Ring-Closing Synthesis of Dibenzothiophene Sulfonium Salts and Their Use as Leaving Groups for Aromatic 18F-Fluorination

Article abstract of DOI:10.1021/jacs.8b06730

Herein, we report a novel intramolecular ring-closing reaction of biaryl thioethers that give access to highly functionalized dibenzothiophene sulfonium salts under mild conditions. The resulting precursors react regioselectively with [¹⁸F]fluo

Full text of DOI:10.1021/jacs.8b06730

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Ring-Closing Synthesis of Dibenzothiophene Sulfonium Salts and
18
Their Use as Leaving Groups for Aromatic F‑Fluorination
Thibault Gendron,†,‡ Kerstin Sander,†,‡ Klaudia Cybulska,‡ Laure Benhamou,†,‡
Pak Kwan Brian Sin,†,‡ Aqsa Khan,‡ Michael Wood,‡ Michael J. Porter,‡ and Erik Årstad*,†,‡
†Institute of Nuclear Medicine, University College London, 235 Euston Road (T-5), London NW1 2BU, United Kingdom
‡Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom
S
* Supporting Information
ABSTRACT: Herein, we report a novel intramolecular ring-closing reaction of
biaryl thioethers that give access to highly functionalized dibenzothiophene
sulfonium salts under mild conditions. The resulting precursors react regioselectively
with [18F]fluoride to give [18F]fluoroarenes in predictable radiochemical yields. The
strategy expands the available radiochemical space and provides superior labeling
efficiency for clinically relevant PET tracers.
ever, few reactions are available to form aryl-sulfonium salts, and
access to the precursors for labeling depends on protection
strategies to enable selective S-arylation of thioethers in the
presence of other reactive functional groups. Here we report that
dibenzothiophene sulfonium salts can be accessed through
intramolecular cyclization of biaryl thioethers under mild
conditions. The strategy overcomes the synthetic limitations
of triarylsulfonium salts and provides a flexible platform for the
design of leaving groups for aromatic 18F-fluorination (Figure
1).
INTRODUCTION
■
Fluorine-18 is uniquely suited for imaging with positron
emission tomography (PET) due to its favorable half-life
(110 min) and high-efficiency, low-energy positron emission
(97% β+, Emean = 0.250 keV). The versatile properties of C−F
bonds and their widespread use in medicinal chemistry further
contribute to the appeal of fluorine-18 for diagnostic imaging
and pharmaceutical research. Yet, incorporation of [18F]fluoride
into biologically active molecules is often difficult, if not
impossible, to achieve. Nucleophilic SN2 and SNAr substitution
reactions with [18F]fluoride remain the most widely used
strategies for labeling, as they are technically simple and robust.
However, target compounds are rarely suitable for this approach,
and radiotracers are therefore typically modified with fluorinated
aliphatic side chains, or highly activated aromatic groups, to
allow labeling to take place. Since the development of SN2
reactions with [18F]fluoride more than 30 years ago, continuous
efforts have been made to expand the radiochemical space.1−3
Recent chemical insights have re-invigorated the field and led to
the discovery of several innovative strategies for radiofluor-
ination. New types of precursors, including aryl boronic acids
and esters,4−6 preformed PdIV or NiII complexes,7,8 N-aryl
sydnones,9 uronium salts,10 iodonium ylides,11,12 and aryl-
sulfonium salts,13−15 now allow direct fluorination of aromatic
ring systems that until recently were beyond reach. While these
methods certainly have expanded the radiochemical space, their
impact on clinical PET remains limited.16 This reflects the
difficulties in preparing highly complex precursors for labeling,
shortcomings of the radiochemical reactions, and, for metal-
based methods, concerns about toxicity.
Dibenzothiophene sulfonium salts have previously been
obtained through activation of aromatic sulfoxides with
Figure 1. Dibenzothiophene sulfonium salts as leaving groups for
aromatic 18F-fluorination. A: coupling of a biaryl building block with the
structure of interest; B: ring-closing to form the dibenzothiophene
sulfonium salt precursor; C: 18F-fluorination. X = Br, I.
We have previously reported that triarylsulfonium salts allow
direct 18F-fluorination of small molecule drug-like compounds
containing non-activated and electron-deficient aromatic
rings.14 The appeal of this approach is the ability to label a
broad range of bioactive molecules under conditions that mirror
conventional substitution reactions with [18F]fluoride. How-
Received: July 3, 2018
© XXXX American Chemical Society
A
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trifluoromethanesulfonic acid, or trifluoromethanesulfonic
anhydride, to form highly reactive Pummerer-type intermediates
that trigger intramolmolecular cyclization.17−19 We envisaged
that direct S-activation of thioethers with a source of
electrophilic halogen, e.g. N-chlorosuccinimide (NCS),20,21
could provide a more concise and flexible synthetic route to
the target compounds.
Scheme 1. Synthesis of Building Block 5a,b and Coupling of
the Biaryl Thiol Moiety with Aryl Halides
a
RESULTS AND DISCUSSION
■
During initial studies with the unsubstituted biaryl thioether 1a,
we found that treatment with NCS and silver triflate afforded the
target dibenzothiophene sulfonium salt 2a, albeit in poor yield
(Table 1). To investigate the influence of electron-donating
groups on the ring-closing reaction, a small library of biaryl
thioethers was prepared. Introduction of methyl groups to rings
A and B, as for 1b, had a marginal impact on the cyclization yield.
However, addition of a tert-butyl substituent on ring A to give 1c
substantially increased the reactivity (14% and 56% for 2b and
2c, respectively). Finally, decoration of ring system A with
methoxy groups, as for 1d and 1e, allowed highly efficient ring-
closure, with formation of 2d and 2e in 82% and 79% yield,
respectively. The sulfonium triflate salts were obtained as stable,
non-hygroscopic solids and could readily be purified by liquid/
liquid extraction and column chromatography on silica gel.
Table 1. Synthesis and Labeling of Dibenzothiophene
a
Sulfonium Salts 2a−e
a
Conditions: (i) 2-ethylhexyl-3-mercaptopropionate, Pd2(dba)3,
Xantphos, Et3N, toluene, reflux, 2 h, 96%; (ii) 3,5-dimethoxyphenyl-
boronic acid, PEPPSI-IPr, K2CO3, toluene/water, reflux, 2 h, 95%;
(iii) 3,5-dimethoxyphenylboronic acid, Pd(OAc)2, iPrNH2, water,
reflux, 24 h, 93%; (iv) a) NaH, THF, 0 °C−RT, 30 min, b)
dimethylthiocarbamoyl chloride, 70 °C, 16 h, 89%; (v) neat, 290 °C,
3 h, 97%; (vi) tBuOK, Pd2(dba)3, DPEPhos (bis[(2-diphenyl-
phosphino)phenyl] ether), toluene, reflux. X = Br, I.
chemical yield (RCY) as determined by radio-high-performance
liquid chromatography (radio-HPLC), whereas the more
electron-rich precursors 2b−e gave RCYs in the range of
29−34%. High regioselectivity in favor of [18F]fluorobenzene
formation was observed for all cases, with the exception of
precursor 2d. In the latter case, introduction of an electron
donating methyl substituent on ring B, to give precursor 2e,
restored regioselectivity. Of the compounds investigated,
sulfonium salt 2e offered the optimal balance between
cyclization yield, reactivity with [18F]fluoride and regio-
selectivity of the labeling reaction.
a
Conditions: (i) NCS, AgOTf, 1,4-dioxane, reflux, 0.5−4 h; (ii)
[18F]fluoride, K222 (Kryptofix 222; 4,7,13,16,21,24-hexaoxa-1,10-
diazabicyclo[8.8.8]hexacosane)/KHCO3, DMSO, 110 °C, 15 min.
b
c
Isolated yield. As determined by radio-HPLC; experiments were
carried out in triplicate.
To allow direct incorporation of the optimized biaryl thiol
moiety 1e into complex structures (Figure 1, Step A), we
designed the two building blocks 5a-b and optimized their
synthesis on multigram scale (Scheme 1A). Briefly, 5a was
obtained in two steps, starting with the Pd-catalyzed coupling of
2-bromo-1-iodo-4-methylbenzene 3 with 2-ethylhexyl-3-
mercaptopropionate to form protected thiol 4.22 Subsequent
Suzuki coupling of 4 with 3,5-dimethoxyphenylboronic acid
provided 5a in 91% overall yield. Compound 5b was obtained in
three steps; Suzuki coupling of 2-bromo-4-methylphenol 6 with
3,5-dimethoxyphenylboronic acid provided 7, which was then
reacted with dimethylthiocarbamoyl chloride to give 8. The final
Dibenzothiophene sulfonium salts can potentially react with
[18F]fluoride by ipso-attack at any of the three S-substituted
carbons, resulting in either release of the desired 18F-fluorinated
arene, or side product formation by opening of the heterocyclic
ring system (red vs blue positions, respectively, Scheme on
Table 1). To assess the reactivity profile of this novel class of
leaving groups, the labeling efficiency of compounds 2a−e with
[18F]fluoride was investigated (Table 1). The radiochemical
reactions were carried out with 5 mg precursor in dimethyl-
sulfoxide (DMSO) at 110 °C for 15 min. The unsubstituted
analog 2a afforded [18F]fluorobenzene in 45
3% radio-
B
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step in the sequence was a Newman−Kwart rearrangement
under thermal conditions,23,24 which provided 5b in 80% overall
yield. Although the building blocks 5a-b underwent rapid
deprotection under basic conditions (Scheme 1B), we were not
able to isolate the corresponding thiol in synthetically useful
yields, as 9 rapidly oxidized to form the corresponding disulfide.
To circumvent this problem, we developed a one-pot procedure
for deprotection of 5a-b and subsequent Pd-mediated coupling
of 9 with aryl halides in situ (Scheme 1B) by combining
previously reported methods for the individual steps.22,25 This
provided a flexible, concise, and high-yielding route to install the
biaryl thioether moiety. Conveniently, the strategy also avoids
the need to handle any foul smelling compounds which
otherwise can be problematic with organosulfur chemistry.
While the synthesis of 5a is shorter and higher yielding than
the route to 5b, deprotection of 5a results in the formation of
2-ethylhexyl acrylate as a byproduct, which can give rise to side
products and complicate purification. The building block 5b
offers several advantages over 5a in that it is a crystalline solid
and the carbamothioate protecting group simplifies purification
and handling. However, the high temperature required for the
Newman−Kwart rearrangement makes this transformation non-
trivial, and deprotection of 5b requires excess potassium tert-
butoxide, which may compromise base-sensitive functional
groups.
in the presence of lanthanum(III) triflate, whereas bismuth(III)
triflate greatly increased the reactivity and provided 11a in 48%
yield (Table 2, entries 2 and 3). Changing the solvent from
1,4-dioxane to acetonitrile (MeCN) further increased the yield
to 79%. Remarkably, under these conditions, thioether 10a
cyclized almost instantly at ambient temperature to give the
target sulfonium salt 11a in 65% analytical yield (Table 2, entry
5) (Method A). When these conditions were applied on a
preparative scale, 11a was obtained in 82% yield. As
bismuth(III) triflate can liberate trifluoromethanesulfonic
acid,28 we hypothesized that the ring-closing reaction was
promoted by formation of a superelectrophile through Brønsted
acid activation of NCS (Scheme 2).29,30 Consistent with this,
trifluoromethanesulfonic acid in combination with NCS also
mediated rapid cyclization of 10a at room temperature (Table 2,
entry 8).
Scheme 2. Proposed Mechanism for the Ring-Closing
Reaction
With a method in hand to couple the biaryl thiol moiety with
functionalized aryls, we optimized the conditions for the
cyclization reaction to give the target dibenzothiophene
sulfonium salts. To ultimately allow labeling of the PET tracer
3-[1 8 F]fluoro-5-(pyridin‑3‑ylethynyl)benzonitrile
([18F]FPEB),26,27 the thioether 10a was prepared (2 steps from
5a, 65% overall yield). Attempted cyclization by treatment of
10a with NCS and silver triflate gave a disappointing 6% yield of
the corresponding sulfonium salt 11a, as determined by HPLC
(Table 2, entry 1). A comparable yield was obtained with NCS
Table 2. Optimization of the Ring-Closing Reaction
On the basis of these findings, we propose the following
mechanism for the ring-closing reaction: protonation of NCS
triggers attack of chlorine on the thioether group to give an
intermediate chlorosulfonium salt, which subsequently rear-
ranges through an intramolecular SEAr reaction to yield the
target dibenzothiophene sulfonium salt (Scheme 2).
To allow cyclization under neutral conditions, we explored
alternative sources of electrophilic chlorine. Several hypo-
chlorite salts mediated ring-closing of the thioether 10a;
however, yields varied considerably, and chlorination of the
dimethoxy-substituted aromatic group became a prominent side
reaction (results not shown). Eventually, we found that calcium
hypochlorite, in an acetate-buffered (pH 4) water−acetone
solvent system,31 reacted cleanly with 10a to give the target
sulfonium salt 11a in 43% yield within 15 min at room
temperature (Table 2, entry 9) (Method B). The latter system is
appealing, as it is exceptionally mild and relies exclusively on
low-toxicity, biocompatible components.
To investigate the scope of the ring-closing reaction, we
prepared a library of biaryl thioethers (Table 3). The
compounds 10b−k were obtained by Pd-mediated coupling of
the building block 5a with the respective aryl bromides or
iodides (see Supporting Information (SI)). When treated with
NCS and bismuth(III) triflate (Method A), the thioethers
10b−i rapidly cyclized (5 min to 2 h) under ambient conditions
a
Aqueous acetate buffer, 1 M, pH 4.
C
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Table 3. Scope Study for Aromatic 18F-Fluorination Using
Dibenzothiophene Sulfonium Salts as Precursors
(Method B) provided an efficient alternative and afforded the
target sulfonium salts 11j,k in 54% and 72% yields, respectively.
The dibenzothiophene sulfonium salts 11b−k were sub-
sequently used to investigate the scope of aromatic 18F-
fluorination (Table 3). To allow direct comparison, the
radiochemical reactions were carried out using the non-
optimized conditions described above. The least reactive of
the compounds, the tolyl salt 11b, afforded 4-[18F]fluorotoluene
in a modest 2% RCY (Table 3, entry 1). However, the
regioisomer 11c reacted to give 3-[18F]fluorotoluene in a
a
synthetically useful RCY of 15
5% (Table 3, entry 2).
Formation of 3-[18F]fluoroanisole in 27 5% RCY demon-
strates that dibenzothiophene sulfonium salts can allow labeling
of electron-rich aryls, provided that the substitution pattern is
favorable (Table 3, entry 3). Electron-deficient aryls and
pyridines were labeled in high RCY (Table 3, entries 4−10).
Notably, 3-[18F]fluoropyridine, which is difficult to label with
many other strategies, was formed in 65
5% RCY. The
sterically hindered tert-butyl ester 11i proved highly reactive and
gave [18F]12i in 84 5% RCY. However, labeling of 11e and
11h was problematic under these conditions due to decom-
position and side product formation. When the temperature was
reduced from 110 to 80 °C, 11e readily reacted to give
[18F]‑1,2,3-trifluorobenzene, a fragment of the PET tracer
[11C]UCB-J,32 in 43 5% RCY. In the case of 11h, the reaction
proceeded cleanly at 75 °C to give 4-[18F]fluorobenzaldehyde, a
well-established prosthetic labeling group,2 in 71% RCY.
To gain a deeper understanding of the fluorination
mechanism and the regioselectivity of the reaction, density
functional theory (DFT) calculations were performed. The
M06-2X hybrid functional was used33 with the 6-31+G(d,p)
basis set. Initial gas-phase calculations showed that the cation of
salt 2e could form a fluoride adduct 13a (Figure 2). In the
lowest-energy conformation Ia of this adduct, the sulfur atom
adopts a trigonal bipyramidal geometry, with a lone pair
occupying an equatorial site, and the fluorine atom and the
methoxy-substituted aromatic ring occupying axial positions.
The nature of the S−F interaction was probed using the
quantum theory of atoms in molecules (QTAIM) approach:34 in
ionic bonds, the electron density ρ at the bond critical point is
typically less than 0.10, while its Laplacian ∇2ρ has a positive
value. For the S−F bond in Ia, the calculated values were
ρ = 0.09 and ∇2ρ = +0.17, indicating that this is essentially an
ionic interaction.35 This conclusion was reinforced by
integration of the electron density in AIM basins: this gave net
charges of −0.77 on the fluorine atom and +0.66 on the sulfur.
Re-minimization of structure Ia under the SMD solvation
model36 with DMSO as solvent led to a lengthening of the S−F
bond (2.54 Å vs 2.00 Å) and an increase in its ionic nature
(calculated charges of −0.94 and +0.51 on F and S, respectively)
but no substantial change in the structure of the sulfonium
cation. All subsequent calculations were carried out with both
gas-phase and solution-phase optimization, with similar results;
the structures and energies presented below are for the solution-
phase calculations (details of gas-phase calculations are provided
in the SI).
a
Conditions: (i) Method A: NCS, Bi(OTf)3, MeCN, RT, 5 min−2 h
or Method B: Ca(OCl)2, acetate buffer pH 4, acetone, 0 °C−RT,
b
15 min; (ii) [18F]fluoride, K222/KHCO3, DMSO, 110 °C, 15 min. As
determined by radio-HPLC. Experiments were carried out in
triplicate. Method A was used. Method B was used. Labeling at
80 °C. Labeling at 75 °C.
c
d
e
f
(room temperature, open to air) to give the target sulfonium
salts 11b−i in good to excellent yields. Although electron-rich
systems proved the most reactive, ring-closing of electron-
deficient substrates, i.e. 10g and 10h, also proceeded cleanly and
in good yields. Introduction of ortho substituents, as for 10e and
10i, had only a marginal impact on the reaction, and the
sterically hindered tert-butyl ester 10i still afforded the
corresponding sulfonium salt 11i in 51% yield (Table 3, entries
4 and 8). However, the pyridyl-substituted thioethers 10j,k
failed to cyclize in the presence of NCS/bismuth(III) triflate,
likely due to the electron-withdrawing effect caused by
pyridinium salt formation with trifluoromethanesulfonic acid.
In these cases, acetate-buffered calcium hypochlorite
A second energy minimum was located for the sulfonium
fluoride salt 13a: conformation IIa, in which the phenyl group
and fluoride ion occupy the axial positions and both benzene
rings of the dibenzothiophene moiety are equatorially disposed.
Conformation IIa has a free energy 8.6 kJ mol−1 higher than that
of conformation Ia. A transition state linking Ia and IIa, labeled
TS-IIIa, could also be located, with a free energy 22.2 kJ mol−1
D
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Figure 2. Calculated free energy profile for formation of fluorobenzene and biphenyls 15 and 16 from sulfonium fluoride salt 13a. Structures are
optimized with M06-2X/6-31+G(d,p), SMD solvation in DMSO. Hydrogen atoms are omitted for clarity.
above that of Ia.37 This low barrier, compared to the barriers for
product formation (vide infra), suggests that the Curtin−
Hammett principle will be applicable and that the relative rates
of product formation will be determined by the energies of the
transition states leading to product, rather than by the relative
populations of conformers Ia and IIa.
From intermediate Ia, two possible routes for the formation of
fluorobenzene and dibenzothiophene 14 were considered: a
stepwise SNAr mechanism proceeding through a Meisenheimer
complex, and a concerted process which could be viewed either
as a direct nucleophilic aromatic substitution or as a reductive
elimination from sulfur. After extensive searching, no local
minimum corresponding to a Meisenheimer complex could be
located; instead a concerted mechanism, passing through a
single transition state TS-IVa, was identified. Similar concerted
mechanisms have been determined in computational studies of
nucleophilic aromatic fluorinations of iodonium(III) ylides and
diaryliodonium salts,12,38 aryl fluorosulfonates,39 and phenol-
uronium adducts.10
Analogous transition states TS-Va and TS-VIa could be
located, connecting conformation IIa of the sulfonium fluoride
salt 13a to biaryls 15 and 16, respectively. These transition states
were found 6.6 and 29.2 kJ mol−1, respectively, higher in energy
than TS-IVa, in accord with the good selectivity for attack on the
phenyl group seen experimentally.
Several other dibenzothiophenium fluorides 13b−k, corre-
sponding to the triflates 11b−k, were modeled to examine any
correlation between calculated activation energies and exper-
imental reactivity. Ground-state conformations and transition
states for fluoride attack on each of the three aromatic rings were
identified. Due to the difficulty in calculating a meaningful
energy for the solvated fluoride ion, the fluoride salts 13a−k
were taken as the zero-energy baseline for each of these
calculations (Table S5, SI). High correlation (R2 = 0.98) was
observed between calculated activation energy for attack on the
isolated aromatic ring and RCY (Figure S13, SI); i.e.,
compounds with low calculated activation energy gave high
RCYs. Moreover, the value of ΔΔG (i.e., the difference between
attack on the isolated ring and the dibenzothiophene) increased
with decreasing activation energy. This is consistent with the
increased regioselectivity observed experimentally for activated
substrates. Interestingly, the labeling yields also correlate with
the Hammett substituent constant σ (R2 = 0.97) and 19F
chemical shifts (R2 = 0.83) of the non-radioactive reference
compounds (Figures S14 and S15, SI). While we have not
measured the rates of the labeling reactions, the strong
correlation of RCYs with the Hammett substitution constant
nonetheless provides a valuable tool to predict the outcome of
radiochemical reactions. For substrates decorated with complex
functional groups, 19F NMR chemical shifts provide a
convenient alternative to determine the suitability of the
labeling reaction.
With the aim to demonstrate practicability of the method, we
prepared the sulfonium salt precursors of five biologically active
compounds, which were subsequently labeled with fluorine-18
(Figure 3). The thioether 10a was used to optimize cyclization
conditions (vide supra) and provided the dibenzothiophene
sulfonium salt precursor 11a for labeling of [18F]FPEB. This
PET tracer, which has been used clinically for imaging of
metabotropic glutamate 5 receptors, was particularly pertinent,
as our previous attempts at preparing the corresponding
triarylsulfonium salt had failed. Using the optimized ring-closing
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Figure 4. Autoradiography with 3-[18F]fluorodeprenyl ([18F]12o).
Specific binding of the tracer [18F]12o to human post-mortem brain
sections of a case with Alzheimer’s disease. Left: medial temporal lobe
section with hippocampus and parahippocampal gyrus; center:
thalamus with adjacent white matter; right: basal ganglia section with
the putamen and caudate nucleus. A: total tracer binding; B: tracer
binding after blocking with the selective MAO-B inhibitor L-deprenyl.
Scale bar: 1 cm. Abbreviations: HP, hippocampus; Thal, thalamus; BG,
basal ganglia.
[18F]fluoride, the radiosynthesis can readily be automated using
conventional equipment and established sequences for trapping
and release of [18F]fluoride, labeling, and purification.
With this proof of concept established, we applied the method
for labeling of the nitroimidazole [18F]12l, a novel candidate
tracer for imaging of hypoxia (Figure 3). The sulfonium salt
precursor 11l was obtained in 67% yield (Method A) from the
corresponding biaryl thioether 10l. Labeling with [18F]fluoride
(DMSO, 110 °C, 15 min, non-optimized) afforded the target
tracer [18F]12l in 32 3% d.c. RCY. The 3-[18F]fluoropyridine
12m ([18F]P3BZA) has recently shown promise for imaging of
melanoma in patients with metastatic disease; however, the
reported radiosynthesis is low yielding.41 Initial attempts to
synthesize the dibenzothiophene sulfonium salt precursor of
[18F]P3BZA 11m (Method B) were unsuccessful (<10% yield)
when the 2-(diethylamino)ethyl amide side chain was in place.
We therefore resolved to cyclize the corresponding ethyl ester
(method B, 54% yield, SI) and subsequently installed the side
chain to give 11m (92% yield). Labeling proceeded cleanly to
provide [18F]P3BZA 12m in 52 5% d.c. RCY (DMSO, 110
°C, 15 min, non-optimized), a substantial improvement on the
Figure 3. Radio-fluorination of biologically relevant tracers with
dibenzothiophene sulfonium salts as precursors for labeling.
reaction conditions (Method A), the labeling precursor 11a was
obtained in 82% yield. The resulting white crystalline solid
proved stable upon storage at ambient temperature over the
course of 3 years (Figure S2, SI). Attempted labeling of 11a
under the conditions used for the model compounds 11b−k
resulted in formation of a radioactive side product, likely due to
hydrolysis of the nitrile group (Table S1, SI). The side product
was practically eliminated by reducing the temperature and
shortening the reaction time. Further optimization revealed that
the precursor load could be lowered to 1 mg, and the solvent
changed to MeCN, without affecting the RCY. In DMSO, the
reaction proceeded at 50 °C (1 mg precursor, 5 min) to give
[18F]FPEB 12a in 75% RCY as determined by HPLC. An
identical RCY was obtained in MeCN at 80 °C. Under these
conditions (1 mg precursor, MeCN, 80 °C, 5 min), hands-on
labeling afforded [18F]FPEB 12a in 55 3% decay-corrected
(d.c.) RCY (43 2% non-decay-corrected (n.d.c.), Figure 3).
The molar activity was 13−20 GBq μmol−1, reflecting the low
levels of activity used for labeling (2 GBq) due to local
constraints.
The high reactivity of 11a, combined with its ease of synthesis
and suitability for long-term storage, demonstrate clear
advantages over other labeling strategies reported for this tracer.
For example, 18F-fluorination of the corresponding spirocyclic
iodonium ylide precursor was recently reported to give
[18F]FPEB in 20% n.d.c. RCY, whereas copper-mediated
labeling of a boronic ester precursor afforded the tracer in a
modest 13% n.d.c. RCY.5,40 As the reaction takes place under
conditions that mirror nucleophilic substitution reactions with
12
4% RCY reported for the corresponding bromide
precursor.41 To further evaluate the scope of the pH-buffered
cyclization method, we chose the 2-[18F]fluoropyridine 12n (2-
[18F]fluoro-H-11ONH) as the next target. Gratifyingly,
cyclization proceeded smoothly and provided the Boc-protected
precursor 11n in 72% yield (Method B). 18F-fluorination of 11n
(DMSO, 110 °C, 15 min, non-optimized) followed by Boc
deprotection afforded [18F]12n in 41 3% d.c. RCY.
Finally, we applied the labeling strategy for development of 3-
[18F]fluorodeprenyl 12o as a monoamine oxidase B (MAO-B)
PET tracer. MAO-B is highly expressed in glial cells and is up-
regulated in a number of neurodegenerative diseases.16,42 [11C]-
L-deprenyl was reported as a MAO-B-selective PET tracer more
than 30 years ago, yet attempted development of fluorine-18-
labeled analogs has so far been unsuccessful, and no other
MAO-B-selective ligand has found clinical use for PET imaging.
To explore the potential for direct aromatic fluorination of
deprenyl, we prepared the corresponding biaryl thioether 10o (3
steps from 5b, 56% overall yield). Cyclization of 10o proceeded
F
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smoothly to give the corresponding dibenzothiophene sulfo-
nium salt 11o in 73% yield (Method A). Subsequent labeling of
11o with fluorine-18 (DMSO, 150 °C, 15 min, non-optimized)
afforded 3-[18F]fluorodeprenyl in 32 2% d.c. RCY, with a
molar activity of 17−30 GBq μmol−1 (starting from 2 GBq of
[18F]fluoride). Autoradiography with [18F]12o in human post-
mortem brain sections of a case with Alzheimer’s disease (Figure
4) revealed tracer binding consistent with the expected
distribution of MAO-B. The specificity of the signal was
confirmed by blocking with the parent compound L-deprenyl.
Further development of [18F]12o as a MAO-B-selective PET
tracer is outside the scope of this study and will be reported
elsewhere.
Funding from the BRC/UCLH Charities (F196, L.B.), CRUK
& EPSRC Comprehensive Cancer Imaging Centre at KCL &
UCL jointly funded by Cancer Research UK, and the
Engineering and Physical Sciences Research Council (EPSRC;
C1519/A16463), an EPSRC Case Studentship in partnership
with GE (P.K.B.S), the UCL MSci in Chemistry (A.K.), and the
UCL MRes Organic Chemistry: Drug Discovery Programme
(M.W.). The QSBB is supported by the Reta Lila Weston
Institute for Neurological Studies and the Progressive Supra-
nuclear Palsy (Europe) Association. This work was undertaken
at UCLH/UCL, which is funded in part by the Department of
Health’s NIHR Biomedical Research Centres funding scheme.
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Corresponding Author
*e.arstad@ucl.ac.uk
ORCID
Thibault Gendron: 0000-0002-2162-3704
Kerstin Sander: 0000-0002-6096-7577
Michael J. Porter: 0000-0002-0376-5434
Erik Årstad: 0000-0002-3240-2106
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