Improved synthesis of [18F]fluoromethyl tosylate, a convenient reagent for radiofluoromethylations

Article abstract of DOI:10.1002/jlcr.949

The utility of [¹⁸F]fluoromethyl tosylate as an [ ¹⁸F]fluoromethylation reagent has been reexamined. The preparation of this potentially useful compound from the reaction of bis(tosyloxy) methane with ¹⁸F- was reported sev

Full text of DOI:10.1002/jlcr.949

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 557–568.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.949
Research Article
Improved synthesis of [18F]fluoromethyl tosylate, a
convenient reagent for radiofluoromethylations
Timothy R. Neal1,*, Scott Apana1 and Marc S. Berridge1,2
1 3D Imaging, LLC, 7650 First Place, Building B, Suite A, Oakwood Village, OH
44146-6713, USA
2 Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA
Summary
The utility of [18F]fluoromethyl tosylate as an [18F]fluoromethylation reagent has been
reexamined. The preparation of this potentially useful compound from the reaction of
bis(tosyloxy) methane with 18F- was reported several years ago, but it had not found
use as a labeling reagent. When the reported reaction of bis(tosyloxy) methane with
18F- was carried out, [18F]fluoromethyl tosylate was formed along with [18F]tosyl
fluoride. The product ratio depended upon reaction conditions, with the yield of
[18F]fluoromethyl tosylate usually in the range of 25–40%. Addition of a small
amount of water to the reaction mixture resulted in a significant increase in the yield
of [18F]fluoromethyl tosylate. Reaction conditions were defined that produced a yield
of 71ꢀ 6% of [18F]fluoromethyl tosylate (decay corrected). The product was
conveniently purified by alumina chromatography. Reaction of [18F]fluoromethyl
tosylate with the (des-fluoromethyl) fluticasone propionate thioacid precursor
produced [18F]fluticasone propionate in improved yield (16%, from fluoride in
production-scale runs) over other synthesis methods. Similarly, formation of
[18F]choline, [18F]fluoromethionine and N-([18F]fluoromethyl)spiperone from the
reaction of [18F]fluoromethyl tosylate with corresponding precursors was exam-
ined. Copyright # 2005 John Wiley & Sons, Ltd.
Key Words: fluorine-18; fluoromethylation; [18F]fluoromethyl tosylate; fluticasone
propionate
Introduction
In conjunction with other work, the preparation [18F]fluticasone propionate
([18F]FP) was desired. The synthesis of [18F]FP by the reaction shown in
*Correspondence to: Timothy R. Neal, 3D Imaging, LLC, 7650 First Place, Building B, Suite A, Oakwood
Village, OH 44146-6713, USA. E-mail: tneal@cyclo-tech.com
Contract/grant sponsor: GlaxoSmithKline
Copyright # 2005 John Wiley & Sons, Ltd.
Received 10 September 2004
Revised 22 September 2004
Accepted 10 March 2005

558
T. R. NEAL ET AL.
18
TsO
HO
F
S
O
S
O
O
O
HO
O
O
-
18
F
F
F
Kryptofix
O
O
F
F
18
1
[
F]FP
Scheme 1. Published route of Aigbirhio et al. for the preparation of [18F]FP
18
F
O
S
O
HS
O
O
HO
HO
O
O
18FCH2X
F
F
F
F
O
O
3
2
[
18F]FP
Scheme 2. Possible alternate route for the preparation of [18F]FP
Scheme 1 has been reported by Aigbirhio et al.,1 and Constantinou et al.,2,3
but the precursor 1 has limited stability in the reaction solution, resulting in
low and variable yields of [18F]FP. Therefore, the feasibility of producing
[18F]FP from the reaction of the FP thioacid precursor 2 with a suitable
[18F]fluoromethyl derivative 3 was explored, as shown in Scheme 2.
At the time this work was begun, [18F]fluoromethyl bromide4–9 (3, X ¼ Br)
and [18F]fluoromethyl iodide5,8,10,11 (3, X ¼ I), had been reported as reagents
for introduction of the [18F]fluoromethyl group. These reagents suffer from
relatively low reactivity and are somewhat inconvenient to prepare. The
preparation of [18F]fluoromethyl triflate (3, X ¼ OTf) has recently been
reported.12,13 Although this precursor is highly reactive, its preparation
involves two steps and requires a specialized synthesis system. It was hoped
some of the disadvantages of these labeling reagents could be circumvented.
The mesylate and tosylate analogs of 3 (X ¼ OMs and OTs) were first
prepared by Coenen and Block several years ago,14,15 but no additional
literature references for these compounds were found. The preparation of
these reagents is depicted in Scheme 3.
Coenen and Block reported that the reaction of diiodomethane with the
silver salt of the appropriate sulfonic acid in refluxing acetonitrile yielded
the corresponding bis(sulfonyloxy) methane derivative.14–16 Reaction of
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 557–568

FLUOROMETHYLATIONS WITH [18F] FLUOROMETHYL TOSYLATE
559
18
R
O
F
R
O
R
O
O
O
O
O
O
O
AgOSO2R
18 -
F
I
I
S
S
S
Scheme 3. Preparation of [18F]fluoromethyl mesylate and tosylate (R=methyl
and p-tolyl, respectively)
bis(mesyloxy) methane and bis(tosyloxy) methane with 18F- resulted in the
formation of [18F]fluoromethyl mesylate and [18F]fluoromethyl tosylate in
approximately 80 and 40% yield, respectively.14,15 (chloromethyl-, bromo-
methyl- and iodomethyl tosylate have been reported)17. The yield of
[18F]fluoromethyl sulfonate was found to increase dramatically as the
concentration of bis(sulfonyloxy) methane was increased over the range of
0.02–0.3 M.14,15 It was stated that the limited solubility of bis(tosyloxy)
methane (maximum 0.25 M) is responsible for the lower yield of the tosyl
derivative.14,15 Reaction of [18F]fluoromethyl mesylate and [18F]fluoromethyl
tosylate with p-chlorophenol was reported to produce p-chloroanisole in 1 and
23% yield, respectively.15 No other reactions of these reagents were reported;
however the results appeared promising for applications involving the labeling
of molecules of interest with 18F. Therefore [18F]fluoromethyl mesylate and
[18F]fluoromethyl tosylate were reexamined in this work as potential
[18F]fluoromethylation reagents.y
Results and discussion
Reaction of bis(mesyloxy) methane with 18F- resulted in the formation of
[18F]fluoromethyl mesylate in good yield. Reaction with 2 produced only a
trace of [18F]FP, consistent with the result of the reported reaction with
p-chlorophenol.15 Consequently, subsequent experiments utilized [18F]fluor-
omethyl tosylate.
Coenen and Block examined the effect of solvent, reaction time and
substrate concentration on the reaction of bis(tosyloxy) methane with 18F-.14,15
Based upon their observations, some modifications were made to determine
the affect on yield. In the present work, the reaction was carried out in
acetonitrile, dimethylformamide and acetone, using 18F- solubilized with
tetrabutylammonium bicarbonate (TBABC), Kryptofix1 2.2.2(Kryptofix)/
K2CO3, and Kryptofix/KHCO3, and with varying amounts of complexing
agent and bis(tosyloxy) methane. None of the modifications made in the
present work resulted in an improvement in yield.
The reaction of 18F- with bis(tosyloxy) methane resulted in the formation of
[18F]fluoromethyl tosylate and a moderately volatile and less polar product,
y We18 and Lim and coworkers19 have presented preliminary results using [18F]fluoromethyl tosylate as a
[
18F]fluoromethylation reagent. Unlabelled fluoromethyl tosylate has been recently reported.13,20
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 557–568

560
T. R. NEAL ET AL.
based upon analysis by TLC and HPLC.18 The reaction of bis(tosyloxy)
methane with unlabeled KF produced fluoromethyl tosylate14,15 and the
same byproduct. When 18F- was solubilized with TBABC or low levels of
Kryptofix /K2CO3, the byproduct predominated. By using a larger amount of
Kryptofix/K2CO3, [18F]fluoromethyl tosylate was the major labeled product.
The effect of solubilization agent upon product distribution is presented in
Table 1.
The yield of [18F]fluoromethyl tosylate was usually in the 25–40% range,
consistent with the reported results.14,15 Although the yield of [18F]fluor-
omethyl tosylate was relatively reproducible, the yield of byproduct was highly
variable. Total consumption of fluoride ion could be raised significantly higher
than 40%, but the increase was due only to increased formation of the
byproduct.
The exclusive formation of the byproduct from this reaction has recently
been reported, and its identity as [18F]difluoromethane was suggested.19
However, in this work the byproduct was identified as [18F]tosyl fluoride. The
reactions of both 18F- and KF with bis(tosyloxy) methane produced material
which had the same Rf (normal-phase TLC) and retention time (reversed-
phase HPLC) as authentic unlabeled tosyl fluoride. De Kleijn and coworkers
have reported that [18F]tosyl fluoride is formed from reaction of 18F- with tosyl
chloride.21,22 The product of a separate reaction of tosyl chloride with high
specific activity 18F- also coeluted on TLC and HPLC with the reaction
byproduct. Further, there was no evidence that [18F]difluoromethane was
formed in the reaction, as previously suggested.19 Production of [18F]difluor-
omethane would require that two fluoride ions react with a single precursor in
a no-carrier-added reaction. This is a highly unlikely event. No other labeled
products were observed in any experiments and typically 595% of the initial
radioactivity was accounted for by the observed products and unreacted
fluoride. Thus, at most a trace of [18F]difluoromethane could have been
produced.
Table 1. Effect of TBABC and amount of Kryptofix on product ratio of 18F-CH2-OTs
and [18F]tosyl fluoridea
Kryptofixb (mg)
Product distribution 18F-CH2-OTs: [18F]tosyl fluoride
1.5
9
12
9:91
26:74
36:64
62:38
68:32
15:85 ꢀ 6, n ¼ 15
15
18
TBABCc
a Data from selected experiments demonstrating a trend.
b Reaction conditions: 10 mg bis(tosyloxy) methane, 100 ml ACN, Kryptofix/K2CO3=3.8, 1108C, 10 min,
n ¼ 1.
c Reaction conditions: 5–10 mg bis(tosyloxy) methane, 5–10 mg TBABC, 100 ml ACN, 1108C, 10 min.
Copyright # 2005 John Wiley & Sons, Ltd.
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FLUOROMETHYLATIONS WITH [18F] FLUOROMETHYL TOSYLATE
561
Table 2. Results of varying the amount of water, bis(tosyloxy) methane, and K-Fix of
the yield of 18F-CH2-OTs
Runa H2O (ml) bis(tosyloxy) methane (mg) Kryptofix (mg) Radiochemical yieldb (%)
1
2c
3
4
5
6
7
8
9
10
11
12
13
0
0
0
0
2.5
2.5
2.5
5
5
5
5
5
5
5
5
7.5
10
10
10
7.5
5
5
5
5
5
5
7.5
7.5
7.5
7.5
15
15
15
10
10
10d
10
10
10
15
12
10
42
29
55
38
74
75
62
71
65
83
69
67
62
76
76
74
72
7.5
14
10
15
15
15
15
15c
16c
17c
10
10
10
a Reaction conditions: 100 ml ACN, 1108C, Kryptofix/K2CO3=5, 10 min.
b Decay corrected.
c 150 ml ACN.
d Kryptofix/K2CO3=2.5.
During attempts to selectively decompose [18F]tosyl fluoride, it was
discovered that addition of a small amount of water to the reaction resulted
in a significant increase in the yield of [18F]fluoromethyl tosylate. Various
conditions were examined to optimize the yield of [18F]fluoromethyl tosylate.
The results of 17 syntheses are summarized in Table 2. In reactions 1–4 no
water was added, with an average yield of 41ꢀ 11%. Reactions 5–17
contained various amounts of water (2.5–10 ml), bis(tosyloxy) methane (5–
10 mg) and Kryptofix (7.5–15 mg). The average yield for these reactions was
significantly higher at 71ꢀ 6%.
Upon completion of the reaction, the solvent was evaporated, the residue
was dissolved in a 9:1 mixture of hexanes:dichloromethane and passed over a
short column of alumina. Most of the [18F]tosyl fluoride was eluted in this
fraction. The product was obtained by elution with a 95:5 mixture of
hexanes:ethyl acetate. By using 4 ml of 95:5 hexanes:ethyl acetate, excess
bis(tosyloxy) methane, 18F- and Kryptofix are strongly retained on the column
and [18F]fluoromethyl tosylate was completely eluted. Evaporation of solvent
afforded [18F]fluoromethyl tosylate ready for reaction with the appropriate
precursor. Figure 1 shows the TLC analysis of a typical crude reaction
mixture, the activity eluted with 9:1 hexanes:dichloromethane and the activity
eluted with 95:5 hexanes:ethyl acetate.
Two factors to explain the affect of water on the reaction were considered.
One possibility was that the fluoride liberated from the selective hydrolysis of
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562
T. R. NEAL ET AL.
18F]Tosyl fluoride
18F-CH2-OTs
18F-CH2-OTs
[
18F]Tosyl fluoride
[
0
20
40
60
80
100
0
20
40
60
80
100
(a)
(b)
18F-CH2-OTs
[
18F]Tosyl fluoride
0
20
40
60
80
100
(c)
Figure 1. TLC analysis of (a) crude reaction mixture, (b) activity eluted with
9:1, hexanes:dichloromethane, (c) activity eluted with 95:5, hexanes:ethyl acetate
(see Experimental Section for details)
[18F]tosyl fluoride would be available to react with precursor, thus driving the
reaction toward the formation of [18F]fluoromethyl tosylate. The other
possibility was that the water affected the reactivity of the fluoride. Briard
and Pike have recently reported a significant increase in fluorination yield
upon addition of a small amount of water to the reaction mixture.23 They
attributed the higher yield to increased solubility of the hydrated fluoride ion
complex.
In one experiment, an anhydrous reaction mixture was heated for 10 min,
the product distribution was determined (unreacted fluoride, [18F]fluoromethyl
tosylate and [18F]tosyl fluoride), water was added and heating was continued
for an additional 10 min. The yield of [18F]fluoromethyl tosylate increased
from 42 to 51% and the yield of [18F]tosyl fluoride decreased from 25 to 14%
after the addition of water. This demonstrates that [18F]tosyl fluoride was
selectively hydrolyzed under these conditions. However, the yield of
[18F]fluoromethyl tosylate was significantly lower than when water was added
at the beginning of the reaction (71ꢀ 6%, Table 2), indicating this was not the
only factor involved. When the reaction was carried out under anhydrous
conditions or the water was added after heating for 10 min, at least 35% of
unreacted fluoride remained; much of this was retained on the walls of the
reaction vial. When water was added at the beginning (runs 5–17, Table 2),
520% of unreacted fluoride remained. Thus, an increased initial activity and/
or solubility of fluoride may also be a factor, possibly as suggested by Briard
and Pike.23
Copyright # 2005 John Wiley & Sons, Ltd.
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FLUOROMETHYLATIONS WITH [18F] FLUOROMETHYL TOSYLATE
563
With a convenient and reproducible procedure for production of
[18F]fluoromethyl tosylate in hand, the preparation of [18F]FP was explored.
It was found that reaction of [18F]fluoromethyl tosylate with 2 in acetonitrile
at 1108C for 1 h using K2CO3 as base lead to the formation of [18F]FP in an
average of 76ꢀ 11% yield (decay corrected, n ¼ 5), based upon TLC analysis
of the reaction mixture. After evaporation of the solvent, the residue was
purified by normal-phase HPLC.
For production runs carried out remotely in a hot cell, [18F]FP was
obtained in ꢁ15% chemical yield (decay corrected radiochemical yield, based
upon starting 18F-) with a radiochemical purity of >95% and a specific
activity of about 1000 mCi/mol 1.75–2 h after EOB. In these runs, the
[18F]tosyl fluoride was not separated, but carried on and the reaction of
[18F]fluoromethyl tosylate with 2 was carried out for 20 min (vs 1 h for the
method development runs). The presence of [18F]tosyl fluoride did not
interfere with the coupling reaction nor purification of [18F]FP and the
reduction in yield from the shorted reaction was considered an acceptable
compromise in order to reduce the total synthesis time. The remote process has
not been optimized; doing so should result in a significant improvement in the
overall radiochemical yield.
The reactions of N,N-dimethylamino ethanol, homocysteine thiolactone and
spiperone with [18F]fluoromethyl tosylate to produce [18F]choline, [18F]fluor-
omethionine and N-([18F]fluoromethyl)spiperone, respectively, were briefly
examined. The reaction conditions employed were the same as those typically
used for the published reactions of [11C]CH3I with each precursor to produce
the corresponding [11C]methyl derivative, and were not optimized. The
products were not thoroughly characterized, but in each case the 18F-labeled
product eluted from HPLC with a very similar retention time to the
corresponding [11C]methyl derivative.
The yield of [18F]choline (92ꢀ 12% decay corrected, n ¼ 5, range 70–98%)
is comparable to the yields reported from the reaction of N,N-dimethylamino
ethanol with [18F]fluoromethyl bromide6 and [18F]fluoromethyl triflate.12
Although the yield of [18F]fluoromethionine was only 14 ꢀ 5% (decay
corrected, n ¼ 5, range 10 –21%), it is most likely that the low yield was
due to the non-optimized reaction conditions rather than an unexpected
lack of reactivity of [18F]fluoromethyl tosylate. The synthesis of N-
([18F]fluoromethyl)spiperone was carried out twice, resulting in yields of
37 and 69%. It is noteworthy that in previous attempts to produce
N-([18F]fluoromethyl)spiperone from the reaction of spiperone with
[18F]fluoromethyl iodide, no reaction was observed.24 The yields from the
reactions with homocysteine thiolactone and spiperone are similar to those
obtained from the reaction of [11C]methyl iodide using the same reaction
conditions.
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564
T. R. NEAL ET AL.
Experimental
Reagents and solvents were obtained from Aldrich Chemical Co. and Fisher
Scientific and used without further purification unless otherwise noted.
Tetrahydrofuran (THF) was freshly distilled from sodium benzophenone ketyl
under argon prior to use. Acetonitrile was freshly distilled from calcium
hydride prior to use. Flash column chromatography was performed on 230
mesh silica gel. Thin layer chromatography (TLC) was carried out on E.
Merck silica gel 60 F254 analytical plates. Radiation detection was performed
with a Bioscan model AR-2000 thin layer plate reader using WinScan Version
3.07 software, and mass detection by UV light. High-performance liquid
chromatography (HPLC) was performed on a Hewlett Packard 1090 system
with a photodiode array detector and a Beckman model 170 radiation
detector. Elution conditions for TLC and HPLC varied and are specified
individually for each compound below. Bis(tosyloxy) methane was prepared as
previously reported from diiodomethane and an excess of silver tosylate,16 and
purification was accomplished by flash chromatography on silica gel, eluting
with a 4:1 mixture of hexanes:ethyl acetate.
[18F]fluoromethyl tosylate
18F- (obtained by 17 MeV proton bombardment of [18O]H2O25) was passed
through anion exchange resin and [18O]H2O was recovered. 18F- was eluted
with aqueous potassium carbonate and added to 10–15 mg (26.6–39.8 mmol)
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8,8,8]hexacosane (Kryptofix). If ne-
cessary, aqueous potassium carbonate solution was added in order to achieve
the desired Kryptofix/K2CO3 ratio (usually 2.5–5.0). The water was
evaporated under reduced pressure at 1108C and dried by coevaporation
with acetonitrile. A solution of 5–10 mg (14.0–28.1 mmol) bis(tosyloxy)methane
dissolved in 100–200 ml anhydrous acetonitrile containing 0–10 ml of water was
added and heated for 10 min at 1108C. The reaction mixture was cooled and
the solvent evaporated under reduced pressure. The residue was thoroughly
mixed with 200 ml of dichloromethane, after which 1.3 ml of hexanes was
added and the mixture was passed over a small (ca. 150 mg) column of neutral
alumina. The column was eluted with 3 ml of 95:5 hexanes:ethyl acetate. The
combined organic fraction was concentrated under reduced pressure and the
residue was used as such for the coupling reaction.
The reaction mixture was analyzed by TLC (plate developed twice with 4:1
hexanes:ethyl acetate, Rf 0.45, [18F]fluoromethyl tosylate; 0.55 [18F]tosyl
fluoride), and by HPLC (4.6 ꢂ 250 mm Alltech Econosphere 5m C18). HPLC
was eluted at 1 ml/min with a linear gradient of water:methanol (each 25 mM
NH4OAc) 55:45 to 40:60 over 25 min (RT: 10.9 min, [18F]fluoromethyl tosylate;
14.1 min, [18F]tosyl fluoride).
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FLUOROMETHYLATIONS WITH [18F] FLUOROMETHYL TOSYLATE
565
[18F]tosyl fluoride
A solution of 9.4 mg (25.0 mmol) Kryptofix1 2.2.2(Kryptofix) and 2.5 mg
(18.1 mmol) K2CO3 dissolved in 150 ml of water was mixed with 115 ml of an
aqueous solution containing 3.7 mCi of 18F-. The resulting solution was dried
under reduced pressure at 1108C and then by coevaporation with anhydrous
acetonitrile. A solution of 3.4 mg (17.8 mmol) of tosyl chloride in 100 ml of
acetonitrile was added. The mixture was heated at 1108C for 10 min, cooled
and passed over a short column (ca. 150 mg) of neutral alumina. The vial was
rinsed with 4 ꢂ 200 ml acetonitrile; each rinse was passed over the alumina. The
solution was analyzed by TLC as described for [18F]fluoromethyl tosylate. Part
of the solution was combined with the product obtained from the reaction of
18F- and bis(tosyloxy) methane, and this mixture was analyzed by TLC (as
above, Rf 0.55) and by HPLC (as above, RT 14.1 min).
[19F]fluoromethyl tosylate
A mixture of 15 mg (39.8 mmol) Kryptofix, 2.6 mg (44.8 mmol) KF and 11 mg
(30.9 mmol) bis(tosyloxy) methane in 250 ml of acetonitrile was heated at 1108C
for 2 h. The reaction mixture was cooled and 5 ml was diluted with 1 ml of
acetonitrile. This solution was analyzed by TLC (as above), and HPLC (as
above). An authentic sample of tosyl fluoride was mixed with the solution and
it was reanalyzed. The tosyl fluoride comigrated with the Rf 0.55 product upon
TLC analysis and coeluted with the RT 14.1 min product upon HPLC analysis.
[18F]fluticasone propionate
Approximately 500 mCi of 18F- was obtained by elution from the ion exchange
resin with 0.8 ml of an aqueous solution of potassium carbonate (containing
3 mg K2CO3). The solution was heated under reduced pressure at 1108C and
dried by coevaporation with acetonitrile. During the drying process, a solution
of 15.3 mg (40.6 mmol) of Kryptofix dissolved in 100 ml of acetonitrile was
added. When dry, a solution of 10.4 mg (29.2 mmol) bis(tosyloxy)methane
dissolved in 200 ml of anhydrous acetonitrile containing 10 ml of water was
added. After heating at 1108C for 10 min, the reaction mixture was
concentrated under reduced pressure. The residue was thoroughly mixed with
200 ml of dichloromethane, after which 1.3 ml of hexanes was added and the
mixture was passed over a small (ca. 150 mg) column of neutral alumina into a
vial containing 2.0 mg (14.5 mmol) of K2CO3. The column was eluted with 3 ml
of 95:5 hexanes:ethyl acetate. The combined organic fraction was concentrated
under reduced pressure at about 508C. When most of the solvent had been
removed, 2.3 mg (4.9 mmol) of the des-fluoromethyl fluticasone thioacid 2
dissolved in 0.4 ml of ethyl acetate was added. The remaining solvent was
carefully evaporated. The residue was dissolved in 150 ml of acetonitrile and
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566
T. R. NEAL ET AL.
the mixture was heated at 1108C for 20 min. The reaction mixture was cooled
and evaporated under reduced pressure. The residue was dissolved in 1 ml of
3:1 hexanes:ethyl acetate and purified by HPLC (4.6 ꢂ 250 mm Alltech
Econosil 10m silica column eluted with 70:30:1 hexanes:ethyl acetate:acetoni-
trile at 2.5 ml/min). Thirty-six millicurie was obtained (16%, decay corrected,
based on 18F-) 120 min after EOB. The purified product was analyzed by TLC
using a 1:1 mixture of hexanes:ethyl acetate (Rf ¼ 0:40) and by HPLC using a
4.6 ꢂ 250 mm Alltech Econosphere 5m C18 column eluted with a mixture of
30:70 water:acetonitrile (each 25 mM ammonium acetate) at 1 ml/min
(retention time=8.1 min).
[18F]fluorocholine
The reaction of 18F- with bis(tosyloxy)methane was carried out as described
above. After elution from the neutral alumina column and evaporation of the
solvent, the residue was dissolved in anhydrous THF and a 50 ml aliquot of this
solution was added to a vessel containing 150 ml (133 mg, 1.5 mmol) of N,N-
dimethylethanolamine and 2 ml of 0.1 M potassium carbonate. The vessel was
heated at 1208C for 5 min. The solvent was evaporated under reduced pressure
at 1208C. The reaction mixture was analyzed by HPLC using a 4.6 ꢂ 250 mm
Alltech Econosil 10m C18 column eluting with an 85:15 mixture of 20 mM
aqueous ammonium acetate:acetonitrile at 2 ml/min (retention time=3.9 min,
retention time of [11C]choline=3.6 min). The average yield was 92ꢀ 12%
(decay corrected radiochemical yield, n ¼ 5), based upon [18F]fluoromethyl
tosylate.
[18F]fluoromethionine
The reaction of 18F- with bis(tosyloxy)methane was carried out as described
above. After elution from the neutral alumina column and evaporation of the
solvent, the residue was dissolved in anhydrous THF and a 50 ml aliquot of this
solution was added to a vessel containing 1 mg (6.5 mmol) of l-homocysteine
thiolactone HCl, 100 ml of water, 250 ml of THF, and 15 ml of 1 M NaOH.
After heating at 708C for 10 min, 10 ml of 1 M HCl was added and the solvent
was evaporated under reduced pressure at 1508C. The reaction mixture was
analyzed by HPLC using a 4.6 ꢂ 250 mm Alltech Econosil 10m C18 column,
eluting with 1 mM aqueous NaH2PO4 at 2 ml/min (retention time=5.3 min,
retention time of [11C]methionine=3.5 min). The average yield was 14ꢀ 5%
(decay corrected radiochemical yield, n ¼ 5), based upon [18F]fluoromethyl
tosylate.
N-([18F]fluoromethyl)spiperone
The reaction of 18F- with bis(tosyloxy)methane was carried out as described
above. After elution from the neutral alumina column and evaporation of the
Copyright # 2005 John Wiley & Sons, Ltd.
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FLUOROMETHYLATIONS WITH [18F] FLUOROMETHYL TOSYLATE
567
solvent, the residue was dissolved in anhydrous THF and a 50 ml aliquot of this
solution was added to a vessel containing 1 mg (2.5 mmol) of spiperone, 150 ml
of THF and 2 ml of 0.4 M tetrabutylammonium hydroxide. After heating at
858C for 2 min, the solvent was evaporated under reduced pressure at 1008C.
The reaction mixture was analyzed by HPLC using a 4.6 ꢂ 250 mm Alltech
Econosphere 10m silica column, eluting with a 95:4.8:0.2 mixture of
chloroform:ethanol:acetic acid at 2 ml/min (retention time=4.4 min, retention
time of [11C]N-methylspiperone=4.6 min). The synthesis was carried out
twice, resulting in yields of 37 and 69% (decay corrected radiochemical yield),
based upon [18F]fluoromethyl tosylate.
Conclusion
The preparation of [18F]fluoromethyl tosylate was reexamined. Reaction of
bis(tosyloxy)methane with 18F- carried out using previously reported
conditions14,15 led to the formation of [18F]fluoromethyl tosylate and [18F]tosyl
fluoride. Labeled tosyl fluoride was identified by chromatographic comparison
with authentic material and with [18F]tosyl fluoride prepared from the reaction
of tosyl chloride and 18F-. Inclusion of a small amount of water in the reaction
mixture significantly increased the yield of [18F]fluoromethyl tosylate. The
reaction of [18F]fluoromethyl tosylate with FP thioacid precursor 2 lead to the
formation of [18F]FP in 76ꢀ 11% yield (decay corrected, n ¼ 5). Reaction of
[18F]fluoromethyl tosylate with N,N-dimethylamino ethanol, homocysteine
thiolactone, and spiperone resulted on the formation of [18F]choline,
[18F]fluoromethionine and N-([18F]fluoromethyl)spiperone, respectively.
Acknowledgements
Financial support of this work by GlaxoSmithKline is gratefully acknowl-
edged.
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