Synthesis and stability of S-(2-[18F]fluoroethyl)-L-homocysteine for potential tumour imaging

Article abstract of DOI:10.1002/jlcr.1539

The F-18 labelled methionine derivative S-(2-[¹⁸F]fluoroethyl)- L-homocysteine ([¹⁸F]FEHCys) was prepared by a one-pot two-step synthesis via the protected S-(2-bromoethyl)-L-homocysteine 1 and S-(2-chloroethyl)-L-homocysteine 2 precursors. The bromoethyl derivative 1 gave higher radiochemical yields (40% at 5 min) at 100°C compared with the chloro-analogue (22% at 100°C in 30 min). However, [¹⁸F]FEHCys was found to be unstable in aqueous systems being transformed to the corresponding hydroxyl derivative within 20 min. Copyright

Full text of DOI:10.1002/jlcr.1539

Research Articles
Received 28 March 2008,
Revised 24 July 2008,
Accepted 28 July 2008
Published online 25 September 2008 in Wiley Interscience
(
www.interscience.wiley.com) DOI: 10.1002/jlcr.1539
18
Synthesis and stability of S-(2-[ F]fluoroethyl)-
L-homocysteine for potential tumour imaging
Thomas Bourdier, Christopher J. R. Fookes, Tien Q. Pham, Ivan Greguric,
Ã
and Andrew Katsifis
1
8
18
The F-18 labelled methionine derivative S-(2-[ F]fluoroethyl)-L-homocysteine ([ F]FEHCys) was prepared by a one-pot
two-step synthesis via the protected S-(2-bromoethyl)-L-homocysteine 1 and S-(2-chloroethyl)-L-homocysteine 2 precursors.
The bromoethyl derivative 1 gave higher radiochemical yields (40% at 5 min) at 1001C compared with the chloro-analogue
1
8
(
22% at 1001C in 30 min). However, [ F]FEHCys was found to be unstable in aqueous systems being transformed to the
corresponding hydroxyl derivative within 20 min.
1
Keywords: S-(2-[ F]fluoroethyl)-L-homocysteine; FEHCys; amino acids; nucleophilic [ F]-fluorination
8
18
Introduction
Results and discussion
1
[
8
F]fluoro-2-deoxy-D-glucose (FDG) is the most widely used Chemistry
radiotracer in tumour diagnosis using positron emission
tomography (PET). However, clinical studies have demonstrated
that in some instances, it is difficult to differentiate neoplasms
Our aim was to establish an efficient one-pot synthesis of
1
8
[ F]FEHCys. Synthesis of the required precursors, protected
S-(2-bromoethyl)-l-homocysteine and S-(2-chloroethyl)-L-
1
1
homocysteine 2, was achieved in four steps (Scheme 1).
from inflammatory tissues. Radiolabelled amino acids, particu-
larly those incorporating the PET radionuclides carbon-11 and
fluorine-18, have been used to overcome some of the
disadvantages of FDG.
11,12
Protection of L-homocysteine with di-tert-butyl dicarbonate
followed by reaction of compound 3 with tert-butyl-2,2,2-
13,14
trichloroacetimidate
in dichloromethane at room tempera-
For this purpose, radiolabelled amino acids and in particular S-
1
2-[ C]methyl)-L-methionine ([ C]MET) have been extensively
1
11
ture afforded quantitatively compound 4. Cleavage of the
disulphide bond to form protected L-homocysteine 5 was
12,15,16
achieved in 90% yield, using tributylphosphine in DMF.
Precursors 1 and 2 and compounds 6 and 7 were prepared in
38–93% yields by coupling 1-bromo-2-haloethane or 2-bro-
(
used in PET tumour imaging in both animals and man; however,
the short half-life of carbon-11 (t1/2 = 20 min) limits the wide-
2
spread application of these tracers. This has prompted the
1
8
development of F-labelled amino acids (t1/2 = 110 min) such as
moethanol with thiol 5 in the presence of potassium carbonate
15,16
18
-[ F]fluoro-L-phenylalanine
3
18
and 2-[ F]fluoro-L-tyrosine.
4,5
4
in DMF at room temperature.
The overall yields of the
These amino acids demonstrated suitable imaging character-
istics, but the radiosynthesis of these compounds is difficult,
long and the radiochemical yield is low.
brominated and chlorinated precursors 1 and 2 for the four
steps were 34 and 74%, respectively. The moderate yield
obtained for precursor 1 was due to extensive decomposition
during purification and its instability in the presence of water.
1
8
18
6,7
Currently, O-(2-[ F]fluoroethyl)-L-tyrosine ([ F]FET), which
shows good imaging properties in differentiating neoplasms
and inflammatory tissues, is a lead candidate in the develop-
1
7
The presence of a sulphur mustard structure
in these
compounds accelerates halide hydrolysis, particularly with the
better leaving group (bromide) present in 1 (Scheme 2). For this
reason, attempts to prepare the corresponding S-(2-tosylox-
yethyl)-L-homocysteine 8, by reaction of alcohol 7 with
p-(toluenesulphonyl) chloride, were unsuccessful, due to the
high instability of 8. Although conversion of 7 into 8 was
1
8
ment of F-labelled amino acids. More recently, a new amino
1
8
acid analogue of MET, S-(2-[ F]fluoroethyl)-l-homocysteine
1
[ F]FEHCys), was synthesized in 10% yield by a two-step
8
(
process using 2-[ F]fluoroethyl tosylate as an intermediate.
1
8
8
1
8
[
[
F]FEHCys was reported to exhibit similar characteristics to
9,10
F]FET in potential tumour imaging.
1
8
In this study, we have developed new precursors and a one-
pot two-step radiolabelling method for the synthesis of
1
[
8
F]FEHCys. In addition, we have evaluated the stability of this
Radiopharmaceuticals Research Institute, Australian Nuclear Science and
tracer for potential biological and clinical applications. For this Technology Organisation, PMB 1 Menai, NSW 2234, Sydney, Australia
purpose, suitably protected S-(2-bromoethyl)-L-homocysteine 1
*
Correspondence to: Andrew Katsifis, Radiopharmaceuticals Research Institute,
Australian Nuclear Science and Technology Organisation, PMB 1 Menai, NSW
234, Sydney, Australia.
E-mail: akx@ansto.gov.au
and S-(2-chloroethyl)-L-homocysteine 2 were synthesized as
precursors and labelled by classical fluorine-18 nucleophilic
substitution.
2
J. Label Compd. Radiopharm 2008, 51 369–373
Copyright r 2008 John Wiley & Sons, Ltd.

T. Bourdier et al.
t
COOH
COOH
COO Bu
a
b
H N
S
BocHN
S
BocHN
S
2
2
2
2
3
(100%)
4 (99%)
c
t
t
COO Bu
COOBu
d
X
BocHN
S
BocHN
SH
(90%)
1
2
6
7
X=Br(38%)
X=Cl(83%)
X=F(90%)
X=OH(93%)
5
Scheme 1. Synthesis of precursors 1-2. Reagents and conditions: (a) Boc
DMF, RT; and (d) 1-bromo-2-haloethane or 2-bromoethanol, K CO , DMF, RT.2
2
2
O, dioxane, Na CO3(aq), RT; (b) tert-butyl-2,2,2-trichloroacetimidate, CH
2
Cl
2
, RT; tributylphosphine,
2
3
t
t
COOBu
t
COO Bu
COOBu
H2O
X
S+
OH
BocHN
BocHN
S
BocHN
S
1
8
X=Br
X=OTs
7
Scheme 2. Proposed mechanism of the hydrolysis of the sulfur mustards.
t
COO Bu
1
COOH
)K[ 18F]-K222,K
)HCl (aq)
CO
2 3
18F
X
2
2
H N
S
BocHN
S
1
2
X=Br
X=Cl
[18
F]FEHCys
18
Scheme 3. Radiosynthesis of [ F]FEHCys.
observed by TLC analysis of the reaction mixture, all attempts to performed with 6 N HCl at 1001C for 5 min. This reaction was
isolate the tosylate resulted in its hydrolysis to alcohol 7.
then quenched with 6 N NaOH and diluted in water. The
resulting solution was analysed by HPLC, which confirmed
1
complete hydrolysis and formation of [ F]FEHCys. However,
8
Radiochemistry
1
during HPLC analysis, instability of [ F]FEHCys was observed.
8
1
The radiosynthesis of [ F]FEHCys from 1 and 2 was accom-
8
18
Indeed, 20 min after quenching this reaction, [ F]FEHCys was
1
3,14,18
plished in two steps,
by classical fluorine-18 nucleophilic
totally transformed to the corresponding alcohol (S-(2-hydro-
xyethyl)-l-homocysteine (HOEHCys)).
substitution, followed by acid hydrolysis of the protecting
groups (Scheme 3). Optimization of the reaction conditions
1
8
involved the reaction of [ F]fluoride at different temperatures
50–1001C) with 5 mg quantities of precursors 1 and 2 in
18
Stability of [ F]FEHCys
(
1
8
acetonitrile containing 10 mg K222 and 2 mg potassium carbo- To investigate the observed instability of [ F]FEHCys, a
nate (Figure 1). At 501C the brominated precursor 1 showed comparative study on non-radioactive FEHCys was carried out.
higher reactivity (30% yield at 30 min) than the chlorinated Non-radioactive FEHCys was prepared by acid hydrolysis of 6 at
analogue 2 (3%). However, the radiochemical yield of both room temperature, which also yielded about 5% of the
precursors was significantly increased at 1001C. At this corresponding alcohol as by-product (Scheme 4). The stability
temperature, the chlorinated precursor 2 delivered a continu- of FEHCys in water at room temperature was studied by HPLC in
ously increasing yield over the 30-min reaction until a maximum H O and NMR in D O using this 95:5 mixture of FEHCys and
2
2
2
of 22% radiochemical yield was reached. Unlike the chlorinated HOEHCys. Hydrolysis of FEHCys, in H O, was observed by HPLC
precursor 2, which is stable up to 1001C at high temperature, after 20 min giving the corresponding alcohol (HOEHCys), with
the brominated precursor 1 showed significant decomposition total transformation after 80 min (Figure 2). The same hydrolysis
2
at 801C after 15 min of reaction, while this decomposition was reaction was observed by NMR in D O; however, this hydrolysis
apparent at 1001C after only 5 min. The highest labelling was much slower, which even after 7 days was not totally
efficiency (40%) was obtained using 5 mg of precursor 1 at transformed (Figure 3). This is expected from the mechanism
1
001C for 5 min.
The radiosynthesis of [ F]FEHCys was then completed by acid between H
hydrolysis to remove both protecting groups. Hydrolysis of intermediate thiirane salt from FEHCys, is known to be much
shown in Scheme 2, because the strong hydrogen bonding
1
8
2
O and fluoride, which assists the formation of the
1
8
19
protected [ F]FEHCys (generated from 1 at 1001C) was weaker in D O. This comparative study on non-radioactive
2
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Copyright r 2008 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2008, 51 369–373

T. Bourdier et al.
45
40
35
30
25
20
15
10
5
0
1
1
00°C, R-Br (n = 5)
00°C, R-Cl (n = 4)
80°C, R-Br (n = 4)
80°C, R-Cl (n = 3)
5
5
0°C, R-Br (n = 3)
0°C, R-Cl (n = 3)
0
5
10
15
20
25
30
35
Time (min)
2 3
Figure 1. Radiolabelling of bromo- and chloro-precursors 1 and 2 (5 mg) in acetonitrile (1 mL) with K222 (10 mg) and K CO (2 mg) as a function of temperature and time.
t
COOBu
COOH
COOH
HCl (aq)
THF
-
-
Cl
F
F
+
Cl
H3+N
OH
+
BocHN
S
H3 N
S
S
6
FEHCys
HOEHCys
Scheme 4. Hydrolysis of compound 6.
F
OH
HOEHC ys
FEHCys
S
S
0
0
0
.04
.02
.00
T
T
4 min
FEHCys
HOEHCys
5 %
1
.0
95 %
1
.00 2.00 3.00 4.00 5.00 6.00 7.00
T
0
Minutes
0
.1
0.12
0.08
0.04
0.00
4
.80
4.60
1.0
4.40
4.40
4.40
4.20
4.00
3.80
20 min
8
3 %
17 %
T
T
1 day
1
.00 2.00 3.00 4.00 5.00 6.00 7.00
Minutes
0
.4
0.20
0.15
0.10
0.05
0.00
HOEHC ys
4.80
4.60
4.20
4.00
3.80
.1
T
80 min
2
49 %
51 %
7 days
1.0
1
.00 2.00 3.00 4.00 5.00 6.00 7.00
Minutes
Figure 2. Investigation of the stability of FEHCys by HPLC (sample: 1 mg of a 95:05
mixture of FEHCys and HOEHCys in 500 mL of water; HPLC conditions: Grace
4
.80
4.60
4.20
4.00
3.80
AlltimaC18 column (150 ꢀ 4.6 mm, 5 mm); mobile phase CH
flow rate 1 mL/min; l = 210 nm).
3 2
CN/H O 10/90, v/v;
Figure 3. Investigation of the stability of FEHCys by NMR (sample: 3 mg of a 95:5
mixture of FEHCys and HOEHCys in 600 mL of D O).
2
FEHCys demonstrated that the fluorine is easily displaced to give
the corresponding alcohol and confirmed that FEHCys is
unstable in aqueous systems.
instability of FEHCys, we repeated the two-step procedure,
1
using 2-[ F]fluoroethyl tosylate, as described in the literature.
8
1
8
8
9,10
However, the same transformation of the resulting [ F]FEHCys
was observed by HPLC, confirming the instability of FEHCys in
aqueous systems.
The radiosynthesis and preliminary biological evaluation
1
of [ F]FEHCys were described by Tang et al with no information
8
on the stability of the product. In order to verify the stability/
J. Label Compd. Radiopharm 2008 51 369–373
Copyright r 2008 John Wiley & Sons, Ltd.
www.jlcr.org

T. Bourdier et al.
1
identical to published data ; LRMS: ES (1ve) m/z 581 (M11);
2
Experimental
48 2 8 2
HRMS: ES (1ve) calcd. for C26H N O S (M11) 581.2938, found
General
581.2930.
All reagents and solvents were purchased from Lancaster, Fluka
or Sigma-Aldrich. All chemicals and solvents were used without
further purification.
Tert-butyl N-(tert-butoxycarbonyl)-L-homocysteinate (5)
To a solution of 4 (3.20 g, 5.51 mmol) in DMF (45 mL) was added
water (4 mL) and tributylphosphine (1.26 g, 6.06 mmol) and the
mixture stirred under nitrogen at room temperature overnight.
The reaction mixture was quenched with water (500 mL) and the
aqueous phase thoroughly extracted with ethyl acetate
All melting points were determined in open capillary tubes
using an SRS Optimet automated melting point system, MPA
1
00, and are uncorrected. H and C NMR spectra were
13
1
measured on a Brucker DPX 400 at 400 MHz ( H) and 100 MHz
1
1
(
3
3 3 2
C) in an appropriate deuterated solvent (CDCl , CD OD, D O).
(
3 ꢀ 240 mL). The combined organic layers were washed with
Chemical shifts are reported as parts per million (d) relative to
tetramethylsilane (0.00 ppm), which was used as an internal
standard. Coupling constants are given in Hz and coupling
patterns are abbreviated as: s (singlet), d (doublet), t (triplet), m
brine (2 ꢀ 150 mL), dried (MgSO ) and the solvents evaporated.
4
The crude residue was purified by chromatography on silica gel
(
colourless oil. H NMR and C NMR identical to published
heptanes/ethyl acetate 90:10) to give 5 (2.90 g, 90%) as a
1
13
(
mutiplet) and dt (doublet of triplet). Low-resolution mass
12
data ; LRMS: ES (1ve) m/z 292 (M11); HRMS: ES (1ve) calcd. for
spectrometry (LRMS) was performed on a Waters Micromass ZQ
Quadrupole Mass Spectrometer, whereas high-resolution mass
spectrometry (HRMS) was performed using a Micromass Qtof
Ultima or AutoSpec TOF. TLCs were run on pre-coated
13 4
C H25NO S (M11) 292.1579, found 292.1583.
Tert-butyl N-(tert-butoxycarbonyl)-S-(2-fluoroethyl)-L-homocystei-
nate (6)
f
aluminium plates of silica gel 60F254 (Merck) and R was
established using an UV lamp at 254 nm. Column chromato-
graphy was undertaken on Merck 60 silica gel (40–63 mm)
columns.
To a solution of 5 (200 mg, 0.68 mmol) in DMF (3 mL) was added
-bromo-2-fluoroethane (133 mg, 1.03 mmol) followed by po-
tassium carbonate (190 mg, 1.37 mmol) and the resultant white
solution stirred for 24 h at room temperature under nitrogen.
The reaction mixture was diluted with water (40 mL) and
extracted with ethyl acetate (3 ꢀ 20 mL). The combined organic
1
1
8
[ F]HF was produced on a GE PET trace cyclotron via the
18
O(p, n) F nuclear reaction (Cyclotek, Australia). The inter-
1
8
mediate product labelled with fluorine-18 was analysed by
HPLC, consisting of a Waters 510 pump, a linear UVIS detector
1
layers were washed with water (40 mL), dried (MgSO ) and the
solvents evaporated. The crude residue was purified by
chromatography on silica gel (heptanes/ethyl acetate 90:10) to
(
l = 210 nm) in series with a Berthhold b -flow detector, on a
4
Phenomenex Bondclone C18 column (300 ꢀ 7.8 mm, 10 mm) at
mL/min with CH CN/H O (70:30, v/v) as the mobile phase.
2
3
2
1
give 6 (207 mg, 90%) as a yellow oil. H NMR (CDCl ) d 5.15–5.05
Quality control analysis of the hydrolysed radioligand was
performed on a Waters 600 W pump, a Waters 2996 photodiode
3
(
m, 1H), 4.54 (dt, J = 47.1, 6.4 Hz, 2H), 4.35–4.20 (m, 1H), 2.80 (dt,
J = 19.9, 6.4 Hz, 2H), 2.65–2.55 (m, 2H), 2.15–2.05 (m, 1H),
1
array detector (l = 210 nm) in series with an Ortec ACE Mate b -
flow detector on a Phenomenex Synergi Hydro RP column
1
3
1
1
3
.95–1.80 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H); C NMR (CDCl ) d
3
71.35, 155.47, 83.17 (J = 171.0 Hz), 82.40, 79.97, 53.44, 33.40,
1.87 (J = 21.5 Hz), 28.49, 28.45, 28.13; LRMS: ES (1ve) m/z 338
(
3 2
250 ꢀ 10 mm, 5 mm) at 2 mL/min with CH CN/H O (10:90, v/v) as
the mobile phase. The identity of the labelled compound was
confirmed by co-injection with the authentic compound on
HPLC. Radioactivity was measured with a Capintec R15C dose
calibrator.
(M11); HRMS: ES (1ve) calcd. for C H NO SF (M11) 338.1805,
15 28 4
found 338.1801.
Tert-butyl N-(tert-butoxycarbonyl)-S-(2-hydroxyethyl)-L-homocys-
teinate (7)
Chemistry and radiochemistry
This compound was synthesized as described for 6 from 5
(
791 mg, 2.71 mmol) and 2-bromoethanol (535 mg, 4.07 mmol).
The crude residue was purified by chromatography on silica gel
heptanes/ethyl acetate 70:30) to give 7 (849 mg, 93%) as a
0
N,N -di(tert-butoxycarbonyl)-L-homocystine (3)
(
1
2
Prepared by the published procedure. The following addi-
1
yellow oil. H NMR (CDCl
H), 3.71 (dt, J = 5.8, 5.8 Hz, 2H), 2.71 (t, J = 5.8 Hz, 2H), 2.65–2.50
m, 2H), 2.39 (s, br, 1H), 2.15–2.05 (m, 1H), 1.95–1.80 (m, 1H), 1.46
3
) d 5.12 (d, J = 6.7 Hz, 1H), 4.35–4.25 (m,
1
3
tional analytical data were obtained: m.p. 158–1591C; C NMR
CD OD) d 175.68, 158.16, 80.69, 53.72, 35.80, 32.54, 28.82; LRMS:
ES (1ve) m/z 469 (M11); HRMS: ES (1ve) calcd. for
1
(
(
(
3
13
s, 9H), 1.43 (s, 9H); C NMR (CDCl
0.06, 60.44, 53.33, 35.53, 33.44, 28.45, 28.14, 27.65; LRMS: ES (1
ve) m/z 336 (M11); HRMS: ES (1ve) calcd. for C15 S (M11)
36.1846, found 336.1845.
3
) d 171.46, 155.59, 82.43,
C
18
H
32
N
2
O
8
S
2
(M11) 469.1703, found 469.1678.
8
H
29NO
5
0
Di(tert-butyl) N,N -bis(tert-butoxycarbonyl)-L-homocystinate (4)
3
Tert-butyl-2,2,2-trichloroacetimidate (11.0 g, 47.77 mmol) was
added to a solution of 3 (4.47 g, 9.55 mmol) in dichloromethane Tert-butyl S-(2-bromoethyl)-N-(tert-butoxycarbonyl)-L-homocystei-
39 mL) under nitrogen. After overnight stirring at room nate (1)
temperature, the solvent was removed under reduced
(
pressure and the crude residue purified by chromatography This compound was synthesized as described for 6 from 5
on silica gel (heptanes/ethyl acetate 80:20) to give 4 (5.50 g, (200 mg, 0.68 mmol) and 1,2-dibromoethane (390 mg,
1
13
9
9%) as a white solid: m.p. 66–681C; H NMR and C NMR 2.06 mmol). The crude residue was purified by chromatography
www.jlcr.org
Copyright r 2008 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2008, 51 369–373

T. Bourdier et al.
1
on silica gel (heptanes/ethyl acetate 90:10) to give 1 (104 mg, [ F]FEHCys had almost completely transformed to the corre-
8
1
3
4
2
9
5
3
C
3
8%) as a yellow oil. H NMR (CDCl ) d 5.15–5.05 (m, 1H), sponding alcohol.
.35–4.20 (m, 1H), 3.46 (t, J = 8.3 Hz, 2H), 2.93 (t, J = 8.2 Hz, 2H),
.65–2.50 (m, 2H), 2.15–2.05 (m, 1H), 1.95–1.80 (m, 1H), 1.47 (s, Conclusion
3
H), 1.44 (s, 9H); C NMR (CDCl ) d 171.29, 155.48, 82.50, 80.05,
3.36, 34.36, 33.47, 30.42, 28.46, 28.27, 28.16; LRMS: ES (1ve) m/z
98 (M[Br ]11), 400 (M[Br ]11); HRMS: ES (1ve) calcd. for
1
3
1
8
We have developed a one-pot two-step synthesis of [ F]FEHCys
via the protected S-(2-bromoethyl)-L-homocysteine 1 and
S-(2-chloroethyl)-L-homocysteine 2 precursors. The bromoethyl
derivative 1 gave higher radiochemical yields (40% at 5 min) at
7
9
81
7
9
15 4
H28NO SBr (M[Br ]) 397.0932, found 397.0922.
1
8
1
001C. However, [ F]FEHCys was found to be unstable in
aqueous systems, which was confirmed by determining the
O by HPLC and in D O by
Tert-butyl N-(tert-butoxycarbonyl)-S-(2-chloroethyl)-L-homocystei-
nate (2)
This compound was synthesized as described for 6 from 5 stability of unlabelled FEHCys in H
200 mg, 0.68 mmol) and 1-bromo-2-chloroethane (301 mg,
.06 mmol). The crude residue was purified by chromatography
2
2
1
8
NMR. Attempts to prepare [ F]FEHCys by the method described
8
in the literature gave the same result, confirming the instability
(
2
1
8
on silica gel (heptanes/ethyl acetate 90:10) to give 2 (199 mg, of [ F]FEHCys prepared by both methods.
1
8
4
2
9
5
3
3%) as a yellow oil. H NMR (CDCl ) d 5.15–5.05 (m, 1H),
3
Acknowledgement
.35–4.20 (m, 1H), 3.62 (t, J = 7.8 Hz, 2H), 2.86 (t, J = 7.8 Hz, 2H),
.65–2.50 (m, 2H), 2.15–2.05 (m, 1H), 1.95–1.80 (m, 1H), 1.47 (s,
H), 1.44 (s, 9H); C NMR (CDCl ) d 171.29, 155.46, 82.46, 80.02, This work was supported by the Cooperative Research Centre in
3.37, 43.09, 34.40, 33.44, 28.44, 28.34, 28.13; LRMS: ES (1ve) m/z Biomedical Imaging Development.
3
76 (M[Cl ]1Na), 378 (M[Cl ]1Na); HRMS: ES (1ve) calcd. for
1
3
3
5
37
3
5
C H NO SCl (M[Cl ]1Na) 376.1335, found 376.1325.
1
5
28
4
S-(2-fluoroethyl)-L-homocysteine hydrochloride (FEHCys)
References
To a solution of the protected amino acid 6 (50 mg) in THF
(
[1] P. D. Shreve, Y. Anzai, R. L. Wabl, Radiographics 1999, 19, 61–77.
[2] W. A. Weber, H. J. Wester, A. L. Grosu, M. Herz, B. Dzewas, H. J.
445 mL) was added 6 N hydrochloric acid (890 mL) and the
reaction mixture stirred at room temperature for 90 min. The
solvent was removed under reduced pressure, and the resulting
solid washed with ethyl acetate (3 ꢀ 6 mL), dried under vacuum
to give FEHCys (21 mg, 58%) as a white solid. Analysis of this
solid by NMR in D O indicated a 95:05 mixture of FEHCys and of
2
1
the corresponding alcohol (HOEHCys). For FEHCys: H NMR
Fedlmann, M. Molls, G. St o¨ cklin, M. Schaiwger, Eur. J. Nucl. Med.
2000, 27, 542–549.
[
[
[
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(
(
2
D O) d 4.69 (dt, J = 47.0, 5.8 Hz, 2H), 4.24 (t, J = 6.1 Hz, 1H), 2.95
13
dt, J = 24.8, 5.8 Hz, 2H), 2.90–2.75 (m, 2H), 2.40–2.15 (m, 2H);
C
NMR (D O)d 173.13, 84.69 (d, J = 164.1 Hz), 53.15, 32.21 (d,
2
1
J = 19.9 Hz), 30.89, 28.05. For HOEHCys: H NMR (D
O) d 4.24 (t,
J = 6.1 Hz, 1H), 3.79 (t, J = 6.1 Hz, 2H), 2.90–2.75 (m, 4H), 2.40–2.15
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2
1
3
(
m, 2H); C NMR (D O) d 172.94, 61.37, 52.99, 34.34, 30.81, 27.71.
2
509–512.
[
9] G. Tang, M. Wang, X. Tang, L. Luo, M. Gan, Acta Pharm. Sin. 2003,
1
Radiosynthesis of S-(2-[ F]fluoroethyl)-L-homocysteine ([ F]FEHCys)
8
18
38, 915–918.
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Republic of China, 20 November 2002.
[
1
8
An aqueous [ F]fluoride solution (6–7 GBq) was added to a
0 mL vial containing a solution of K CO (2 mg, 20 mL in H
and K222 (10 mg, 100 mL in CH CN). The solvent was evaporated
1
2
3
2
O) [11] P. Serafinowski, E. Dorland, K. R. Harrap, J. Balzarini, E. De Clercq,
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3379–13381.
3
[
[
under a stream of nitrogen at 1001C under vacuum and the
residue azeotropically dried twice more by further addition of
anhydrous acetonitrile (2 ꢀ 1 mL). To the activated K222/potas-
1
13] J. McConathy, L. Martarello, E. J. Malveaux, V. M. Camp, N. E.
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1
8
sium [ F]fluoride was added the precursor 1 (5 mg, 13 mmol)
in acetonitrile (1 mL) and the mixture heated at 1001C for
[
5
min before the addition of 6 N HCl (500 mL). After 5 min at
1001C, 6 N NaOH (500 mL) and water (1 mL) were added and the [15] K. Yoshiizumi, F. Nakajima, R. Dobashi, N. Nishimura, S. Ikeda,
resulting solution was directly analysed on a semi-preparative
HPLC column (Phenomenex Synergi Hydro RP column
Bioorg. Med. Chem. 2002, 10, 2445–2460.
[
[
[
[
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(
250 ꢀ 10 mm, 5 mm); mobile phase CH
3
CN/H
rate 2 mL/min; l = 210 nm) and [ F]FEHCys was observed at
5.2 min. However, 20 min after quenching the reaction mixture,
2
O 10/90, v/v; flow
1
8
1
J. Label Compd. Radiopharm 2008 51 369–373
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