Fast and reliable generation of [18F]triflyl fluoride, a gaseous [18F]fluoride source

Article abstract of DOI:10.1039/c8cc03206h

A novel strategy for the production of reactive [¹⁸F]fluoride has been developed, omitting time consuming azeotropic drying procedures. Gaseous [¹⁸F]triflyl fluoride is formed instantaneously at room temperature from hydrated [¹⁸F]fluoride, followed by distillation in less than 5 minutes into a dry aprotic solvent, in which dry [¹⁸F]fluoride is released in presence of base with >90% radiochemical yield. The reactivity of the [¹⁸F]fluoride has been confirmed by reaction with several model compounds and by the synthesis of the PET tracers [¹⁸F]fluoroestradiol ([¹⁸F]FES) and O-2-[¹⁸F]fluoroethyl-l-tyrosine ([¹⁸F]FET), providing good isolated radiochemical yields and molar activities of up to 123 GBq μmol^?1.

Full text of DOI:10.1039/c8cc03206h

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Fast and reliable generation of [18F]triflyl fluoride,
a gaseous [18F]fluoride source†
Cite this:DOI: 10.1039/c8cc03206h
A. Pees, *a C. Sewing,a M. J. W. D. Vosjan,b V. Tadino,c J. D. M. Herscheid,a
a
a
Received 20th April 2018,
Accepted 1st June 2018
A. D. Windhorst
and D. J. Vugts
DOI: 10.1039/c8cc03206h
rsc.li/chemcomm
A novel strategy for the production of reactive [18F]fluoride has been since the base cannot be removed.3 As a consequence, alternative
developed, omitting time consuming azeotropic drying procedures. methods have been developed to circumvent the drying procedure.
Gaseous [18F]triflyl fluoride is formed instantaneously at room tempera- Firstly, the eluent for eluting [18F]fluoride from the anion-exchange
ture from hydrated [18F]fluoride, followed by distillation in less than resin has been varied: the use of strong organic bases in
5 minutes into a dry aprotic solvent, in which dry [18F]fluoride is MeCN,3 tetraethylammonium hydrogen carbonate in polar
released in presence of base with 490% radiochemical yield. The aprotic solvents,4 protic solvents in combination with cryptand
reactivity of the [18F]fluoride has been confirmed by reaction with and potassium salt,5 solutions of sulfonyl derivatives6 as well as
several model compounds and by the synthesis of the PET tracers alcoholic solutions of precursors containing a quaternary
[
18F]fluoroestradiol ([18F]FES) and O-2-[18F]fluoroethyl-L-tyrosine ammonium, diaryliodonium or triarylsulfonium functionality7 have
([18F]FET), providing good isolated radiochemical yields and molar been reported. Secondly, modified anion exchange resins have been
activities of up to 123 GBq lmolÀ1
.
used, containing e.g. macroporous copolymers loaded with long
alkyl chain quaternary ammonium salts2 or the phosphonium
Fluorine-18, a popular radionuclide used for Positron Emission borane [(Ph2MeP)C6H4(BMes2)]+.8 Thirdly, the use of additives in
Tomography (PET), can be produced via the nuclear reaction the labelling solution has been described, which make azeotropic
18O(p,n)18F by irradiation of an oxygen-18 enriched water target drying of the eluate unnecessary. Sergeev et al. reported the use of
and is obtained as strongly hydrated [18F]fluoride, which is titanium dioxide nanoparticles as catalyst and water adsorbent
unreactive towards nucleophilic substitution reactions. To allowing radiofluorination in aqueous mixtures with up to 25 vol%
enhance the reactivity of [18F]fluoride and recover expensive of water.9 Finally, electrodeposition has been extensively studied,
enriched target water, the radionuclide is processed before especially with regard to its use in microfluidic devices: after anodic
further reaction. Most commonly, [18F]fluoride is trapped on deposition of [18F]fluoride from the water target, it is recovered
an anion-exchange resin, eluted with a mixture of MeCN and under reversed voltage in aprotic solvent containing a phase transfer
water containing a complex of inorganic base and cryptand catalyst.10–14 In conclusion, all these alternative and improved
(typically K2CO3/kryptofix-K2.2.2.) and dried by repeated azeo- methods solve one or more of the aforementioned issues.
tropic distillation with MeCN.1,2
We present a novel strategy which allows for fast generation
However, this procedure has several drawbacks: (i) it is time- of dry [18F]fluoride which can be broadly applied in radio-
consuming and complicated to miniaturise, e.g. for the use in fluorination reactions. In a first step, [18F]fluoride is trapped
microfluidic devices; (ii) significant amounts of radioactivity can be on an anion-exchange column to recover the target water,
lost during azeotropic drying due to decay and unspecific adsorp- followed by elution from the column with an aqueous potas-
tion to the walls of the reaction vessel; (iii) most importantly sium salt solution and conversion to volatile [18F]triflyl fluoride
substantial amounts of base are needed to isolate [18F]fluoride (b.p. À25 1C)15 using bistriflate 1. After distillation [18F]triflyl
from the cartridge thereby limiting the subsequent reaction scope, fluoride is trapped in a dry aprotic solvent and dry [18F]fluoride
is released in the presence of base and kryptofix-K2.2.2. (see
a Department of Radiology & Nuclear Medicine, Location Radionuclidecenter,
De Boelelaan 1085C, 1081 HV Amsterdam, The Netherlands.
Scheme 1). The type and amount of base are variable and thus
can be adapted with regard to the subsequent radiofluorination
reaction. This method provides dry [18F]fluoride in a very short time
and allows for subsequent radiofluorination under mild conditions.
Furthermore, gaseous [18F]triflyl fluoride 2 can be transported over
longer distance, as e.g. is also done with [11C]CO2. During the course
E-mail: a.pees@vumc.nl
b BV Cyclotron VU, De Boelelaan 1081, 1081 HV Amsterdam, The Netherlands
c ORA Neptis, Rue de la Gendarmerie 50/B, 5600 Philippeville, Belgium
† Electronic supplementary information (ESI) available: Synthesis and characterisation
of reference compounds and experimental details. See DOI: 10.1039/c8cc03206h
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[18F]fluoride was eluted from the cartridge, whereas commonly
1 mL of K2CO3/kryptofix-K2.2.2. solution is needed for complete
elution. However, it was noticed that this high elution efficiency
was only realised with the stepwise elution. When eluting with
500 mL 0.1 M potassium sulfate at once, only 85 Æ 5% of the
radioactivity was recovered (n = 6). Because of the small volume
of the eluent it came to significant losses of radioactivity in the
tubing. By flushing the column and the tubes with 850 mL DMF
after the elution with 0.1 M potassium sulfate, the efficiency
could be increased to 97 Æ 3% (n = 8).
Scheme 1
[
18F]Triflyl fluoride formation and reaction to dry [18F]fluoride.
The conversion of the eluted [18F]fluoride to [18F]triflyl
fluoride was performed in different solvents to determine
which of them provided the best radiochemical yield. Reactions
in DMF, MeCN, THF and dioxane were studied. MeCN and
DMF both resulted in radiochemical yields of over 90%, while
reaction in dioxane and THF provided much lower radiochemical
yields (see Table S2 of the ESI†). Because DMF proved to be slightly
superior to MeCN in the overall radiochemical yield, it was used for
all further experiments.
of our work a patent application outlining the role of sulfonyl
fluorides in volatilising fluoride for PET was published, although
exemplification did not extend to triflyl fluoride.6b
Initial studies showed, that [18F]fluoride can be eluted from
an anion-exchange cartridge using a 0.1 M potassium sulfate
solution without the need for a cryptand, such as kryptofix. In
reactions of aliquots of this aqueous [18F]fluoride-containing
solution with bistriflate 1 in polar aprotic solvent, volatile
[18F]triflyl fluoride 2 was formed at room temperature. Further-
more, the addition of base, e.g. KHCO3 or K2CO3 used for the
standard elution procedure, led to decomposition of the product
and formation of free [18F]fluoride. This fuelled our idea to use
[18F]triflyl fluoride as carrier to transfer [18F]fluoride from an
aqueous to a polar aprotic medium. Hence, the following reaction
setup was developed: [18F]fluoride was eluted from the cartridge
using a 0.1 M potassium sulfate solution. An aliquot or the total
volume was taken and added to a solution of bistriflate 1 in DMF.
Instantaneously formed [18F]triflyl fluoride 2 was distilled at room
temperature under a gentle stream of helium (10 mL minÀ1) to a
second reaction vessel, where it was trapped in a solution of KHCO3
and kryptofix in MeCN. Hereinafter, the optimisation process of the
whole setup is described.
Next, the amount of water that is allowed in the [18F]triflyl
fluoride formation was investigated. When precursor 1 was
reacted for 5 minutes at room temperature in DMF in the
presence of different amounts of water, B5% of water led to
optimal radiochemical yields (490%, determined by HPLC) for
all examined precursor concentrations, being 5, 10, 50 and
100 mM. With increased water content, the radiochemical
yields dropped and became less reproducible (see Table S3
of the ESI†). However, when the temperature was raised from
20 to 40 1C, up to 33% of water was allowed and 490% isolated
radiochemical yield could be obtained again.
To promote dryness of the distilled radioactivity in the
second reaction vessel for subsequent radiofluorination,
[18F]triflyl fluoride was distilled over a drying column. Different
materials were examined (see Table 1). Whereas calcium sulfate
trapped a notable amount of radioactivity during the distillation,
only low amounts of radioactivity (r1%) remained on the drying
column when using copper(II)sulfate, magnesium sulfate, sodium
sulfate or phosphorus pentoxide (sicapent). P2O5 showed 0.2 Æ 0.1%
(n = 2) retained radioactivity and high radiochemical conversions of
the distilled [18F]triflyl fluoride in the subsequent reactions.
Finally, the trapping efficiency of [18F]triflyl fluoride was
investigated, which proved to be rather difficult. Only at tem-
peratures of À100 1C, satisfactory trapping of [18F]triflyl fluoride in
THF with radiochemical yields of up to 95% could be achieved, but
the yields were strongly varying. A more reproducible trapping
efficiency was obtained at higher temperatures, when the [18F]triflyl
fluoride was converted instantaneously in the trapping solution
To investigate the efficiency of the elution of [18F]fluoride
from the anion exchange resin (Chromafixs 30-PS-HCO3) with
0.1 M potassium sulfate solution, [18F]fluoride was eluted in
small steps of 100 mL and the eluted amount of radioactivity
was measured (n = 4). Fig. 1 shows the percentage of eluted
radioactivity relative to the starting amount of radioactivity on
the cartridge for volumes up to 500 mL. Compared to the
standard eluent, the elution efficiency was much higher: with
only 500 mL of 0.1 M potassium sulfate solution, Z99% of the
Table 1 Drying columns
Drying column
Remaining activity on drying column (%)
CaSO4
CuSO4
MgSO4
Na2SO4
P2O5
15.0 Æ 1.0
0.6 Æ 0.6
1.0 Æ 0.0
0.7 Æ 0.2
0.2 Æ 0.1
Fig. 1 Elution efficiency of 0.1 M K2SO4 in water.
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Scheme 3 Aliphatic
[
18F]fluorination of different model compounds;
non-isolated and non-decay corrected, n = 2.
radioactivity of the [18F]triflyl fluoride reaction (n = 2) was
trapped in the 1,4-dinitrobenzene solution by near quantitative
conversion to [18F]fluoronitrobenzene. Thus, this method had a
high trapping efficiency as well as a high conversion to the final
radiofluorinated product. Additionally, the procedure was time-
saving as distillation and reaction were performed at once.
Next to the radiofluorination of 1,4-dinitrobenzene, radio-
Scheme 2 Aromatic [
18F]fluorination of different model compounds.
* Red: strong electron withdrawing; green: weak electron withdrawing;
blue: electron donating; non-isolated and non-decay corrected, n = 2.
into free [18F]fluoride and trapped as such in a solution of fluorination of other compounds has been carried out to
KHCO3 and kryptofix-K2.2.2.. 94 Æ 1% (n = 3) radiochemical yield investigate the performance of the [18F]triflyl fluoride derived
(percentage of distilled and trapped radioactivity relative to the [18F]fluoride in radiofluorination reactions. Aromatic molecules
eluted amount of [18F]fluoride) was obtained by trapping with strong electron withdrawing groups, weak electron withdraw-
the [18F]triflyl fluoride by quantitative conversion to [18F]fluoride ing groups and electron donating groups (see Scheme 2) as well as
in a 26.6 mM KHCO3/kryptofix-K2.2.2. solution in MeCN at room aliphatic molecules with different leaving groups (see Scheme 3)
temperature. The distillate was used in a model reaction to test the were chosen as model compounds. The radiochemical yields were
reactivity of the [18F]fluoride. 1,4-Dinitrobenzene 3 was converted to determined by HPLC for all model reactions (n = 2). Of the
4-[18F]fluoronitrobenzene at 50 1C within 5 minutes with a radio- nitrobenzenes, para-dinitrobenzene 3 and ortho-dinitrobenzene 5
chemical yield of 495% (determined by HPLC) (see Scheme 2). To could be radiofluorinated in MeCN at 50 1C in 97 Æ 1% and
assess the suitability of other solvents for trapping at room 96 Æ 1% yield, respectively, whereas meta-dinitrobenzene 7 could
temperature, solutions of KHCO3 and kryptofix-K2.2.2. in DMF, not be converted to the desired product under these conditions.
DMA, THF and DMSO were tested. Trapping in DMF and DMA Compared to conventional syntheses described in literature, shorter
resulted in comparable trapping efficiencies as MeCN providing reaction times and lower temperatures could be applied.16,17 For
the [18F]fluoride in radiochemical yields of 95 Æ 1% and 95 Æ 3% example the radiofluorination of ortho-dinitrobenzene 5 resulted
(n = 2), respectively. Also in THF a good trapping efficiency was after 5 minutes at 50 1C in 96 Æ 1% yield, while according to
achieved, however radiochemical yields were slightly lower than literature temperatures of 130 1C and reaction times of 10 minutes
with DMF and DMA as solvent (90 Æ 4%; n = 2). In DMSO, are needed.16 The radiofluorination yield of 4-nitrobenzonitrile 4 was
the trapping was least efficient and not very reproducible: dry low as expected (5 Æ 1%). Also para-substituted nitrobenzenes
[18F]fluoride was obtained in radiochemical yields of 62 Æ 19% carrying a methyl, bromo, aldehyde or methyl ester group
(n = 2). Besides KHCO3, the use of other bases has been investigated showed no or minor conversion to the radiofluorinated product
(see Table S5 of the ESI†). With a solution of K2CO3 and kryptofix in because the aromatic rings were not sufficiently activated by the
MeCN, a base-cryptand combination often used in radiofluorina- substituents for radiofluorination (see Scheme 2). Besides
tion reactions, a bit lower trapping efficiencies of 72–92% were nitro precursors, also para-substituted N,N,N-trimethylammonium
obtained. Similarly efficient trapping (77–92% radiochemical yield) benzene precursors have been explored. With strong electron with-
was observed, when dibenzo-18-crown-6/K2CO3 or (n-Bu)4NH4SO4/ drawing groups such as the nitro and nitrile group high radio-
Na2CO3 was employed. Only very low trapping efficiencies of 1–15% chemical yields close to quantitative were obtained. Analogous to the
were observed when using DABCO and kryptofix-K2.2.2. without any nitro precursor, no conversion to the [18F]fluorinated product was
base at room temperature. A further possibility, which may be observed with the electron donating methyl group. With the weak
convenient in the automated synthesis of a tracer, is immediate electron withdrawing aldehyde group good yields of 81 Æ 1% were
reaction of the trapped radioactivity with the precursor. Thus, obtained, which is comparable to literature results.18
[18F]triflyl fluoride was directly distilled into a solution of
As aliphatic model compounds, a series of 3-substituted
1,4-dinitrobenzene, KHCO3 and kryptofix-K2.2.2. in MeCN phenyl propanes with different halogens and sulfonates as
heated at 50 1C and reacted for 5 minutes. 82 Æ 3% of the leaving groups has been studied (see Scheme 3). With all
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alternative drying strategies where the labelling solution con-
tains too much water, base or other additives; (3) this methods
allows in some instances for labelling under milder conditions
than conventionally dried [18F]fluoride; (4) the type and amount
of base and cryptand can be varied freely and therefore can be
tailored to the need of the subsequent radiofluorination reaction
which is in contrast to conventional labelling conditions and
many of the alternatives summarized in this manuscript.
The project is financially supported by The Netherlands
Organization of Scientific Research (NWO) grant no. 731.015.413
and BV Cyclotron VU.
Scheme 4 PET tracers synthesized with the [18F]triflyl fluoride method
(n = 2).
leaving groups, high radiochemical yields of over 90% were
obtained in the [18F]fluorination reaction. However, reaction
conditions giving the optimal yields were differing depending
on the leaving group. Whereas 1-phenyl-3-tosyl propane 15 was
[18F]fluorinated in 5 minutes at 80 1C, radiofluorination of the
corresponding mesylate 16 required higher temperatures of
120 1C and quantitative [18F]fluorination of the halides only
occurred after 15 minutes at 80 1C. Next to the phenyl propanes,
two different 3-substituted tosyl propanes were radiofluorinated.
1-[18F]Fluoro-3-tosyl propane was obtained from the ditosylate
precursor 19 in good radiochemical yields (71 Æ 3%) at moderate
temperature (50 1C). In literature, higher reaction temperatures
(90 1C) were reported,19 indicating that [18F]fluoride obtained by
the [18F]triflyl fluoride method enables labelling under milder
reaction conditions. Labelling of the corresponding tosyl azide
at 80 1C yielded 89 Æ 7% of 1-azido-3-[18F]fluoro propane after
5 minutes reaction time.
In addition to the model compounds, two tracers were
synthesized from [18F]triflyl fluoride derived [18F]fluoride to
prove the applicability of this method in PET tracer synthesis
(see Scheme 4). [18F]Fluoroestradiol ([18F]FES) 22, which targets
the estrogen receptor and is used for breast cancer imaging,
was successfully synthesized with isolated radiochemical yields
of 17 and 57%. The amino acid analogue O-2-[18F]fluoroethyl-L-
tyrosine ([18F]FET) 23 was synthesized from the ((2S)-O-(2-
tosyloxyethyl))-N-trityl-tyrosine-tert-butyl ester precursor and was
likewise obtained with moderate to good radiochemical yields
Conflicts of interest
There are no conflicts to declare.
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via [18F]triflyl fluoride is fast and reliable. Dry [18F]fluoride can
be obtained within 5 minutes and with recovery yields of 490%,
whereas the conventional drying procedure can take 10–30 minutes
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Chem. Commun.
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