No-carrier-added [18F]fluoroarenes from the radiofluorination of diaryl sulfoxides

Article abstract of DOI:10.1039/c3cc37795d

No-carrier-added [¹⁸F]fluoroarenes were synthesized through the radiofluorination of diaryl sulfoxides with [¹⁸F]fluoride ion. Diaryl sulfoxides bearing a para electron-withdrawing substituent readily gave the corresponding 4-[¹⁸F]fluoroarenes in high RCYs. This process broadens the scope for preparing novel ¹⁸F-labeling synthons and PET radiotracers.

Full text of DOI:10.1039/c3cc37795d

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No-carrier-added [18F]fluoroarenes from the
radiofluorination of diaryl sulfoxides†
Cite this: Chem. Commun., 2013,
49, 2151
Joong-Hyun Chun, Cheryl L. Morse, Frederick T. Chinz and Victor W. Pike*
Received 26th October 2012,
Accepted 29th January 2013
DOI: 10.1039/c3cc37795d
www.rsc.org/chemcomm
No-carrier-added [18F]fluoroarenes were synthesized through the
radiofluorination of diaryl sulfoxides with [18F]fluoride ion. Diaryl
sulfoxides bearing a para electron-withdrawing substituent readily
gave the corresponding 4-[18F]fluoroarenes in high RCYs. This process
broadens the scope for preparing novel 18F-labeling synthons and
PET radiotracers.
With the growth of positron emission tomography (PET)1 as a
powerful modality for biomedical research has emerged a
corresponding need for the development of more efficient
methods for producing the required positron-emitting radio-
tracers. Many of these radiotracers are required to be labeled
rapidly with fluorine-18, which has a short half-life of 109.7 min.
[18F]Fluoride ion has become the preferred source of this radio-
nuclide because it can be prepared in very high activities and in
high no-carrier-added (NCA) specific activities (several Ci per
mmol of carrier) from a moderate energy cyclotron with the
18O(p,n)18F reaction on [18O]water.2 For many radiotracers, label-
ing at an aryl position provides for requisite metabolic stability
and especially resistance to undesirable defluorination.
Fig. 1 Various radiosynthetic approaches to [18F]fluoroarenes.
Several methods have been used to produce [18F]fluoroarenes
from [18F]fluoride ion (Fig. 1).3 These include the Balz–Schiemann radiochemical yields on complex substrates, and like the Balz–
reaction, the Wallach reaction, classical aromatic nucleophilic Schiemann reaction is now seldom used. Classical SNAr is the
substitution reactions (SNAr), and the fluorination of hypervalent most widely established method for preparing [18F]fluoroarenes
compounds, such as diaryliodonium and triarylsulfonium as PET radiotracers with high specific radioactivity. High radio-
salts. The Balz–Schiemann reaction has the disadvantage of chemical yields can be achieved in homoarenes with nitro or
low radiochemical yield (RCY; theoretical maximum B25%) trimethylamino substituents as the leaving group, provided that
and unavoidable dilution of specific radioactivity from tetra- the aryl ring is activated with an electron-withdrawing group in
fluoroborate anion in the precursor. The Wallach reaction may ortho or para position.4 This method can also be used to prepare
deliver high specific radioactivity but often gives very low 18F-labeled heteroarenes, such as 2-[18F]fluoropyridines and
4-[18F]fluoropyridines.5 Moreover, the radiofluorination of diaryl-
iodonium salts has now been shown to be effective to label
Molecular Imaging Branch, National Institute of Mental Health,
homoarenes and pyridines in any desirable position, irrespective
of needs for electron-withdrawing groups.6,7 This method is now
finding applications for preparing otherwise difficult to access
radiotracers.8 Recently, hypervalent triarylsulfonium salts have
also been found useful for preparing [18F]fluoroarenes.9
National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive,
Bethesda, MD 20892-1003, USA. E-mail: pikev@mail.nih.gov;
Fax: +1 301 480 5112; Tel: +1 301 594 5986
† Electronic supplementary information (ESI) available: Experimental details, 1H
and 13C NMR spectra of prepared diaryl sulfoxides, and selected radio HPLC
radiochromatograms. See DOI: 10.1039/c3cc37795d
As a part of our ongoing interest in the use of hypervalent
precursors for radiofluorination, we were attracted to investigate
‡ Present address: Molecular Imaging Program at Stanford (MIPS), Department of
Radiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
c
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Table 1 RCYs of NCA [18F]fluoroarenes from the radiofluorination of symme-
the radiofluorination of diaryl sulfoxides. Here, we show that
many diaryl sulfoxides readily react with NCA [18F]fluoride ion
to give [18F]fluoroarenes in high RCY.
trical diaryl sulfoxides in DMF
Substituted diaryl sulfoxides (Fig. 2) were purchased (10 and
11) or readily synthesized, either through the oxidation of
the corresponding diaryl sulfides with m-chloroperbenzoic acid
(1–3, 6–9 and 13–20) or by treatment of an appropriate arene
with thionyl chloride (4, 5, 12), and they were obtained in
moderate to good yields;10 see ESI† for full synthesis details.
A commercial microfluidic apparatus (Nanotek; Advion,
Ithaca, NY) was used as an expedient platform for testing
the amenability of the available series of diaryl sulfoxides to
radiofluorination. Detailed descriptions of this apparatus and
of its operation may be found in our previous publication.7 Dry
NCA no-carrier-added [18F]fluoride ion-kryptofix 2.2.2 complex
(18Fꢀ-K 2.2.2- K+) and the test diaryl sulfoxide were separately
dissolved in DMF. Each solution was infused into the fused silica
micro-reactor (internal volume: 31 mL) of the apparatus at a fixed
equal rate (4–10 mL minꢀ1) and at a set temperature. The resulting
reactor effluent was quenched with aqueous MeCN and analyzed
directly with reverse phase HPLC equipped with a radioactivity
detector. Reaction conditions were varied to search for optimal
RCYs (see ESI,† Fig. S1, for radiochromatograms from the radio-
fluorination of 3 between 100 and 200 1C). Because adsorption
of [18F]fluoride ion onto reaction vessel walls is commonly
encountered in radiofluorination reactions,11 the recoveries of
radioactivity from the apparatus were also measured; these were
found to be 75 ꢁ 11% (mean ꢁ SD, n = 16).
Conditionsb
Entry
Substratea
Temp. (1C)
Timed (s)
RCYc of Ar18F (%)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
9
150
200
200
160
200
200
180
200
200
200
200
200
236
236
251
236
188
188
188
236
188
236
236
236
1a, 91 (76)
2a, 82 (66)
3a, 66 (59)
4a, 21 (11)
5a, 7 (5)
6a, 2 (1)
7a, 94 (72)
8a, 4 (3)
9a, 68 (44)
10a, 0
9
10
11
12
10
11
12
11a, 0
12a, 0
a
b
5 mM in DMF. Conditions giving the highest RCYs among 8–12
different runs, except for entries 10–12 where the most extreme of the
c
tested conditions are given. RCYs are those determined with HPLC.
RCYs given in parentheses are with correction for radioactivity adsorption
in the apparatus. Estimated residence time in the micro-reactor.
d
the nitro group in SNAr reactions, including those with [18F]fluoride
ion.4 Similarly, high RCYs were obtained from symmetrical
substrates bearing other electron-withdrawing substituents,
such as p-cyano or p-trifluoromethyl (entries 2 and 3). The substrate
bearing p-fluoro substituents gave only a low yield of [18F]p-difluoro-
benzene (entry 4), and that bearing m-nitro groups gave almost no
yield of 3-[18F]fluoronitrobenzene (entry 6).
[18F]Fluoroarenes were rapidly obtained from these reactions. In
the radiofluorination of symmetrical diaryl sulfoxides, where
both aryl rings carried a p-electron withdrawing group (Table 1,
entries 1–5), p-substituted [18F]fluorobenzenes were produced in
moderate to excellent RCYs, except in the case of the substrate
having weakly electron-withdrawing p-bromo substituents (entry 5).
A very high RCY of 4-[18F]nitrofluorobenzene was obtained from 1
under quite mild reaction conditions (entry 1). Under these
conditions there was no chromatographic evidence of substitu-
tion of the nitro group by [18F]fluoride ion (Fig. 3). This result is
quite remarkable given the well-known strong nucleofugacity of
2- and 4-[18F]Fluoropyridines were obtained in high RCYs
from the respective dipyridinyl sulfoxides (Table 1, entries 7 and 9).
However, only a low RCY of 3-[18F]fluoropyridine was obtained from
3,30-dipyridinyl sulfoxide (entry 8). No radiofluorinated arenes were
obtained in the absence of a substituent (entry 10), nor when methyl
or methoxy substituents were in p-position (entries 11 and 12).
Altogether, these results indicate that the electronic features needed
in the diaryl sulfoxides for radiofluorination to proceed efficiently
resemble those required for classical SNAr reactions.
Unsymmetrical diaryl sulfoxides also gave [18F]fluoroarenes.
When one aryl ring carried a p-nitro substituent and the other no
substituent, 4-[18F]fluoronitrobenzene was obtained in high RCY
with no accompanying [18F]fluorobenzene (Table 2, entry 1).
Fig. 3 Radio-HPLC chromatogram of the reaction mixture from the radio-
fluorination of 4,40-dinitrodiphenyl sulfoxide.
Fig. 2 Diaryl sulfoxide precursors used in this study.
2152 Chem. Commun., 2013, 49, 2151--2153
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Table 2 RCYs of [18F]fluoroarenes from the NCA radiofluorination of unsymme-
In summary, we report a new radiosynthetic method for
producing NCA [18F]fluoroarenes based on the reactions of
diaryl sulfoxides bearing p-electron-withdrawing groups with
[18F]fluoride ion. These reactions are relatively mild, rapid and
efficient and should prove useful in PET radiotracer synthesis,
especially where it is desirable to retain a potentially nucleofugic
aryl nitro group. The reported TSPO 18 kDa radiotracer, [18F]PK
14105 ([18F](R)-N-sec-butyl-1-(2-fluoro-5-nitrophenyl)-N-methyl-
isoquinoline-3-carboxamide), provides a specific example where
this new labeling method might prove useful.13 Moreover, these
reactions may also provide alternative access to potentially useful
labeling synthons, such as 4-[18F]cyanofluorobenzene.
trical diaryl sulfoxides in DMF
Conditionsb
RCYc (%)
Entry Substratea Temp. (1C) Timed (s) Ar18
F
Ar018F
1
2
3
4
5
6
7
8
13
14
15
16
17
18
19
20
130
120
150
200
140
200
140
200
224
236
314
236
314
236
236
236
1a, 64 (56)
1a, 93 (89)
1a, 76 (68)
16a, 73 (55) 10a, 0 (0)
17a, 46 (32) 1a, 43 (25)
18a, 61 (43) 10a, 0 (0)
19a, 36 (20) 1a, 45 (35)
10a, 0 (0)
2a, o1 (o1)
4a, 0 (0)
This work was funded by the Intramural Research Program
of the National Institutes of Health (NIMH). We are grateful to
the NIH clinical PET center for supplying fluorine-18.
20a, 0 (0)
10a, 0 (0)
a
b
5 mM in DMF. Conditions giving highest RCYs among 8–12 differ-
Notes and references
ent runs, except for entry 8 where the most extreme tested condition is
given. RCYs are those determined with HPLC. RCYs given in parenth-
c
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 2151--2153 2153