[18F]Fluoromethyl iodide ([18F]FCH2I): Preparation and reactions with phenol, thiophenol, amide and amine functional groups

Article abstract of DOI:10.1016/j.jfluchem.2004.06.017

In this study, we report the synthesis and reactivity of [ ¹⁸F]fluoromethyl iodide ([¹⁸F]FCH₂I) with various nucleophilic substrates and the stabilities of [¹⁸F] fluoromethylated compounds. [¹⁸F]FCH

Full text of DOI:10.1016/j.jfluchem.2004.06.017

Journal of Fluorine Chemistry 125 (2004) 1879–1886
www.elsevier.com/locate/fluor
[18F]Fluoromethyl iodide ([18F]FCH2I):
preparation and reactions with phenol, thiophenol,
amide and amine functional groups
a,b
a,b
Ming-Rong Zhanga,b, , Masanao Ogawa , Kenji Furutsuka ,
*
Yuichiro Yoshidaa,b, Kazutoshi Suzukia
aDepartment of Medical Imaging, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
bSHI Accelerator Service Co. Ltd., 5-9-11, Kitashinagawa, Shinagawa-ku, Tokyo 141-8686, Japan
Received 20 August 2003; received in revised form 7 April 2004; accepted 30 June 2004
Available online 11 August 2004
Abstract
In this study, we report the synthesis and reactivity of [18F]fluoromethyl iodide ([18F]FCH2I) with various nucleophilic substrates and the
stabilities of [18F]fluoromethylated compounds. [18F]FCH2I was prepared by reacting diiodomethane (CH2I2) with [18F]KF, and purified by
distillation in radiochemical yields of 14–31% (n = 25). [18F]FCH2I was stable in organic solvents commonly used for labeling and aqueous
solution with pH 1–7, but was unstable in basic solutions. [18F]FCH2I displayed a high reactivity with various nucleophilic substrates such as
phenol, thiophenol, amide and amine. The [18F]fluoromethylated compounds synthesized by the reactions of phenol, thiophenol and tertiary
amine with [18F]FCH2I were stable for purification, formulation and storage. In contrast, the [18F]fluoromethylated compounds synthesized
by the reactions of primary or secondary amines, and amide with [18F]FCH2I were too unstable to be detected or purified from the reaction
mixtures. Defluorination of these [18F]fluoromethyl compounds was a main decomposition route.
# 2004 Elsevier B.V. All rights reserved.
Keywords: [18F]Fluoromethyl iodide; [18F]Fluoromethylation; PET ligand; Defluorination
1. Introduction
of FCH2I have not been elucidated nor reviewed well. So far,
only several reactions of FCH2I with nucleophilic substrates
were reported. FCH2I reacted with triphenyl phosphine to
form a stable ylide, which was an effective route for
introducing fluoromethyl moiety to a substrate [2]. Further,
FCH2I reacted with phenol, benzoic acid, diphenylamine,
and a-toluenethiol to give the corresponding fluoromethy-
lated products [3]. However, the reactions of FCH2I with
these nucleophiles were not reproducible since some of the
fluoromethylated products seemed unstable [4,5]. It was
reported that fluoromethyldialkylamine derivatives, which
were prepared by cleaving N,N-acetals (aminals) with acid
fluoride but were not synthesized by reacting FCH2I with
dialkyl amines, were unstable [4].
Reaction of perfluoroalkyl halides with nucleophilic
substrates containing O, S, N and P atoms is a significant
characteristic of perfluoroalkyl halides [1]. It was reported
that many perfluoroalkyl halides such as CF2Cl2, CF2Br2,
CF2BrCl, CHClF2, CF3Br and CF3I reacted easily with
phenol, thiophenol and aniline in the presence of base to
yield the corresponding fluorinated products in good che-
mical yields [1]. Fluoromethyl iodide (FCH2I), as an analo-
gue of the perfluoroalkyl halides which was previously
prepared by reacting diiodomethane (CH2I2) with mercury
iodide, is also expected to display high reactivity with
nucleophiles [2]. However, unlike other perfluoroalkyl
halides, the characteristics including reactivity and stability
On the other hand, in the flurine-18 (18F) chemistry,
[18F]fluoromethylation of nucleophilic substrates has
become an effective approach for developing a positron
emission tomography (PET) ligand [6–11]. Since
* Corresponding author. Tel.: +81-43-206-4041; fax: +81-43-206-3261.
E-mail address: zhang@nirs.go.jp (M.-R. Zhang).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.06.017

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M.-R. Zhang et al. / Journal of Fluorine Chemistry 125 (2004) 1879–1886
reagent in a more reproducible yield and with improved
purity, we performed the fluorination reaction (Scheme 1)
using an automated system previously developed in our
laboratory for production of [18F]FCH2CH2Br [15].
Scheme 1. Preparation of [18F]FCH2I and reaction of [18F]FCH2I with
phenol, thiophenol, amide and amine.
The reaction of [18F]KF with CH2I2 was fast and it was
typically allowed to proceed within 2 min at 110 8C in our
experiment. After [18F]FÀ produced from the irradiated
target chamber was dried to remove CH3CN and water,
CH2I2 in o-dichlorobenzene was added into the heated
mixture containing [18F]KF and 4,7,13,16,21,24-hexaoxa-
1,10-diazabicyclo[8,8,8]hexacosane (Kryptofix 222, phase
transfer reagent). Using helium gas, [18F]FCH2I resulted in
the mixture was distilled at once, passed through short
columns filled with NaOH and P2O5, and then trapped into
an organic solvent (DMF, CH3CN or THF) on cooling. The
purification of [18F]FCH2I (bp: 53–54 8C [16]) by distilla-
tion was effective, since this procedure can leave behind all
non-volatile impurities such as metal ions from the irra-
diated target chamber, the unreacted [18F]FÀ and the phase
transfer reagent. However, long-time distillation caused
increase in the amount of CH2I2 (bp: 180 8C) flushed to
the trapped solution of [18F]FCH2I and decreased the effi-
ciency of fluoromethylation significantly. The NaOH and
P2O5 columns could delete any acidic and basic radioche-
mical impurity contained in the [18F]FCH2I vapor. In the
final trapped solution (500 mL), the radiochemical purity of
[18F]FCH2I was greater than 98%, and the concentration of
CH2I2 was less than 10 ppm detected by HPLC analysis as
shown in Section 4. The automated process took 21 Æ 2 min
from the end of bombardment with a reproducible radio-
chemical yield of 14–31% (n = 25).
[18F]fluoromethyl group displays similar electronic and
steric properties with [11C]methyl group, the [18F]fluoro-
methylated ligands [12,13] may have tracer properties such
as binding affinity and pharmacokinetics, etc. similar to the
corresponding [11C]methyl ligands prepared from the same
substrates. However, although the radiosyntheses of
[18F]FCH2Br [6–9], [18F]FCH2I [3] and [18F]FCH2OTf
[10,11] were previously carried out, the application of
[18F]fluoromethylation for labeling has been limited to a
much narrower extent compared with [11C]methylation,
[18F]fluoroethylation and [18F]fluoropropylation. The incon-
venient preparation and undetermined reactivity of
[18F]fluoromethyl regents and the putative instability of
[18F]fluoromethylated products may preclude the wide use-
fulness of [18F]fluoromethylation.
In the present study, we tried to elucidate the stability and
reactivity of [18F]FCH2I with various nucleophilic sub-
strates, and to examine the stability of [18F]fluoromethylated
compounds. Since the isotopic effects of 18F on 19F are
generally small [14], the characteristic of [18F]FCH2I may
be extremely similar with that of the non-radioactive FCH2I.
Here, we report (1) efficient synthesis of [18F]FCH2I with a
reproducible yield (Scheme 1); (2) stability of [18F]FCH2I in
organic solvents and aqueous solutions; (3) reactivity of
[18F]FCH2I with phenol, thiophenol, amide and amine
functional groups (Scheme 1); (4) stabilities of [18F]fluor-
omethylated products.
2.2. Stability of [18F]FCH2I in organic solvents and
aqueous solutions
2. Results and discussion
The results on the stability of [18F]FCH2I in organic
solvents and aqueous solutions are listed in Table 1. The
radiochemical purity of the [18F]FCH2I solution was mon-
itored by analytical HPLC in a radioactivity concentration
of 37–130 MBq/mL. After maintaining the product for
2.1. Preparation of [18F]FCH2I from CH2I2
[18F]FCH2I was previously synthesized by a displace-
ment reaction of CH2I2 with [18F]KF [3]. To obtain this
Table 1
Stability of [18F]FCH2I in organic solvents and aqueous solutions at 25 8C
Solventa
Maintenance time (min)
Radiochemical purity (%)b
Solvent
Maintenance time (min)
Radiochemical purity (%)
DMF
10
180
10
96
93
98
89
97
95
98
89
DMF/NaHc
Acetone/NaOHd
H2O, pH 7
H2O, pH 3
H2O, pH 1
H2O, pH 9
H2O, pH 11
H2O, pH 14
10
10
10
10
10
10
10
10
74
53
97
95
87
71
12
3
THF
180
10
CH3CN
Acetone
a
180
10
180
500 mL.
b
Radiochemical yield was determined by analytical HPLC on the reaction mixture. All results were presented as mean values (n = 3) with a maximum range
of Æ5%.
c
10 mL, 1.5 g/20 mL DMF.
5 mL, 0.2 N aqueous NaOH solution.
d

M.-R. Zhang et al. / Journal of Fluorine Chemistry 125 (2004) 1879–1886
1881
180 min at 25 8C, the radiochemical purity of [18F]FCH2I
2.3. Reactions of [18F]FCH2I with phenol, thiophenol,
amide and amine functional groups
remained >90% in the organic solvents commonly used for
labeling, e.g., DMF, THF, acetone and CH3CN. Even in
aqueous solutions of pH 1–7, [18F]FCH2I was also relatively
stable with minor decomposition (<15%). The stability of
[18F]FCH2I against base was also examined since a basic
reaction condition was often necessary for labeling nucleo-
philic substrates. As shown in Table 1, in the basic condi-
tions (NaH/DMF and NaOH/acetone), the radiochemical
purities of [18F]FCH2I products were decomposed to 74
and 53% after maintaining them for 10 min at 25 8C. More-
over, [18F]FCH2I was unstable in the aqueous NaOH solu-
tion of pH 9–14, and [18F]FÀ was detected in these alkaline
solutions. Defluorination of [18F]FCH2I may be a main
decomposition route, which was often observed in the synth-
esis and in vivo evaluation of 18F-labeled compounds [17].
As model nucleophilic substrates, we first selected some
simple organic structures with one functional group to
determine their reactivities with [18F]FCH2I (Scheme 2).
Then, we selected some substrates of PET ligands for
imaging the distribution of neurotransmitters and enzymes
in a brain (Scheme 2). These substrates with phenol, thio-
phenol, amide and amine functional groups had been reacted
with [11C]CH3I and [18F]FCH2CH2Br to form [11C]methy-
lated and [18F]fluoroethylated ligands which were stable for
purification, storage and in vivo evaluation [18]. Therefore,
comparing the [18F]fluoromethylated products (Scheme 3)
with the corresponding [11C]methyl and [18F]fluoroethyl
analogues is helpful to further elucidate the characteristics
Scheme 2. Structures of nucleophilic substrates used in this study.
Scheme 3. Structures of stable [18F]fluoromethylated compounds identified in this study.

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M.-R. Zhang et al. / Journal of Fluorine Chemistry 125 (2004) 1879–1886
Table 2
Reactivity of [18F]FCH2I with phenol, thiophenol, amide and amine at 25 8C
Substrate No.
Base
Radiochemical yield (%)a for reaction mixture
Radiochemical purity (%)b for final product after purification
18F]fluoromethylated product 18F]FÀ
[
18F]fluoromethylated product 18F]FÀ
[
[
[
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
NaH
NaH
NaH
NaH
NaH
NaH
NaH
86
<1
3
96
n.d.d
<1
n.d.
n.d.
81
76
99
85
1
98
91
2
96
54
10
7
n.d.
<1.
n.d.
––e
––
80
90
45
20
33
66
40
95
85
7
89
c
–
n.d.d
n.d.
n.d.
n.d.
n.d.
46
–
–
–
–
–
–
–
––
––
––
97
<1
2
38
11
n.d.
96
n.d.
––
Radiochemical yield was determined by analytical HPLC from a sample withdrawn from the reaction mixture. All results were presented as mean values (n
= 3) with a maximum range of Æ5%.
b
Radiochemical purity was determined by analytical HPLC from a sample withdrawn from the final product. All results were presented as mean values (n =
3) with a maximum range of Æ5%.
c
No base was used.
d
No corresponding peak was detected.
e
The reaction mixture was not purified.
of [18F]FCH2I. Moreover, since the isotopic effects of 18F on
19F are generally small [14], the reactivity of [18F]FCH2I
with nucleophilic substrates may be extremely similar to that
of the non-radioactive FCH2I.
were found to retain >95% radiochemical purities in the
saline solutions (data not shown). In addition to these
compounds, [18F]FMcN5652, a [18F]fluoromethylated thio-
phenol derivative was also reported to be stable for purifica-
tion, formulation and storage [12].
The results on the reactions of [18F]FCH2I with phenol,
thiophenol, amide and amine are shown in Table 2.
Although phenol and thiophenol themselves are not
strong nucleophiles, they form reactive alkoxide and thiolate
for alkylation by treatment with a base such as NaH, NaOH
or n-Bu4NOH. As can be seen in Table 2, in the presence of
NaH, phenol (1) and 2-naphthol (2) displayed high reactiv-
ities with [18F]FCH2I to form [18F]1a and [18F]2a with 86
and 75% radiochemical yields. Compound 3 [18a] reacted
with [18F]FCH2I to give [18F]3a in a high radiochemical
yield (85%). Although 3 has amide and piperazine moieties
in its molecule, these functional groups did not react with
[18F]FCH2I. The [11C]methylation of 3 also occurred only at
the hydroxy group to form the O-[11C]methylated product in
a moderate radiochemical efficiency (41%) under the same
condition [18a]. Because of the high electron-withdrawing
effect of fluorine, [18F]FCH2I is more reactive than
[11C]CH3I with nucleophile substrates. Similar to phenol,
thiophenol (4) also displayed an excellent reactivity with
[18F]FCH2I with a labeling efficiency of 91%.
To determine the stabilities of [18F]fluoromethylated
products, [18F]1a–4a were purified from the reaction mix-
tures using semi-preparative HPLC, respectively, under the
conditions shown in Section 4. The radioactive fractions
corresponding to [18F]1a–4a were concentrated to remove
the eluting phases, and re-dissolved with saline to give
radiochemically pure (>95%) products (Table 2). After
leaving these products at 25 8C for 180 min, [18F]1a–4a
Reactivities of three amide substrates 5–7 with
[18F]FCH2I were examined after they were treated with
NaH in advance, respectively (Table 2). The sodium salt
of N-phenyl benzamide (5) was highly reactive with
[18F]FCH2I to give a main product observed in analytical
HPLC chart for the reaction mixture. However, the product
appeared unstable and purification was not successful. The
sodium salt of amide 6 [18b] was reacted with [18F]FCH2I
for 10 min at 25 8C. After the reaction was terminated, a
main product peak was observed in the analytical HPLC
chart for the reaction mixture (Fig. 1a). By comparing the
retention time (tR = 6.7 min) of this peak with those of the
[11C]methylated (tR = 6.6 min) [18b] and [18F]fluoroethy-
lated (tR = 6.9 min) [18c] of 6 under the same HPLC
conditions, which were proportional to their lipophilicities,
the product could be assumed to the [18F]fluoromethylated
product of 6. To determine the identity and stability, the
[18F]fluoromethylated product was tried to purify from the
reaction mixture using a semi-preparative HPLC system.
However, HPLC analysis for the fraction corresponding to
the [18F]fluoromethylated product showed that a by-product
was yielded during purification in addition to the desired
peak (Fig. 1b). Using ion exchange chromatography, the
by-product was assigned to [18F]FÀ by co-injection with the
standard KF solution. After removing the HPLC solvents
carefully under reduced pressure at 40 8C, the peak corre-
sponding to the [18F]fluoromethylated product disappeared,

M.-R. Zhang et al. / Journal of Fluorine Chemistry 125 (2004) 1879–1886
1883
Fig. 1. Reaction of [18F]FCH2I with amide 6: (a) HPLC chart for the reaction mixture of 6 and [18F]FCH2I; (b) HPLC chart for the radioactive fraction
corresponding the [18F]fluoromethylated product of 6 after purification using semi-preparative HPLC; (c) HPLC chart for the final product re-dissolved in saline
after removing the eluting phase under reduced pressure at 40 8C. HPLC conditions: Capcell Pak C18 (Ø 4.6 mm  250 mm), CH3CN/H2O (7/3), 2 mL/min.
and only [18F]FÀ was detected in the saline solution of the
left residue (Fig. 1c). Another amide 7 [18c] also showed a
similar reaction pattern to 6.
fluoromethyldialkylamines were unstable (4). Defluorination
was found to be a main decomposition route of the unstable
[18F]fluoromethylated products in these experiments.
Primary, secondary and tertiary amines displayed differ-
ent reaction results when they were reacted with [18F]FCH2I
as shown in Table 2. In the case of primary and secondary
amines (8–12), no desired fluoromethylated products were
obtained. In addition to the unreacted [18F]FCH2I, only
[18F]FÀ as a main product was detected in the reaction
mixtures, although these substrates could react with
[11C]CH3I and [18F]FCH2CH2Br to form corresponding
stable [11C]methylated and [18F]fluoroethylated products
[18c,d]. In contrast to the primary and secondary amines,
tertiary amines 13 and 14 reacted with [18F]FCH2I to form
the desired tetraammonium products [18F]13a and [18F]14a
with moderate radiochemical yields, respectively. Moreover,
[18F]13a and [18F]14a could be purified from the reaction
mixtures to give radiochemically pure (>95%) products
which were stable for 180 min at 25 8C. In fact, [18F]14a
([18F]choline) which could be reproducibly synthesized by
reacting 14 with [18F]FCH2Br or [18F]FCH2OTf, is currently
used as a PET marker for oncology [8–10]. On the other
hand, the hydrochloride of tertiary amine 15 did not react
with [18F]FCH2I as expected.
In the present experiments, [18F]1a–4a and [18F]13a,14a
prepared by the reactions of phenols 1–3, thiophenol 4 and
tertiary amines 13,14 with [18F]FCH2I were stable, whereas
the [18F]fluoromethylated products prepared by the reac-
tions of amides 5–7 with [18F]FCH2I were unstable for
purification and storage, although their presence in the
reaction mixtures could be determined. However, the
[18F]fluoropromethylated products by the reactions of pri-
mary (8,9) and secondary (11,12) amines were not detected
in the reaction mixtures. On consideration of the high
reactivity of [18F]FCH2I, we believe that these amines 8–
12 can react with [18F]FCH2I to yield the [18F]fluoromethy-
lated products. Failure to detect their presence in the reaction
mixtures may be that these products were too unstable.
These findings are consistent with Bohme’s results which
3. Conclusions
In this study, we examined the preparation, stability and
reactivity of [18F]FCH2I and the stability of [18F]fluoro-
methylated compounds. [18F]FCH2I was prepared by react-
ing CH2I2 with [18F]FÀ in a radiochemical yield of 14–31%
(n = 25). This reagent was stable in various organic solvents
and unstable in basic solutions. [18F]FCH2I displayed high
reactivity with phenol, thiophenol, amide and amine func-
tional groups. The [18F]fluoromethylated products from
phenol, thiophenol and tertiary amine were stable for pur-
ification and storage, whereas those from amide and primary
or secondary amines were unstable. Therefore, the applica-
tion scope of [18F]fluoromethylation for labeling was much
narrower than that of [11C]methylation. The substrates
selected for [18F]fluoromethylation may be limited to phe-
nol, thiophenol and tertiary amine compounds.
Since the isotopic effects of 18F on 19F are very small, the
characteristics of [18F]FCH2I and [18F]fluoromethylated
compounds elucidated in the present study should be extre-
mely similar to those of the non-radioactive FCH2I and
fluoromethylated compounds. These findings obtained by
using [18F]FCH2I may be applicable to the non-radioactive
FCH2I and fluoromethylated products.
4. Experimental
4.1. Materials and general methods
Nuclear magnetic resonance (1H-NMR) spectra were
recorded on a JNM-GX-270 spectrometer with tetramethyl-
silane as an internal standard. All chemical shifts (d) were
reported in parts per million (ppm) downfield from the

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M.-R. Zhang et al. / Journal of Fluorine Chemistry 125 (2004) 1879–1886
standard. Fast atom bombardment-mass spectra (FAB-MS)
were obtained on a JEOL NMS-SX102 spectrometer. Col-
umn chromatography was done on Merck Kieselgel gel 60
(2H, d, J = 46 Hz), 6.82–6.93 (3H, m), 7.10–7.51 (6H, m),
11.69 (1H, br). FAB-MS (m/e) calcd for C20H23ClFN3O2
(M+ + 1): 392.18. Found: 392.27.
F
254 (70–230 mesh). Fluorine-18 (18F) was produced by the
18O(p, n)18F nuclear reaction using a CYPRIS HM-18
cyclotron (Sumitomo Heavy Industry, Tokyo). Radioactivity
was determined with a dose calibrator (IGC-3R Curiemeter,
Aloka, Tokyo). HPLC was performed using a JASCO HPLC
system (JASCO, Tokyo): effluent radioactivity was moni-
tored using a NaI (Tl) scintillation detector system. The
following columns were used: Finepak Sil C18 for analysis
or Megapak Sil C18 for purification (JASCO, Tokyo),
Capcell Pak C18 (SHISEIDO, Tokyo) and J’sphore ODS
H80 (YMC, Tokyo). In the analysis of 18F-labeled com-
pounds, unlabeled reference samples 1a–4a and 13a,14a
were used for comparison in all HPLC runs. If not otherwise
stated, chemicals were purchased from Aldrich Chemical
(Milwaukee, WI) and Wako Pure Industries (Osaka) with the
highest grade commercially available.
4.5. Fluoromethyl thiophenyl ether (4a)
A mixture of thiophenol (4, 11 mg, 0.1 mmol), FCH2I
(20 mg, 0.125 mmol) and anhydrous K2CO3 (15 mg,
0.105 mmol) in ether (2 mL) was stirred at 0 8C for 12 h.
The reaction mixture was chromatographed on silica gel
with pentane to give 4a (7 mg, 49%) as a colorless liquid.
1H-NMR (CDCl3) d: 5.65 (2H, d, J = 46 Hz), 7.04–7.57 (5H,
m). FAB-MS (m/e) calcd for C7H7FO (M+ + 1): 143.05.
Found: 143.15.
4.6. Fluoro-N,N,N-triethylmethylammonium iodide (13a)
A mixture of triethylamine (13, 20 mg, 0.2 mmol),
FCH2I (32 mg, 0.2 mmol) in methanol/ether (1/2, 4 mL)
was stood at 4 8C for 48 h. The precipitate resulting from the
reaction mixture was filtered to give 13a (4 mg, 7%) as a
colorless crystal. FAB-MS (m/e) calcd for C7H17FIN (M+ +
1): 262.04. Found: 262.10.
4.2. Fluoromethyl phenyl ether (1a)
A mixture of phenol (1, 18 mg, 0.2 mmol), FCH2I (40 mg,
0.25 mmol) and anhydrous K2CO3 (30 mg, 0.21 mmol) in
ether (2 mL) was stirred at 0 8C for 3 h. The reaction mixture
was chromatographed on silica gel with pentane to give 1a
(8 mg, 31%) as a colorless liquid. 1H-NMR (CDCl3): d 5.35
(2H, d, J = 46 Hz), 7.10–7.49 (5H, m). FAB-MS (m/e) calcd
for C7H7FO (M+ + 1): 127.05. Found: 127.13.
4.7. N,N-Dimethyl-N-fluoromethyl-2-
hydroxyethanaminium iodide (14a)
A mixture of N,N-dimethylethanolamine (14, 22 mg,
0.25 mmol), FCH2I (40 mg, 0.25 mmol) in methanol/ether
(1/2, 4 mL) was stood at 4 8C for 72 h. The precipitate
resulting from the reaction mixture was filtered to give
14a (5 mg, 8%) as a colorless crystal. FAB-MS (m/e) calcd
for C5H13FINO (M+ + 1): 250.00. Found: 250.07.
4.3. Fluoromethyl 2-naphthyl ether (2a)
A mixture of 2-naphthol (2, 14 mg, 0.1 mmol), FCH2I
(20 mg, 0.125 mmol) and anhydrous K2CO3 (15 mg,
0.11 mmol) in ether (2 mL) was stirred at 0 8C for 10 h.
The reaction mixture was chromatographed on silica gel
with pentane to give 2a (12 mg, 68%) as a colorless liquid.
1H-NMR (CDCl3): d 5.27 (2H, d, J = 46 Hz), 6.86–7.19 (2H,
m), 7.29–7.84 (5H, m). FAB-MS (m/e) calcd for C11H9FO
(M+ + 1): 177.06. Found: 177.20.
4.8. Production of [18F]fluoride
Aqueous [18F]fluoride ([18F]FÀ) was produced in a target
chamber by 18O(p, n)18F reaction on 10–20% enriched
[18O]H2O using 18 MeV protons (15.8 MeVon target) from
the cyclotron. After bombardment, the irradiated water was
transferred by helium gas through a PEEK tube into a
Dowex 1-X8 anion exchange column (carbonate form; Ø
3 mm  25 mm), for trapping [18F]FÀ and enabling collec-
tion of the enriched [18O]H2O for recycling use. The [18F]FÀ
was removed from the resin by elution with aqueous K2CO3
(3.3 mg/300 mL) solution into a glass vial containing Kryp-
tofix 222 (30 mg) in CH3CN (1.5 mL) and transported to a
reaction vessel in a hot cell.
4.4. N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-
fluoromethylbenzamide (3a)
A
mixture of N-[2-[4-(4-chlorophenyl)piperazin-1-
yl]ethyl]-3-hydroxybenzamide (3, 14 mg, 0.039 mmol)
[18a], FCH2I (7 mg, 0.044 mmol) and anhydrous K2CO3
(12 mg, 0.086 mmol) in DMF (3 mL) was stirred at 25 8C
for 3 h. The reaction mixture was quenched with CHCl3, and
washed with water and saturated NaCl solution. After the
organic layer was dried over Na2SO4, the solvent was
removed to give a residue. The residue was chromato-
graphed on silica gel with CHCl3/hexane (5/1) to give 3a
(10 mg, 65%) as a colorless crystal; m.p.: 107–109 8C
(recrystallized from CHCl3/CH3OH = 20/1). 1H-NMR
(CDCl3) d: 2.55–2.94 (8H, m), 3.15–3.24 (4H, m), 5.31
4.9. Radiosynthesis of [18F]FCH2I
After [18F]FÀ from the irradiating room was dried to
remove H2O and CH3CN at 110 8C for 15 min, CH2I2
(50 mL) in o-dichlorobenzene (300 mL) was flowed into
the radioactive mixture with a helium gas. Then, [18F]FCH2I
resulted in this vessel was distilled under a helium flow (90–

M.-R. Zhang et al. / Journal of Fluorine Chemistry 125 (2004) 1879–1886
1885
100 mL/min) at 130 8C for 2 min and cooled into another
vessel containing solvents (500 mL) for trapping at À15 to
À20 8C. The radiochemical yield of [18F]FCH2I was 14–
31% (n = 13) based on the total [18F]FÀ recovered from the
target room. The radiochemical purity of [18F]FCH2I was
assayed by analytical HPLC (FinePak Sil C18-T5, Ø 4.6 mm
 250 mm). The mobile phase was KH2PO4 (10 mM)/
CH3CN (1/1) with a flow rate of 2 mL/min and the retention
time was 4.3 min for [18F]FCH2I. Confirmation for the
identity of [18F]FCH2I was achieved by co-injection with
the authentic non-radioactive FCH2I prepared by the reac-
tion of CH2I2 with HgF2 [2].
rate (6 mL/min). The fraction corresponding to the desired
radioactive product was collected in a rotary evaporator and
evaporated to dryness at about 40 8C under reduced pres-
sure. After the residue was re-dissolved in 3 mL of saline,
the product was obtained with a radiochemical purity of
>95%. Confirmation for the identity of each product was
achieved by co-injection with the non-radioactive authentic
sample using the analytical HPLC column.
The stability of the [18F]fluoromethylated compound in
its prepared form was evaluated by monitoring its radio-
chemical purity using the HPLC system described above.
After these products were maintained for 180 min, their
radiochemical purities were measured.
4.10. Determination on stability of [18F]FCH2I in
various solvents
The stability of [18F]FCH2I in various trapped solvents
was evaluated by monitoring its radiochemical purity using
the HPLC system described above. After leaving the solu-
tion for the designated time spans, the radiochemical purities
of the [18F]FCH2I solutions were measured according to the
analytical condition described above, respectively.
Acknowledgements
The authors thank the staff of Cyclotron Operation Sec-
tion and Radiopharmaceutical Chemistry Section of
National Institute of Radiological Sciences (NIRS) for their
support in the operation of the cyclotron and production of
the radioisotopes.
4.11. Reactions of [18F]FCH2I with phenol, thiophenol,
amide and amine
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chemical yields of [18F]fluoromethylated products were
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