a key intermediate, iodosobenzene diacetate
(4), synthesized by the oxidation of iodobenzene (5)
Previous
R2
OAc
OAc
+
I
I
I
R2
AcOOH
-OTs
R1
R1
R1
5
4
2
OAc
OAc
I
Present
R2
4
SnBu3
TsOH
I
Bu6Sn2,
5
OTs
OH
2
Pd(PPh3)4
R1
6
R2
7a: R2 = H
7b: R2 = OMe
Scheme 2. Synthesis of diphenyliodonium tosylates (2).

8634
M.-R. Zhang et al. / Tetrahedron Letters 48 (2007) 8632–8635
groups (R = H, Me, Cl and OMe) was synthesized by
reacting the corresponding iodo-(5) or bromobenzene
analogues with di(tributyltin) in toluene under the pres-
ence of Pd catalyst, as shown in Scheme 2.
such as CH3CN, THF and DMF. Moreover, while using
microwaves to radiate the reaction mixture, [18F]fluo-
rination progressed rapidly at 5 min to give 50–78%
reaction efficiency. On the other hand, compared to
Kryptofix222 (10 mg) as the phase-transfer reagent, the
application of tetrabutylammonium bicarbonate
(nBu4NHCO3, 10 mg) gave higher efficiency of [18F]fluo-
rination. As control, while not using [18F]FÀ, the reac-
tion mixture of 2 (R1 = R2 = H) with same equivalent
of nBu4NF was heated in THF under reflux for 8 h to
give 1 in 84% chemical yield.
Since 6 could not react with 4, we thus converted 4 to
more reactive [hydroxy(tosyloxy)iodo]benzene analogue
(7). Commercial [hydroxy(tosyloxy)iodo]benzene 7a
(R = H, Koser’s reagent14) reacted with 6 to yield 2
(R1 = H, Me, Cl and OMe; R2 = H) in a high chemical
yield (51–72%).9 On the other hand, based on the
consideration that the nucleophilic reagent [18F]FÀ
attacking the diphenyliodonium salt occurs preferably
at the electron-deficient benzene ring, we designed
anisyliodonium as a leaving group to increase the regio-
selectivity of 18F into a desired benzene ring as much as
possible. The reaction of 4 with toluenesulfonic acid in
anhydrous CH3CN gave 7b (R = OMe), which has
never been reported as a novel compound. However,
we found that 7b was so unstable that it was immedi-
ately decomposed while being purified from the reaction
mixture. Thus, we reacted 4 with toluenesulfonic acid
to give 7b in situ, which was directly treated with 6 in
anhydrous CH3CN to give crude 2 under the atmos-
phere of N2. The resulting precipitate was filtered and
washed with diethyl ether several times to yield pure 2
to apply for radiosynthesis. By this procedure, starting
from 5, we prepared 2 with various substitution groups
(R1 = OMe, Me, H, and Cl; R2 = OMe) in chemical
yields of >80%.
Table 1 shows the reaction results of 2 with [18F]FÀ
according to the reaction conditions listed. These reac-
tions (entries 1–8) gave moderate or high efficiency
(32–90%) of [18F]fluorination. In addition to [18F]fluo-
rinating efficiency, we further determined the regioselec-
tivity of [18F]FÀ into the desired benzene ring. As
expected, the reaction of [18F]FÀ attacking 2 occurred
preferably at the relatively electron-deficient benzene
ring. As shown in entries 5–8, the reaction of 2 substi-
tuted by the 4-methoxy group in the benzene ring with
[18F]FÀ gave the desired product [18F]1 (R1 = Me, Cl
and H) in a higher ratio than the byproduct [18F]1
(R2 = OMe). These results revealed that the regioselec-
tivity of 18F was dependent upon electron effects of the
two benzene rings. Obviously, the electron density in
the anisole ring is higher than that in benzene, toluene
and chlorobenzene rings, which gave [18F]1 (R1 = Me,
Cl and H) with a higher ratio than [18F]1 (R2 = OMe).
Thus, by distinguishing the electron density of the two
benzene rings in 2, the desired [18F]fluorinating product
could be preferably obtained.
Next, we carried out the reaction of 2 with [18F]FÀ to
optimize conditions to achieve high [18F]fluorinating
efficiency. The nucleophilic substitution of the non-
carried added [18F]FÀ proceeds via SNAr-mechanism
to yield [18F]1 and the corresponding iodobenzenes.11
The reaction of 2 (R1 = R2 = H, 2–5 mg) with [18F]FÀ
(0.5–1 mCi) in several anhydrous solvents (500 lL) at
50–150 °C for 5–30 min gave [18F]1 with radiochemical
yields of 25–82%. Among the reaction solvents, DMSO
was favourable for [18F]fluorination over other solvents
Finally, we used this method to prepare [18F]3a, which is
a
18F vision of [11C]DAA1106,4 a PET ligand for imag-
ing peripheral-type benzodiazepine receptor in the brain
in our facility. The [18F]ligand has some advantages over
11C vision especially in delivery usefulness. For the bro-
mine analogue 3 c,15 two diphenyliodonium compounds
8 were prepared by the reaction of 3d with 7a (R = H)
Table 1. Reaction of diphenyliodonium tosylate (2) with [18F]FÀ
18
18
F
F
18F-
2
+
DMSO, 80°C,
nBu4NHCO3,
20 min
R
R
1
2
[18F]1
(Desire Product)
[18F]1
(By-product)
Entry
R1
R2
Yield of fluorinationa (%)
Ratio (%)
[
18F]1 (R1)
[
18F]1 (R2)
1
2
3
4
5
6
7
8
H
Me
Cl
OMe
OMe
Me
H
H
H
H
H
OMe
OMe
OMe
OMe
90
53
32
80
90
45
79
86
100
19
53
2
100
80
94
93
0
81
47
98
0
20
6
Cl
7
a Radiochemical yield was determined by analytical HPLC of the reaction mixture. All results were presented as mean values (n = 3) with a maximum
range of 5%. The radioactive products were identified using authentic non-radioactive samples.

M.-R. Zhang et al. / Tetrahedron Letters 48 (2007) 8632–8635
8635
CH3
CH2
OCH3
OCH3
O
C
Bu6Sn2,
Pd(PPh3)4
+
I
R
N
O
7
3c
3d
-OTs
toluene, reflux,
3 days
CH3CN, rt, 3 h
8
18F-
18F]3a
18F
R
+
8
[
DMSO, 80°C, nBu4NHCO3,
[
18F]1
20 min
R
Yield of [18F]fluorination (%)
Ratio (%)
8a: R = H
8b: R = OMe
97
29
74
65
3
71
*: Radiochemical yield was determined by analytical HPLC of the reaction mixture.
All results were presented as mean values (n =3) with a maximum range of 5%. The
radioactive products were identified using authentic non-radioactive samples.
Scheme 3. Radiosynthesis of [18F]DAA1106 ([18F]3a).
and 7b (R = OMe), respectively (Scheme 3). Since 8a
and 8b were unstable, they were used for radiosynthesis
after the respective coupling reaction without further
purification. [18F]Fluorinating reactions were immedi-
ately accomplished by heating 8a and 8b (5 mg) with
[18F]FÀ(3–5 mCi)/nBu4NHCO3 (10 mg) in DMSO
(500 lL) at 80 °C for 20 min, respectively. After the
reaction, the radioactive mixture was analyzed to deter-
mine the [18F]fluorination efficiency and the ratio of
[18F]3a to the byproduct [18F]1 (R = H or OMe). As
shown in Scheme 3, the two reactions gave high
[18F]fluorination efficiency (74% and 65%). For the
[18F]fluorination of 8a (R = H), the byproduct [18F]1
(R = H) was formed with a high ratio (97%), whereas
[18F]3a could not be obtained. For the [18F]fluorination
of 8b (R = OMe), [18F]3a was obtained in 71% ratio and
[18F]1 (R = OMe) was only yielded with a low ratio
(29%). This result supported that the relatively
electron-deficient ring of the diphenyliodonium salt is
preferred for nucleophilic attack by [18F]FÀ.7,11 To our
knowledge, this is the first report of a practical PET
ligand containing [18F]fluorobenzene synthesized by
the reaction of diphenyliodonium salt with [18F]FÀ.
Molecular Imaging Program on Research Base for
PET Diagnosis from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT),
Japanese Government.
References and notes
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2005, 32, 109.
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In conclusion, we determined a suitable method for pre-
paring a practical PET ligand [18F]1 containing [18F]fluo-
robenzene ring with an electron-donating group using
the reaction of diphenyliodonium salt (2) with [18F]FÀ.
We are trying to synthesize other useful PET ligands con-
taining [18F]fluorobenzene using this reaction.
12. Martin-Santamaria, S.; Carrol, M. A.; Carrol, C. M.;
Carter, C. D.; Pike, V. W.; Rzepa, H. S.; Widdowson, D.
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Acknowledgements
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We thank the staff of the Cyclotron Operation Section
and Radiochemistry Section, Department of Molecular
Probes, National Institute of Radiological Sciences
(NIRS) for their support in the operation of the cyclo-
tron and production of radioisotopes. This study was
partially supported by a consignment expense for