Neither azeotropic drying, nor base nor other additives: A minimalist approach to 18F-labeling

Article abstract of DOI:10.1039/c4ob01336k

A novel, efficient, time-saving and reliable radiolabeling procedure via nucleophilic substitution with [¹⁸F]fluoride is described. Different radiolabeled aliphatic and aromatic compounds were prepared in high radiochemical yields simply by hea

Full text of DOI:10.1039/c4ob01336k

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Neither azeotropic drying, nor base nor other
additives: a minimalist approach to 18F-labeling†
Cite this: Org. Biomol. Chem., 2014,
12, 8094
R. Richarz,‡a,b P. Krapf,‡a,b F. Zarrad,a,b E. A. Urusova,b,c B. Neumaier*a,b and
B. D. Zlatopolskiya,b
A novel, efficient, time-saving and reliable radiolabeling procedure via nucleophilic substitution with
[
18F]fluoride is described. Different radiolabeled aliphatic and aromatic compounds were prepared in high
radiochemical yields simply by heating of quaternary anilinium, diaryliodonium and triarylsulfonium
18F]fluorides in suitable solvents. The latter were obtained via direct elution of 18F− from an anion
Received 30th June 2014,
Accepted 15th August 2014
[
exchange resin with alcoholic solutions of onium precursors. Neither azeotropic evaporation of water,
nor a base, nor any other additives like cryptands or crown ethers were necessary. Due to its simplicity
this method should be highly suitable for automated radiosyntheses, especially in microfluidic devices.
DOI: 10.1039/c4ob01336k
www.rsc.org/obc
drying with acetonitrile. K2.2.2 captures K+, and consequently
increases the nucleophilicity of 18F− by means of charge separ-
Introduction
Positron emission tomography (PET) offers quantitative real ation. To prepare the radiofluorinated compound, the dried
time 3D-visualization of physiological and pathological pro- residue of [K2.2.2K+]18F− is usually taken up in a solution of
cesses in vivo by means of probes labeled with β+-emitting the precursor in a polar aprotic solvent and heated for a short
nuclides (PET-nuclides). Among PET-nuclides, fluorine-18 period of time. The precursor should contain a suitable
(18F) is the most widely used since it is easily accessible in >50 leaving group for nucleophilic substitution with [18F]fluoride.
GBq quantities from H218O via the high-yielding 18O(p,n)18F Instead of K2CO3, other basic salts such as KHCO3 or K2C2O4/
nuclear reaction. Furthermore, 18F exhibits a low β+-energy K2CO3 in combination with a cryptand or Cs+ or tetraalkyl-
[E(β+) = 630 keV, 97%] resulting in PET images with high spatial ammonium carbonates or bicarbonates without a cryptand can
resolution.1 In addition, the half-life of 18F (109.8 min) enables be used.4 For more demanding radiofluorinations, radiolabeling
multistep radiosynthesis and allows distribution of the radio- can be substantially hampered by adsorption of 18F− onto the
labeled tracers to regional medical centers.
vessel walls (up to >50%).
Although numerous methods of 18F-labeling have been
A plethora of methods describing the production of highly
developed, the vast majority of radiofluorinated compounds reactive [18F]fluoride without the use of azeotropic drying
are prepared via aliphatic and aromatic nucleophilic substi- were reported. However, all of them suffer from significant
tution reactions with 18F−.2 In accordance with the production limitations.
route, [18F]fluoride is obtained in a H218O solution (1–3 mL).
Lemaire et al.5 avoided azeotropic drying by applying solu-
Owing to tenacious hydration, water significantly diminishes tions of phosphazene superbases like P2Et in MeCN contain-
the nucleophilicity of 18F−. To remove the bulk of water, ing water for almost quantitative elution of 18F− from the
18F− is usually trapped on an anion-exchange resin3 and then anion exchange resin. The eluate was added to a solution of
eluted with an aqueous solution of K2CO3. Thereafter, 2.2.2- the appropriate labeling precursor (up to 40 mg) and BTMG
cryptand (K2.2.2) in acetonitrile is added and the water is (2-tert-butyl-1,1,3,3-tetramethylguanidine) as an additional base
removed by time-consuming (7–15 min) repetitive azeotropic in anhydrous MeCN. Several radiofluorinated compounds were
successfully prepared by heating of the resulting mixture for a
short time. However, the extremely strong basic conditions
raise the question whether this reaction milieu is compatible
aInstitute of Radiochemistry and Experimental Molecular Imaging, University
Clinic Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
with the majority of precursors for radiofluorination. Addition-
ally, this method requires high amounts of P2Et and BTMG,
which are known to be highly toxic.
E-mail: bernd.neumaier@uk-koeln.de
bMax Planck Institute of Metabolic Research, Gleueler Str. 50, 50931 Cologne,
Germany
cClinic of Nuclear Medicine, RWTH Aachen University, Pauwelsstr. 30,
Aerts et al.6 avoided azeotropic drying using water-wettable
macroporous copolymers loaded with a long alkyl chain qua-
ternary ammonium carbonate to directly recover [18F]fluoride
52074 Aachen, Germany
†Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ob01336k
‡These authors contributed equally to this work.
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from [18O]H2O. [18F]Fluoride was eluted with MeCN in the
form of n-tetradecyltrimethylammonium [18F]fluoride together
with n-tetradecyltrimethylammonium carbonate.
Table 1 Preparation of [18F]fluorobenzaldehydes using iodonium pre-
cursors without azeotropic drying and any additivesa
This eluate was directly used for 18F-nucleophilic substi-
tutions. This method was disadvantageous with respect to the
need for high precursor amounts (15–40 mg) as well as in a
majority of cases of high amounts of an additional base
(K2CO3/K2.2.2 or Et4NHCO3) necessary to achieve high radio-
chemical yields.
Temperature [°C], Elution yield RCCc
time [min]
Entry LG+X− nb Solvent
of [18F]− [%] [%]
Wessmann et al.7 used highly concentrated KOH/K2.2.2 in
anhydrous MeCN to efficiently elute [18F]fluoride from an anion
exchange resin. An efficient 18F-incorporation via nucleophilic
aliphatic substitution was demonstrated using small aliquots of
18F− eluate. In upscaling experiments high amounts of radio-
labeling precursors were to be applied to achieve an acceptable
level of radiochemical conversion (RCC).§
1
TfO−
TfO−
Br−
2
3
3
3
4
4
95% DMF 130, 10
30
30
6
30
20
55
2
22
34
5
51
51
2d
3
4
5
6
DMSO
DMF
130, 10
160, 10
95% DMF 160, 15
DMSO 90, 10
90% DMF 160, 15
Br−
Br−
TfO−
a 18F− (200–500 MBq) was eluted from a QMA cartridge with a solution
of the iodonium precursor in the corresponding solvent (5 mg
in 500 μL). The resulting solution was heated at T °C for t min.
b n – substitution position. c H2O (4 mL) was added to quench the
reaction and completely solubilize surface-adsorbed 18F− and RCC
determined by radio-HPLC. d With 20 mg precursor. Each experiment
was carried out at least in triplicates. The standard deviation of RCC
did not exceed 20% of its mean value.
Quite recently, Chun et al.8 published radiofluorination of
diaryliodonium tosylates under organic-aqueous (up to 28%
water) and cryptand-free conditions using K2CO3 as a base.
Their method allowed to obtain moderate yields of 18F-
labeled compounds directly using the irradiated [18O]water
without the need for azeotropic drying and cryptand addition.
Unfortunately, the narrow scope significantly confines the of [18F]fluoride from an anion exchange resin with iodonium
practical utility of this method. Only (4-methoxyphenyl)aryli- [18F]FBA precursors in anhydrous DMF or DMSO was exam-
odonium salts containing selected strong electron-withdrawing ined (Table 1). With (3- and 4-formylphenyl)phenyliodonium
groups, CN, CO2R and CO(4-EWGAr) in the 2- or 4-position to triflates, radioactivity recovery amounted up to 30% (in the
iodine, could be radiolabeled yielding the corresponding [18F]- case of bromides up to 20%). The precursor eluate was directly
fluorobenzonitriles, [18F]fluorobenzoates and [18F]fluorobenzo- heated for 10–15 min.
phenones in moderate RCYs. Furthermore, the relatively low
Afterwards, an excess of water was added to quench the
concentration of 18F− in irradiated [18O]H2O limits the accessi- reaction and, most importantly, completely solubilize surface-
ble amounts of 18F-labeled compounds, especially using adsorbed 18F−.10 Formation of 3-[18F]FBA and 4-[18F]FBA in
microfluidic devices (reaction volume <50 μL).
RCCs up to 22 and 51%, respectively, was observed. Unreacted
Usually, basic salts are used to elute [18F]fluoride from an 18F− was the only impurity detected in the case of (para-formyl-
anion-exchange resin. At the same time, it can be quantitat- phenyl)phenyl iodonium salt precursors. In the case of meta-
ively recovered using neutral salts (e.g. isotonic saline). On the substituted salts, formation of [18F]fluorobenzene was also
other hand trimethylammonium and aryliodonium salts are observed. In contrast to other nucleophilic 18F-substitutions,
widely used as precursors for the preparation of radiofluori- the radiofluorination reactions of diaryliodonium salts tolerate
nated aromatic compounds. These onium salts which are the presence of water well.8 Consequently, water was added to
highly soluble in organic solvents could, we thought, be used the corresponding solvent to improve the elution yield of 18F−.
directly to elute [18F]fluoride from the anion-exchange resin. When (para-formylphenyl)-phenyliodonium triflate in 90%
Furthermore, we examined if the resulting onium [18F]fluoride DMF was used for elution, the radioactivity recovery amounted
salts could be directly converted into 18F-labeled compounds to 55% and 4-[18F]FBA was obtained in radiochemical conver-
without addition of a base or any other ingredients under sions (RCCs) of up to 51% within 15 min.11
“minimalist” conditions.
Elution of 18F− with onium salts
Results and discussion
Initial experiments
Radiofluorinated fluorobenzaldehydes (2-, 3- and 4-[18F]FBA)
were chosen as model compounds. They serve as versatile
building blocks for different radiosyntheses.9 First, the elution
The elution of 18F− with onium salts in aprotic solvents like
DMF or DMSO was rather ineffective (recovery <60%).
However, after some pilot experiments we found that the
elution of 18F− with onium salts in various alcohols was much
more effective (Fig. 1). Especially, with solutions of these salts
in MeOH or EtOH the total recovered radioactivity averaged
90–98%. Elution with precursors in higher alcohols was less
efficient. In particular, low-boiling methanol not only enabled
elution of more than 95% of the initially applied [18F]fluoride
but could also be completely removed at 70–80 °C within
§Radiochemical conversion (RCC) refers to the amount of radiofluoride which is
transformed to the desired 18F-labeled compound. It was determined by radio-
HPLC. Radiochemical yield (RCY) refers to the isolated yield of the radio-
chemically and chemically pure radiolabeled compound.
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Table 3 Preparation of [18F]fluorobenzaldehydesa
Temperature [°C], RCCc
Entry nb LG+X−
Solvent
time [min]
[%]
1
2
3
4
4
4
4
4
2
2
2
2
2
3
3
3
Me3N+I−
DMSO
DMSO
DMSO
DMF
DMSO
MeCN
DMSO
DMSO
DMSO
DMSO
80, 10
80, 10
150, 10
115, 10
80, 10
80, 10
80, 10
130, 15
80, 1–2
80–200, 10–15
75(65)d
87
90
Me3N+HCO3
−
Me3N+ClO4
−
4
Me3N+TfO−
Me3N+TfO−
63
5e
6
40–65
68
Me3N+HCO3
Me3N+I−
−
7
8
62(62)d
64(46)d
30–46
63–80
6
Me3N+TfO−
Me3N+TfO−
9e
10
11
12
13f
Me3N+ClO4
−
Me3N+I−
Sulfolane 200, 10
(4-MeOPh) I+ClO4 DMSO
−
150, 10
130, 10
40
45
PhI+Br−
DMF
Fig. 1 Recovery yield for the elution of 18F− from a QMA cartridge with
onium salts in anhydrous alcohols.
a 18F− was eluted from a QMA cartridge with precursor (5–8 mg) in
MeOH, methanol was evaporated under He flow (Ar/N2 can be used
instead) at 70–80 °C, the residue was dissolved in the appropriate
solvent and the resulting solution was heated at T °C for t min.
b n – substitution position. c H2O (4 mL) was added to quench the
reaction and solubilize surface-adsorbed 18F− and RCC determined by
radio-HPLC. d RCC with 2 mg precursor in 100 µL solvent. e K2.2.2/
K2CO3 protocol. f CsHCO3/TEMPO protocol.12b Each experiment was
carried out at least in triplicates. If the standard deviation of RCC
exceeded 20% of its mean value the range of RCC is given. TEMPO –
2,2,4,4-tetramethylpiperidine-N-oxyl.
Table 2 Elution of 18F− from a QMA cartridge with different amounts of
onium saltsa
Amount
Entry [mg]
Recovery of 18F− [%]
1
2
3
4
5
6
7
8
9
10
8
5
2.5
1
0.7
0.5
0.3
0.1
99
—
99
99
—
—
97
—
85
—
98
—
—
96
89
78
—
44
—
—
99
97
—
—
80
68
65
—
—
98
92
—
—
84
82
76
N,N,N-trimethylanilinium precursors. The counter-ion of the
precursor salt significantly influenced radiolabeling. From the
corresponding perchlorates in DMSO highest RCCs of 80%
and 90% for 2- and 4-[18F]FBA were achieved within 10 min, at
130 and 150 °C respectively. With bicarbonate or iodide salts,
2- and 4-[18F]FBA were obtained in good to excellent RCCs (up
to 68% and 87%, respectively) at 80 °C. In all cases, [18F]fluor-
ide was the only radioactive impurity detected after quenching
the reaction mixture with an excess of H2O. Reproducibility
and scalability were excellent.
a Target [18O]water was passed through an anion exchange resin. The
cartridge was washed with anhydrous MeOH and 18F− was eluted by a
solution of the corresponding precursor in MeOH (500 μL).
Thus, 4-[18F]FBA was prepared in 65–75% RCY from 43–47
GBq [18F]fluoride (n = 20, non-decay corrected) with >99%
radiochemical purity (RP) within 23 min using the bicarbonate
precursor. Unreacted [18F]fluoride was removed by solid phase
extraction (SPE). By comparison, using the conventional
K2CO3/K2.2.2 protocol, 2- and 4-[18F]FBA could be obtained
best in RCYs of 30–55%. Furthermore, a concurrent for-
mation of labeled side-products (5–25%) was observed. In
addition very short reaction times and a narrow temperature
range (60–120 s at 90 5 °C) had to be applied to obtain
reasonable RCCs and RCPs of 2-[18F]FBA since 2-[18F]FBA
was unstable under basic reaction conditions. In contrast,
the use of the perchlorate precursor under “minimalist”
conditions yielded 2-[18F]FBA in high RCCs of 63–80%
2–3 min without the need for azeotropic drying. Radioactivity
loss during the evaporation step was negligible (<2%).
With regard to radiosynthesis in microfluidic devices, we
studied the dependence of [18F]fluoride elution yield on behalf
of the precursor amount (Table 2). The elution yield of 18F−
exceeded 85% with only 0.1 mg precursor in the case of the
basic bicarbonate salt. Radioactivity recovery of more than
75% was reached using only 0.3–0.5 mg of non-basic iodide,
triflate or perchlorate precursors.
[18F]Fluorobenzaldehydes
Once a reliable method for the elution of [18F]fluoride had
been established, we focused on the preparation of [18F]FBAs
and an optimization of the radiosynthesis with respect to pre-
cursor, reaction solvent and temperature (Table 3).11 In the
case of 2- and 4-[18F]FBA, the best RCCs were achieved with
within
a broad reaction temperature and time range
(8–15 min at 80–200 °C). The dependence of RCC on the
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Table 4 Preparation of [18F]1 from onium precursors without azeotro-
precursor amount was briefly examined. RCCs of 2- and
4-[18F]FBA obtained from 2 mg of N,N,N-trimethylanilinium
iodide salts were similar to those obtained from 5 mg pre-
cursor (Table 3, entries 1 and 7; given in parentheses). In
the case of other onium salts RCCs were lower (Table 3,
entry 8; given in parentheses; see also Table S4, entries 3,
10, 15, and Table S5, entries 3, 5, 8; given in parentheses in
the ESI†).11 Consequently, all further experiments were
carried out with precursor amounts of 5–8 mg.
pic drying and addition of a basea
Temperature [°C],
time [min]
RCCb
[%]
As with 2- and 4-isomers, 3-[18F]FBA could be prepared from
the corresponding N,N,N-trimethylanilinium salts. However, due
to the weaker activating effect of the carbonyl group at the meta-
position, RCCs were low (not more than 6%) even under harsh
reaction conditions (Table 3). Using (4-methoxyphenyl)-iodonium
salt precursors, 3-[18F]FBA could be prepared in moderate RCCs
of up to 40%, which were comparable to those obtained under
conventional radiofluorination conditions.11,12 Again 18F− was
the only radioactive impurity which could be detected.
Entry
LG+X−
Solvent
−
1
Me3N+HCO3−
Me3N+HCO3
Me3N+TfO−
Me3N+I−
Sulfolane
DMSO
DMSO
Sulfolane
DMSO
DMSO
130, 15
200, 15
130, 30
200, 15
130, 10
120, 10
30
29
0
0
56
56
2
3c
4c
5
(4-MeOPh)I+I−
(4-MeOPh)I+I−
6d
a 18F− was eluted from a QMA cartridge with precursor in MeOH,
MeOH was evaporated under He flow at 70–80 °C, the residue was
dissolved in the appropriate solvent and the resulting solution was
heated at T °C for t min. b H2O (4 mL) was added to quench the
reaction and solubilize surface-adsorbed 18F− and RCC determined by
radio-HPLC. c K2.2.2/K2CO3 protocol. d CsHCO3/TEMPO protocol. Each
experiment was carried out at least in triplicates. The standard
deviation of RCC did not exceed 10% of its mean value.
18F-Labeled model peptide [18F]1
To further explore the scope of the novel radiofluorination pro-
cedure, its applicability was tested for several practically rele-
vant radiosyntheses. First, we studied the feasibility of the
n.c.a. one-step preparation of 18F-benzoylated peptides via direct
aromatic nucleophilic radiofluorination.13 In all radiosynth-
eses published so far additional electron withdrawing groups,
such as CN, CF3 and F, have to be used in order to increase the
reactivity of the trimethylammonium or nitro leaving group
and ensure acceptable labeling yields. These hydrophobic
groups could noticeably increase the overall lipophilicity of the
radiolabeled conjugates (especially in the case of short pep-
tides) and, consequently, unfavourably affect their biodistribu-
tion. We studied whether direct 18F-peptide labeling could also
Scheme 1 Synthesis of the 18F-labeled active ester
“minimalist” conditions.
[
18F]2 under
be carried out without an additional activating group. 4-[18F]- 4-[18F]fluorobenzoate ([18F]TFB, [18F]2) (Scheme 1), which is
Fluorobenzoyl-βAla-Phe-OMe [18F]1 was chosen as a model the carbo-analog of 2,3,5,6-tetrafluorophenyl 6-[18F]fluoro-
peptide. Initially, different N,N,N-trimethylammonium peptide nicotinate ([18F]F-Py-Tfp).14 [18F]TFB is a novel amine-reactive
precursors were investigated (Table 4). Using the conventional prosthetic group which can be used for labeling of peptides and
K2CO3/K2.2.2 radiofluorination procedure, no formation of proteins similar to the well known N-succinimidyl 4-[18F]fluoro-
[18F]1 was observed (entries 3, 4), whereas preparation of [18F]1 benzoate ([18F]SFB).15 However, all published radiosyntheses
under “minimalist” conditions led to the desired radiolabeled of [18F]SFB using the K2.2.2/K2CO3 protocol for radiofluorina-
conjugate as a single product in RCCs of up to 30%. Appli- tion consist of time-consuming and demanding procedures
cation of the corresponding (4-methoxyphenyl)iodonium comprising 2–3 reactions and multiple operation steps.16
iodide precursor allowed to reduce the reaction time from 15 In contrast, [18F]F-Py-Tfp can be prepared in good yield via
to 10 min and to raise the RCC to 56%. These almost neutral direct radiofluorination of the respective pyridine-2-N,N,N-
reaction conditions are comparable to or even milder than trimethylaminium precursor using less basic TBAHCO3 or
those described in the literature for the preparation of radio- KHCO3/K2.2.2. Unfortunately, formation of [18F]F-Py-Tfp is
labeled bombesin analogs and RGD peptides using additional accompanied by the concurrent formation of 2,3,5,6-tetrafluoro-
activating groups (DMSO, K2.2.2/K2CO3 or Cs2CO3, 70–130 °C, phenyl 6-(2,3,5,6-tetrafluorophenoxy)-nicotinate which should
4–15 min).13 The scope and limitations of the application of be completely separated from the radiolabeled active ester best
radiofluorination under “minimalist” conditions for the one- by HPLC.
step 18F-labeling of more complicated peptides are left to be
investigated in further studies.
Under “minimalist” conditions the radiolabeled active ester
[18F]2 was successfully prepared from the corresponding iodo-
nium precursor 3 in one step in a fair 24% RCC. Under con-
ventional K2.2.2/K2CO3 conditions an extensive decomposition
18F-Labeled active ester [18F]2
The novel radiofluorination method was applied to the prepa- of 3 was observed and only trace amounts of [18F]2 (<1%)
ration of an 18F-labeled active ester, 2,3,5,6-tetrafluorophenyl could be detected in the reaction mixture.
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Radiolabeling of sulfonium salt 5
Recently, triarylsulfonium salts have been proposed as precur-
sors for radiofluorination of aromatic compounds.17 1-[18F]-
fluoro-4-iodobenzene ([18F]FIB, [18F]4), a valuable building
block for radiolabeling via transition metal-catalyzed cross-
coupling reactions, was prepared from commercially available
(4-iodophenyl)diphenylsulfonium triflate (5) (Scheme 2).18 As
with anilinium and iodonium salts, almost complete 18F−
recovery from the anion exchange cartridge was achieved with
sulfonium salt 5 in MeOH. [18F]4 was prepared under “minim-
alist” conditions in 60–66% RCC using diglyme as a solvent at
85 °C for 10 min. Concurrent formation of [18F]fluorobenzene
(20–25%) was observed. Using K2CO3/K2.2.2, [18F]FIB was
obtained in RCCs of up to 40–50%.
Aliphatic 18F-labeling – preparation of [18F]FDR
Fig. 2 Comparison between conventional K2CO3/K2.2.2 and the
“minimalist” radiofluorination method.
Finally, the novel radiolabeling procedure was used for the syn-
thesis of 5-[18F]fluoro-D-ribose ([18F]FDR, [18F]6) (Scheme 3).
[18F]FDR is a hydrophilic prosthetic group for radiolabeling of
biopolymers via oxime ligation.19,20 First, the onium group-
containing precursor for radiolabeling has to be prepared. To
this end, protected D-ribose 720 was converted to the inter-
mediate dansyl sulfonate ester 8 which in turn was treated
with methyl triflate to give the desired precursor 9 with a 54%
yield over two steps (Scheme 3). [18F]Fluoride was eluted from
the solid support with 9 in MeOH almost quantitatively. After
MeOH removal, MeCN was added and the resulting solution
was heated at 80 °C for 10 min. Deprotection of the labeled
intermediate was accomplished by addition of 1 N HCl and
heating at 105 °C for 5 min. [18F]FDR was obtained in 72%
RCC. By comparison using the conventional K2CO3/K2.2.2 pro-
tocol, [18F]6 was prepared from the corresponding tosylate pre-
cursor 1020 in 58% RCC.
Conclusion
In all nucleophilic radiosyntheses with 18F− published to
date, a base often in combination with a cryptand or crown-
ether has been used. We demonstrated for the first time that
application of these ingredients is dispensable and in some
cases even counterproductive. 18F-Labeled compounds could
be efficiently prepared using only [18F]fluoride and onium
salt precursors. The radiolabeling method based on this
finding consists of direct elution of
alcoholic solutions of precursors bearing
[
18F]fluoride with
quaternary
a
ammonium, diaryliodonium or triarylsulfonium functionality
followed by heating of the resulting [18F]fluoride salt in a suit-
able solvent. A comparison of conventional K2CO3/K2.2.2 and
the novel radiofluorination method is shown in Fig. 2. The
versatility and the exceptionally wide scope of the novel radio-
fluorination procedure were demonstrated by the preparation
of several useful 18F-labeled prosthetic groups and by the
one-step preparation of a radiolabeled model peptide. Label-
ing yields were comparable to or in many cases even better
than those achieved with the classical K2.2.2/K2CO3 method.
Importantly, our novel method eliminates not only the need
for a base or other additives but also the need for time-con-
suming azeotropic evaporation steps. Besides, it enables the
synthesis of base-sensitive radiotracers and the use of base-
sensitive precursors. Moreover, due to its simplicity and the
fact that all starting materials and products are soluble in
organic solvents, the novel procedure should be well suited
for automated radiosyntheses, especially in microfluidic
devices.
Scheme 2 Preparation of [18F]FIB from sulfonium precursor 5 under
“minimalist” conditions.
Acknowledgements
We thank F. Wharton for her careful proofreading of the
manuscript.
Scheme 3 Preparation of [18F]FDR.
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