Synthesis of [18F] Fluoroclofilium as a potential cardiac imaging agent for PET studies

Article abstract of DOI:10.1002/jlcr.747

N-4-(4-chlorophenyl)butyl-N,N-diethyl-7-[ ¹⁸F]fluoroheptylammonium ([¹⁸F]-fluoroclofilium) has been prepared as a potential cardiac imaging agent. For the synthesis of this radiolabelled ammonium salt, its tosyloxylated analogue was prepared as a precursor, and the non-radioactive fluorine analogue was synthesized as a reference compound. Radiofluorination was achieved by the treatment of N-4-(4-chlorophenyl)butyl-N,N-diethyl-7-(p-toluenesulfonyloxy)-heptylammonium p-toluenesulfonate with ¹⁸F^- in the presence of Kryptofix-2.2.2 in acetonitrile. Copyright

Full text of DOI:10.1002/jlcr.747

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 1151–1160.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.747
Research Article
Synthesis of [18F]Fluoroclofilium as a potential
cardiac imaging agent for PET studies
K. H. Yu1, Y. S. Kim1, S. W. Kim2, J. H. Park2, S. D. Yang2,
W. Herdering3,* and A. Knoechel3
1 Department of Chemistry, Dongguk University, 3 Pildong, Chunggu,
Seoul 100-715, South Korea
2 Cyclotron Application Laboratory, Korea Cancer Center Hospital,
Seoul 139-240, South Korea
3
.
Institut fu.r Anorganische und Angewandte Chemie, Universitat Hamburg,
Hamburg 20146, Germany
Summary
N-4-(4-chlorophenyl)butyl-N,N-diethyl-7-[18F]fluoroheptylammonium ([18F]-
fluoroclofilium) has been prepared as a potential cardiac imaging agent. For
the synthesis of this radiolabelled ammonium salt, its tosyloxylated analogue
was prepared as a precursor, and the non-radioactive fluorine analogue was
synthesized as a reference compound. Radiofluorination was achieved by the
treatment of N-4-(4-chlorophenyl)butyl-N,N-diethyl-7-(p-toluenesulfonyloxy)-
heptylammonium p-toluenesulfonate with 18FÀ in the presence of Kryptofix-
2.2.2 in acetonitrile. Copyright # 2003 John Wiley & Sons, Ltd.
Key Words: fluoroclofilium; [18F]fluoroclofilium; radiofluorination; PET
Introduction
The quaternary ammonium derivative clofilium (1) is well known for its
class III antiarrhythmic properties.1 HERG potassium channels are
.
*Correspondence to: Dr. W. Herdering, Institut fur Anorganische und Angewandte Chemie,
Universitat Hamburg, Hamburg 20146, Germany. E-mail: herderin@chemie.uni-hamburg.de
.
Contract/grant sponsor: Korean Science and Engineering Foundation; contract/grant number:
KOSEF 951-0710-007-2
Contract/grant sponsor: Nuclear R&D Program from the Ministry of Science & Technology
Contract/grant sponsor: Dongguk University Research Fund
Copyright # 2003 John Wiley & Sons, Ltd.
Received 2 April 2003
Revised 3 July 2003
Accepted 11 July 2003

1152
K. H. YU ET AL.
blocked by clofilium in a nanomolar range and this binding is believed
to be the reason for its antiarrhythmic action.2 [14C] labelled clofilium
showed high myocardial uptake3 and radioactive labelling of its
aromatic residue by several iodine isotopes has been carried out.4 Here
we report on the synthesis of [18F]fluoroclofilium (2).
C2H5
C2H5
N+
N+
18F
CH2
Cl
(CH2)4
CH2
(CH2)5
CH3
Cl
(CH2)4
CH2
(CH2)5
C2H5
C2H5
2
1
Results and discussion
Previously labelling of clofilium with iodine isotopes was carried out in
the aromatic ring by iodine exchange yielding a product of low specific
activity. We decided to introduce the F-18 into the o-position of the
heptyl side chain. This approach allowed no carrier added (n.c.a)
introduction of F-18 by nucleophilic substitution.5 As leaving group the
p-tosyloxy residue was chosen. Before starting the F-18 labelling we had
to synthesize the reference compound 5 and the precursor 10. Retro-
synthesis led us to the known tertiary amine 9,6 the previously described
heptyl ditosylate 37 and fluoroheptyl tosylate 4.
For the synthesis of the amine 9 we started with the reduction of the
commercially available 4-(4-chlorobenzoyl)propionic acid 6 by the
borane-tert-butylamine complex in dichloromethane. Contrary to
published data8 the reaction time required 9 days stirring at 408C in a
closed-reaction vessel to yield the substituted butanol 7, after
purification on a silica gel column, in a good yield (71%). Compound
7 was treated with an excess of tosyl chloride in pyridine to give the
tosylate 8, after chromatographic purification, in 70% yield. Stirring
compound 8 in diethylamine at 508C for 1 day led to the amine 9 in 90%
yield.
Reaction of the commercially available 1,7-heptandiol with tosyl
chloride was carried out in 58% yield to give the known ditosylate 3,
which was treated thereafter with tetrabutylammonium fluoride
(TBAF) in acetonitrile, generating the fluoro compound 4 in moderate
yield (31%). The reference compound 5 was synthesized in a closed
vessel in acetonitrile as solvent by reaction of a slight excess of the fluoro
compound 4 with the amine 9 at 858C; the yield was 80%. The produced
ammonium salt (cation 5 and tosylate as anion) was precipitated as an
oil by addition of petrol ether (see Scheme 1).
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1151–1160

SYNTHESIS OF [18F]FLUOROCLOFILIUM
1153
TosCl / Pyridine
HO CH2 (CH2)5
CH2 OH
TosO CH2
(CH2)5
CH2 OTos
3
TBAF / MeCN
F
9 / MeCN
CH2 (CH2)5
CH2 OTos
4
C2H5
N+
Cl
(CH2)4
CH2
(CH2)5
CH2
F
5
C2H5
O
AlCl3 / CH2Cl2
Borane-t-butylamine
Cl
CH2 CH2 CH2 CH2 OH
Cl
C
CH2 CH2 CO2H
6
7
TosCl / Pyridine
Diethylamine
Cl
CH2 CH2 CH2 CH2 OTos
8
C2H5
3 / MeCN
Cl
CH2 CH2 CH2 CH2 N
9
C2H5
C2H5
N+
Cl
(CH2)4
CH2
(CH2)5 CH2 OTos
10
C2H5
Scheme 1.
After crystallization in ether the elemental analysis (CHN) corre-
1
sponded to the expected ammonium salt. The H-NMR was consistent
with the presence of two different p-substituted aromatic rings, three
methyl groups and 13 methylene groups. The methylene group in o-
position of the heptyl side chain at 4.41 ppm was split into a doublet of
2
3
triplets (dt; JHF=47.3 Hz, JHH=6.0 Hz). The 19F-NMR signal at
À218.7 ppm can be analyzed as a triplet of triplet (tt;2JHF=46.8 Hz,
3JHF=24.3 Hz). The intense peak (100%) at m/e 356 in the FAB mass
spectrum corresponded with the mass of cation 5.
Treating the amine 9 with a three-fold excess of the ditosylate 3 at
858C generated as main product the desired precursor 10 as ammonium
salt (cation 10 and tosylate as anion) but also as by-product a 1,7-
disubstituted heptane di-ammonium compound. The by-product was
extracted with water from a dichlormethane solution. The MS spectrum
(FAB) of the main product 10 and of the by-product showed strong
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J Label Compd Radiopharm 2003; 46: 1151–1160

1154
K. H. YU ET AL.
peaks at m/e 508 and 748, respectively, consistent with the cation 10 and
the not shown di-ammonium cation. In a separate experiment in which
the amine 9 was used in excess with respect to the ditosylate 3, the di-
ammonium compound was generated as the main product. HPLC
analysis on a RP-18 column indicated that the purity of the precursor 10
after clean up was 595%. Compound 10 was treated with TBAF in
acetonitrile at 858C for 1 h. Resulting compound 5 was identified by its
retention time on a RP-18 column. The 19F-NMR showed the expected
pattern in the form of a triplet of triplets.
For the labelling procedure with F-18 two often used phase transfer
catalysts were tried out, tetrabutylammonium carbonate and Kryptofix
2.2.2 in acetonitrile, of which the Kryptofix method according to Klatte
et al.5 gave the best results. After 30 min at 858C the yield, as determined
by radio-TLC, was 575%.
C2H5
C2H5
18F- / MeCN
N+
N+
18F
CH2
Cl
(CH2)4
CH2
(CH2)5
CH2 OTos
Cl
(CH2)4
CH2
(CH2)5
Kryptofix 2.2.2.
or TBA
C2H5
C2H5
2
10
First, the reaction solution was passed through a small alumina
cartridge to remove unreacted F-18. Further separation from excess of
precursor and catalyst by HPLC (Figure 1) occurred on a RP-18
column with aqueous phosphate buffer whereupon the labelled
compound was produced in high chemical and radiochemical purity
(595%). The absence of an UV absorption reflects the absence of cold
clofilium. The specific activity was 530 GBq/mMol.
Conclusion
[18F]Fluoroclofilium labelled in the o-position of the heptyl side chain
has been synthesized in a specific activity of 530 GBq/mmol and a
radiochemical purity of 595%.
Experimental
All chemicals were purchased from Aldrich, Fluka or Sigma in analyti-
cal grade and were used without further purification. Elemental analysis
were performed with the CHN-O-RAPID (Analysesystem GmbH,
Hanau, FRG ) instrument. Preparative column chromatography (flash
Copyright # 2003 John Wiley & Sons, Ltd.
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SYNTHESIS OF [18F]FLUOROCLOFILIUM
1155
Figure 1. HPLC analysis of the purified [18F]Fluoroclofilium (2). UV (277 nm)
and c-detection (511 keV) profiles were recorded simultaneously. HPLC was
performed on a reverse-phase column (Nova-Pak C18, 3.9 Â 300 mm, 4 lm.
Eluent: MeOH/0.05 M K2HPO4 with 10% MeOH 60/40 at a flow rate of
1 ml/min)
mode, 0.5 bar) was carried out on silica gel (15 mm). Gel plates (HPTLC,
silica gel 60 F254) were purchased from Merck (Darmstadt). Radioactive
spots were detected using a Bioscan AC-3000 scanner. For analytical
HPLC a Gynkotek System (Column: Lichrospher 100 RP-18 end-
capped; 5 mm; 125 Â 4 mm; flow: 1 ml/min; l: 277 nm) was used and
for semipreparative HPLC a Young–Lin system equipped with a
Young–Lin UV instrument (Column: RP-18, 300 Â 3.9 mm2; 4 mm; flow
1 ml/min; l: 277 nm). For g-detection a Raytest GABI instrument was
used. As components of eluents were used CH2Cl2 (A), n-hexane (B),
acetone (C), CH3OH (D) and 0.05 M KH2PO4 with 10% MeOH (E).
1H-NMR spectra were recorded mostly on a Bruker WP 80 spectro-
meter and in a few cases on a Bruker AM 360. All chemical shifts were
reported on ppm scale with TMS as internal standard. 19F-NMR
spectra were recorded on a Bruker WP 80 with 1% CDF3 in CDCl3
as external standard. MS spectra of non-ionic compounds were
recorded on MAT 311 A (70 eV, Varian MAT) mass spectrometer.
Organic ammonium compounds were measured by the FAB Method
(Xenon gun, m-nitrobenzylalcohol as matrix). [18F]fluorine was
produced on a MC-50 cyclotron by irradiation of a H128O water target.
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K. H. YU ET AL.
4-(4-Chlorophenyl)butanol (7)8
Borane-tert-butylamine-complex in an amount of 24.4 g (281 mmol) was
added to an ice cold solution of 18.7 g (140 mmol) of aluminum chloride
in 200 ml of CH2Cl2. After 10 min 10.0 g (46.8 mmol) of 3-(4-
chlorobenzoyl)propionic acid (6) was slowly added to the reaction
mixture. The suspension was refluxed for 9 days in a closed system
under dry nitrogen. After cooling the mixture was poured under
vigorous stirring into 500 ml of ice with 200 ml of 0.1 M HC1. After 2 h
stirring the organic phase was separated and washed 3 times with 50 ml
of water, saturated aqueous NaHCO3 and then dried over anhydrous
sodium sulfate and filtered. After evaporation the product was purified
by column chromatography (A:C 9/1). After Kugelrohr distillation
(1508C at 12 mm Hg) 6.1 g (71%) of an oil was obtained. TLC: Rf = 0.5
1
(A:C 9/1). H-NMR (CDCl3): d=7.24 (d; 2 H, Ar-H), 7.07 (d; 2 H, Ar-
H), 3.62 (t; 2 H, HOCH2), 2.57 (m; 3 H, Ar-CH2 and OH), 1.7–1.4 (m;
4 H, CH2–CH2). MS (m/e): 184 (20%, M+), 166 (4%), 151 (10%), 138
(100%), 131 (40%), 125 (94%).
4-(4-Chlorophenyl)butyltosylate (8)
Tosyl chloride in an amount of 7.20 g (38.0 mmol) was added slowly to
3.50 g (19.0 mmol) of compound 7 in 50 m1 of anhydrous pyridine at
08C. The mixture was stirred for 30 min at 08C, stirred for an additional
3 h at room temperature and quenched with 3 ml of water. After 15 min
and addition of 100 ml of CH2Cl2 the pyridine was extracted with 100 ml
of conc. HCl in 600 ml of ice water. The organic layer was separated and
washed twice with 70 ml of water and dried over anhydrous sodium
sulfate and filtered. Concentration in vacuum followed by purification by
column chromatography (A:B:C 48/50/2) yielded 4.5 g (70%) of an oily
1
product. TLC: Rf = 0.6 (A:B:C 45/50/5). H-NMR (CDCl3): d=7.70
(d; 2 H, CH3 Ar-H), 7.33 (d; 2 H, CH3Ar-H), 7.20 (d; 2 H, ClAr-H), 7.05
(d; 2 H, C1Ar-H), 4.01 (m; 2 H, OCH2), 2.55 (m; 2 H, ClAr-CH2), 2.44
(s; 3 H, CH3), 1.80–1.50 (m; 4 H, CH2CH2–CH2CH2). MS (m/e): 338
(4%, M+), 166 (14%), 138 (100%), 131 (46%), 125 (50%). Anal. for
C17H19ClO3S (M 338.9) cal. C 60.26 H 5.65, exp. C 60.21 H 5.80.
N-4-(4-Chlorophenyl)butyl-N,N-diethylamine (9)6
A mixture of 3.45 g (10.2 mmol) of compound 8 in 50 ml of dry
diethylamine was stirred for 24 h at 508C. After evaporation of the
Copyright # 2003 John Wiley & Sons, Ltd.
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SYNTHESIS OF [18F]FLUOROCLOFILIUM
1157
excess of diethylamine 50 ml of 2 M NaOH was added to the resulting
white solid. The aqueous phase was extracted twice with 70 ml of
CH2Cl2. The combined organic extract was dried over sodium sulfate,
filtered and evaporated. Purification by column chromatography
(A:B:C 45/50/5) followed by Kugelrohr distillation gave 2.20 g (90%)
of compound 9 as a yellow oil ( b.p 158–1608C at 50 mm Hg). TLC:
1
Rf = 0.3 (A:B:C 45/50/5). H-NMR (CDCl3): d=7.20 (d; 2 H, Ar-H),
7.05 (d; 2 H, Ar-H), 2.50 (q, 7.l Hz; 4 H, CH2-CH3), 2.50 (m; 4 H,
CH2(CH2)2-CH2), 1.7–1.4 (m; 4 H, CH2–CH2–CH2–CH2), 1.00 (t,
7.l Hz; 6 H, CH3). MS (m/e): 239 (l%, M+), 224 (3%), 125 (8%), 86
(100%). Anal. for C14H22ClN (M 239.8) cal. C 70.1 H 9.25 N 5.84, exp.
C 69.4 H 8.98 N 6.04.
1,7-Di-tosyloxyheptane7 (3)
Three grams (22.6 mmol) of 1,7-heptandiol in 35 ml of anhydrous
pyridine was added 13.2 g (67.7 mmol) of tosyl chloride at 08C. The
mixture was stirred for 15 min, allowed to reach ambient temperature
and stirred for a further 3 h. Then it was quenched with 3 ml of water
and stirred for a further 1 h. 100 ml of CH2Cl2 was added and the
pyridine removed by extraction with a solution of 40 ml of conc. HC1 in
200 ml of ice water. The dichloromethane phase was washed twice with
50 ml of water, dried over sodium sulfate and filtered. After evaporation
of the solvent, purification by column chromatography (A:B:C 48/50/2)
and recrystallization from CH2Cl2/n-hexane yielded 5.6 g (58%) of
compound 3. mp: 76–788C. TLC: Rf = 0.45 (A:B:C 45/50/5). 1H-NMR
(CDCl3): d=7.73 (d, 8.2 Hz; 4 H, Ar-H), 7.30 (d, 8.2 Hz; 4 H, Ar-H),
3.96 (t, 6.1 Hz; 4 H, O-CH2), 2.44 (s; 6 H, CH3), 1.7–1.1 (m; 10 H). MS
(m/e): 440 (0.7%, M+), 268 (0.4%, M+-Tos-OH), 173 (8%), 155 (10%),
97 (100%), 91 (40%).
7-Fluoroheptyltosylate (4)
Five milliliters of anhydrous acetonitrile was added to 1.43 g (4.54 mmol)
of tetra butyl ammonium fluoride trihydrate. The mixture was
evaporated in vacuum to remove the water. This procedure was repeated
twice. Compound 3 in an amount of 2.05 g (4.54 mmol) in 10 ml of
anhydrous acetonitrile was added to the reaction flask. The mixture was
stirred for 4 h at 858C in a closed tube. The solvent was evaporated in
vacuum. Flash column chromatography (A:B:C 49/50/1) provided
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K. H. YU ET AL.
400 mg (31%) of compound 4 as an oil. TLC: Rf= 0.65 (A:B:C 45/50/5).
1H-NMR (CDCl3): d=7.79 (d, 8.2 Hz; 2 H, Ar-H), 7.33 (d, 8.2 Hz; 2 H,
Ar-H), 4.70 (t, 5.9 Hz; 1 H, CH2-F), 4.11 (m; 1 H, CH2-F), 4.02 (t, 6.2 Hz;
2 H, CH2O), 2.45 (s; 3 H, CH3), 2.0–1.1 (m, 10 H). 19F-NMR:
2
3
d=À218.74 (tt, J=46.4 Hz, J=24.4 Hz). MS (m/e): 288 (2%, M+),
173 (90%), 155 (68%), 116 (30%), 96 (22%), 91 (100%). Anal. for
C14H21FO3S (M 288.3) cal. C 58.3 H 7.34, exp. C 57.8 H 7.29.
N-4-(4-Chlorophenyl)butyl-N,N-diethyl-7-fluoroheptylammonium
p-toluenesulfonate (5)
Four hundred milligrams (1.39 mmol) of compound 4 and 330 mg
(1.38 mmol) compound 9 were dissolved in 2 ml of anhydrous
acetonitrile and stirred for 24 h at 858C. After cooling with an ice bath
the reaction mixture was added dropwise under stirring to 70 ml of cold
n-hexane. An oily compound was separated from solution. The hexane
was decanted. The oily residue was stored in a refrigerator until
compound 5 was produced as an amorphous white solid. The solid was
treated with ether whereupon the material crystallized in a yield of 80%
(580 mg). mp: 48–508C. HPLC: tR=4.1 min (D:E 60/40), tR=9.9 min
1
(D:E 50/50). H-NMR (CDCl3, 360 MHz): d=7.74 (d; 2 H, CH3Ar-H),
7.21 (d; 2 H, ClAr-H), 7.09 (d; 2 H, CH3Ar-H), 7.08 (d; 2 H, ClAr-H),
4.41 (dt, 2J=47.3 Hz, 3J=6.0 Hz; 2 H, CH2-F), 3.3 1(q;3J=7.2 Hz, 4 H,
NCH2CH3), 3.20 (m; 2 H, N-CH2), 3.1 (m; 2 H, N-CH2), 2.60 (t;
3J=6.8 Hz; 2 H, ArCH2), 2.29 (s; 3 H, ArCH3), 1.60 (m;
8 H,CH2CH2CH2), 1.30 (m; 6 H, CH2), 1.24 (t, 3J=7.2 Hz; 6 H,
2
3
CH2CH3). 19F-NMR: d=À218.7 (tt, J=46.8 Hz, J=24.3 Hz). MS
(m/e): 356 (4%, M+-OTos), 336 (1%), 327 (1%), 312 (1%), 224 (44%),
174 (44%), 155 (20%), 125 (48%), 91 (54%), 86 (00%), 72 (50%). MS
(FAB): m/e 356.3 (100%, M+-Anion). Anal. for C28H43ClFNO3S (M
528.2) cal. C 63.7 H 8.21 N 2.65, exp. C 63.4 H 8.25 N 2.91.
N-4-(4-Chlorophenyl)butyl-N,N-diethyl-7-tosyloxyheptylammonium
p-toluenesulfonate (10)
Four hundred and eighty milligrams (2.00 mmol) of compound 9 and
2.64 g (6.00 mmol) of compound 3 were dissolved in 3 ml of anhydrous
acetonitrile and stirred for 8 h at 858C in a closed tube. After cooling
with an ice bath the reaction mixture was added dropwise to 70 ml of ice
cold diethylether. An oily product separated from the solution and was
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SYNTHESIS OF [18F]FLUOROCLOFILIUM
1159
taken up in 30 ml of CH2Cl2. The solution was washed 3 times with
100 ml of water. The dichloromethane layer was dried over sodium
sulfate, filtered and evaporated in vacuum. Anhydrous acetonitrile in an
amount of 20 ml was added to the oily residue. The reaction mixture was
evaporated again. Storage in a refrigerator provided a crystalline
product in 68% (920 mg) yield. mp: 58–608C. HPLC: tR=8.1 min (D:E
1
60/40). H-NMR (CDCl3, 360 MHz): d=7.77 (d, 5.4 Hz; 2 H), 7.75 (d,
5.4 Hz; 2 H), 7.35 (d, 5.4 Hz; 2 H), 7.21 (d, 5.4 Hz; 2 H), 7.09 (d, 5.4 Hz;
4 H), 3.99 (t, 6.3 Hz; 2 H, CH2O), 3.32 (q, 7.3 Hz; 4 H, NCH2CH3), 3.21
(m, 2 H; N-CH2), 3.12 (m, 2 H, N-CH2), 2.61 (t, 6.7 Hz; 2 H, C1ArCH2),
2.44 (s; 3 H, CH3 tosylester), 2.30 (s; 3 H, CH3Ar, tosylanion), 1.66 (m;
8 H, CH2), 1.30 (m; 6 H, CH2), 1.24 (t, 7.2 Hz; 6 H, CH3CH2N). MS
(FAB) m/e: 508.3 (100%, M+-OTos). Anal. for C35H50ClNO5S (M
680.3) cal. C 61.8 H 7.41 N 2.06, exp. C 61.6 H 7.46 N 2.11.
1,7-Heptanediyl-di-[N-4-(4-chlorophenyl)butyl-N,N-diethylammonium]
di-p-toluenesulfonate
Forty eight milligrams (0.20 mmol) of compound 9 and 29 mg
(0.06 mmol) of compound 3 were dissolved in 2 ml of anhydrous
acetonitrile. The reaction mixture was stirred for 72 h at 858C in a closed
tube. After cooling the reaction mixture was added dropwise to 10 ml of
diethyl ether and was stored in a refrigerator for 2 weeks to give a
crystalline compound in a yield of 36 mg (60%). HPLC: tR=4,2 min
1
(D:E 60/40), tR=12.0 min (D:E 50/50). H-NMR (CDCl3, 360 MHz):
d=7.73 (d, 8.l Hz; 4 H), 7.20 (d, 8.4 Hz; 4 H, ClAr-H), 7.08 (d; 7.8 Hz;
4 H), 7.05 (d, 8.4 Hz; 4 H, ClAr-H), 3.30 (m; 4 H; NCH2), 3.27 (q, 7.4 Hz;
8 H, CH2CH3), 3.18 (m, 4H; NCH2), 2.56 (t, 6.8 Hz; 4H, C1ArCH2),
2.30 (s; 6 H, CH3), 1.75–1.35 (m; 18 H, CH2CH2CH2), 1.18 (t, 7.2 Hz;
12H, NCH2CH3). MS (FAB) m/e: 748.0 (100%, M+-OTos), 730.1
(40%), 547.9 (95%). Anal. for C49H72Cl2N2O6S2 (M 920.1) cal. C 64.0
H 7.89 N 3.04, exp. C 63.4 H 7.85 N 3.43.
Radiochemistry: N-4-(4-Chlorophenyl)butyl-N,N-diethyl-7-([18F]fluoro-
heptyl)ammonium salt (2)
The reaction was carried out in a device developed for FDG synthesis.9
The F-18 activity (50 mCi) was produced by 18O (p, n) 18F reaction. The
activity was extracted from H218O by a small anion exchanger and then
eluted by aqueous potassium carbonate into the reaction vessel. The
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K. H. YU ET AL.
radioactive solution was evaporated together with 20 mg of Kryptofix
2.2.2 in 1 ml of acetonitrile in a nitrogen stream at 858C under a slight
vacuum. One milligram of acetonitrile was added twice to repeat the
drying procedure. Then 10 mg of compound 10 dissolved in 1 ml of
anhydrous acetonitrile was added. The reaction mixture was heated for
30 min at 858C in the closed-reaction vessel. Radio-TLC showed a yield
of more than 75% of compound 2. Thereupon the solvent was
evaporated, the residue was dissolved in 1 ml of HPLC eluent (E) and
passed through a small aluminum oxide Sep-Pak cartridge. 0.2 ml of the
resulting eluent (1.5 ml) was purified on HPLC (Column: RP-18,
300 Â 3.9 mm; 4 mm; flow 1 ml/min; l: 277 nm). The radiochemical
purity of the [18F]fluoroclofilium was more than 95%. After purification
the solvent was removed in a nitrogen flow and the residue dissolved in
2 ml of isotonic solution.
Acknowledgements
This work was supported by grant no. KOSEF 951-0710-007-2 from the
Korean Science and Engineering Foundation, Nuclear R&D Program
from the Ministry of Science & Technology in Korea and Dongguk
University Research Fund.
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