[18F]/19F exchange in fluorine containing compounds for potential use in 18F-labelling strategies

Article abstract of DOI:10.1002/jlcr.1670

Exchange of [¹⁸F]fluoride with ¹⁹F in various organofluorine compounds in concentrations ranging from 0.06 to 56 mM was explored. We aimed to explore whether exchange reactions can be a potential useful labelling strategy, when there are no requirement of high specific radioactivity. Parameters such as solvents, temperature, conventional vs microwave heating, and the degree of fluorine load in some aromatic and alkyl compounds were investigated with regard to radiochemical yield and specific radioactivity. A series of fluorobenzophenones (1-6), 1-(4-fluorophenyl)ethanone (7), various activated and deactivated fluoro benzenes (8-16), N-(pentafluorophenyl)benzamide (17), (pentafluorophenyl)formamide (18), (tridecafluorohexyl)benzene (19) and tetradecafluorohexane (20) were subjected to [¹⁸F]/¹⁹F exchange. To test this strategy to label biologically active molecules containing fluorine atoms in an aryl group, two analogues of WAY-100635 (21-22), Lapatinib (23), 2,5,6,7,8-pentafluoro-3- methylnaphthoquinone (24) and 1-(2,4-difluorophenyl)-3-(4-fluorophenyl)-propan- 1-one (25) were investigated. The multi-fluorinated molecules containing an electron-withdrawing group were successfully labelled at room temperature, whereas the monofluorinated, as well as those containing an electron-donating group, required heating for the exchange reaction to take place. Copyright

Full text of DOI:10.1002/jlcr.1670

Research Article
Received 25 May 2009,
Revised 4 July 2009,
Accepted 6 July 2009
Published online 25 August 2009 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1670
[18F]/19F exchange in fluorine containing
compounds for potential use in F-labelling
18
strategies
Elisabeth Blom, Farhad Karimi, and Bengt Langstrom
Ã
˚
¨
Exchange of [18F]fluoride with 19F in various organofluorine compounds in concentrations ranging from 0.06 to 56 mM was
explored. We aimed to explore whether exchange reactions can be a potential useful labelling strategy, when there are no
requirement of high specific radioactivity. Parameters such as solvents, temperature, conventional vs microwave heating,
and the degree of fluorine load in some aromatic and alkyl compounds were investigated with regard to radiochemical
yield and specific radioactivity. A series of fluorobenzophenones (1–6), 1-(4-fluorophenyl)ethanone (7), various activated
and deactivated fluoro benzenes (8–16), N-(pentafluorophenyl)benzamide (17), (pentafluorophenyl)formamide (18),
(tridecafluorohexyl)benzene (19) and tetradecafluorohexane (20) were subjected to [18F]/19F exchange. To test this
strategy to label biologically active molecules containing fluorine atoms in an aryl group, two analogues of WAY-100635
(21–22), Lapatinib (23), 2,5,6,7,8-pentafluoro-3-methylnaphthoquinone (24) and 1-(2,4-difluorophenyl)-3-(4-fluorophenyl)-
propan-1-one (25) were investigated. The multi-fluorinated molecules containing an electron-withdrawing group were
successfully labelled at room temperature, whereas the monofluorinated, as well as those containing an electron-donating
group, required heating for the exchange reaction to take place.
Keywords: nucleophilic 18F-fluorination; halogen exchange; organofluorine compounds; perfluoro compounds
(20), two analogues of WAY-100635 (21–22), Lapatinib (23),
2,5,6,7,8-pentafluoro-3-methylnaphthoquinone (24) and 1-(2,4-
difluorophenyl)-3-(4-fluorophenyl)propan-1-one (25).
Introduction
Positron emission tomography (PET) is a non-invasive imaging
technique allowing in vivo measurements and quantification of
biological and biochemical processes.1–3 PET is not only a
diagnostic tool in oncology, cardiology, and neurology, but also
used in drug development.4,5 It might also find applications in
other fields where there are questions related to response
systems, as in plant physiology. There are a number of positron-
emitting radionuclides like 15O, 13N, 11C, 18F, 76Br, and 124I, as
well as metals including 68Ga and 64Cu with various properties of
interest. Radionuclides like 11C and halogens, especially 18F, are
of particular interest due to their synthetic potential.6,7 As time
is an important parameter in labelling, we were interested in
developing a fluorous8-labelling strategy, using polyfluorinated
compounds as a way to control reactivity, and facilitate the
separation of these fluorous precursors from their non-fluorous
products, by using fluorous solid-phase extraction9 as an
efficient technology for fast and reliable purification. We wanted
to explore the F-exchange for two reasons: (1) there are already
a number of drugs containing one or more fluorine atoms
and (2) in some drug-development studies, specific radioactivity
is not mandatory, i.e. to perform pharmacokinetic studies,
making it possible to use F-exchange as a labelling method.
We therefore explored [18F]/19F exchange in a series of
fluorobenzophenones (1–6), 1-(4-fluorophenyl)ethanone (7),
various activated and deactivated fluoro benzenes (8–16),
N-(pentafluorophenyl)benzamide (17), (pentafluorophenyl)for-
mamide (18), (tridecafluorohexyl)benzene (19), tetradecafluorohexane
Results and discussion
Fluorine is a small, highly electronegative atom.10 Covalently
bound fluorine is larger than a hydrogen atom but occupies a
smaller van der Waals volume than a methyl, amino, or hydroxyl
group.11 Fluorine substituent effects on pharmacokinetics and
pharmacodynamics are often observed.12,13 The replacement of
a hydrogen atom or a hydroxyl group by a fluorine atom is a
strategy that is therefore used often by medicinal chemists in
drug development.14 The replacement of a hydrogen atom by a
fluorine atom can alter the pKa, dipole moment, lipophilicity,
hydrogen-bonding properties, or chemical reactivity.15
Halogen exchange is well known,16,17 but is rarely been
applied in 18F-labelling18–20 because tracers with high-specific
radioactivity are generally desired.21 Therefore, it was interesting
to explore the scope of 18/19F exchange reactions and its
limitations with respect to specific radioactivity. Twenty-two
fluorinated compounds were used in these 18/19F exchange
Department of Biochemistry and Organic Chemistry, Box 576, Husargatan 3,
BMC, S-751 23 Uppsala, Sweden
˚
*Correspondence to: Bengt Langstro¨m, Department of Biochemistry and Organic
Chemistry, Box 576, Husargatan 3, BMC, S-751 23 Uppsala, Sweden.
E-mail: Bengt.Langstrom@biorg.uu.se
J. Label Compd. Radiopharm 2009, 52 504–511
Copyright r 2009 John Wiley & Sons, Ltd.

E. Blom et al.
experiments
methanone (1), phenyl(3,4,5-trifluorophenyl)methanone (2), not explored in this study.
(Scheme
1):
(pentafluorophenyl)(phenyl)- The labelling position in the multi-fluorinated compounds was
(3,4-difluorophenyl)(phenyl)methanone (3), (4-fluorophenyl)-
The effect of solvent on the fluorine-exchange reaction was
(phenyl)methanone (4), (3-fluorophenyl)(phenyl)methanone (5), investigated. Solutions of (pentafluorophenyl)(phenyl)metha-
(2-fluorophenyl)(phenyl)methanone (6), 1-(4-fluorophenyl)etha- none (1; 150 mL, 0.31 mM) were reacted repeatedly with n.c.a.
none (7), hexafluorobenzene (8), (trifluoromethyl)benzene (9), [18F]fluoride at room temperature for 15 min in different
1,2,3,4,5-pentafluoro-6-(trifluoromethyl)benzene (10), 1, 2, 3, 4, 5- solvents or mixtures of solvents. When N,N-dimethylformamide
pentafluoro-6-nitrobenzene (11), (pentafluorophenyl)amine (12), (DMF) was used, the incorporation of 18F was 2571% (n = 3). No
2,3,4,5,6-pentafluoro-N-methylaniline (13), pentafluorophenol radiolabelled product was obtained in 1-n-butyl-3-methylimida-
(14), 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenol (15), 1,2,3,4,5- zolium trifluoromethanesulfonate (ionic liquid) or a mixture of
pentafluoro-6-methoxybenzene (16), N-(pentafluorophenyl) ionic liquid/acetonitrile (1:1). In a mixture of acetonitrile and
benzamide (17), (pentafluorophenyl)formamide (18), (trideca- DMF (1:9) or in pure acetonitrile lower incorporation of 17 and
fluorohexyl)benzene (19) and tetradecafluorohexane (20)) 5%, respectively, were observed. The highest incorporation was
(Figure 1). Approximately the same amount of no-carrier-added obtained in dimethyl sulfoxide (DMSO) (9771% (n = 4)).
(n.c.a.) [18F]fluoride (E0.5 GBq) was used in each experiment.
A series of experiments were set up in DMSO to explore the
impact of concentration and temperature on this exchange
reaction. The incorporation of [18F]fluoride was approximately
99% when 1 was used at a concentration of 0.46 mM at room
temperature (reaction volume 150 mL). When the concentration
of 1 was decreased to 0.23 and 0.11 mM, the incorporation
decreased to 94 and 90%, respectively, at room temperature. At
a lower concentration (0.06 mM), the incorporation at room
R-18
F
+
R-F + [18F-]
19F-
R-F = 1-20
R = aryl, alkyl
Scheme 1. General 18/19F exchange reaction.
O
O
O
F
F
O
F
F
F
F
F
F
F
F
F
F
(4)
(2)
(3)
(1)
F
O
O
O
F
F
F
F
F
CH3
F
F
(8)
(7)
(6)
(5)
CF3
NO2
NH2
CF3
F
F
F
F
F
F
F
F
F
F
F
F
F
(10)
F
F
(9)
(11)
(12)
H3C
OH
OH
OCH3
NH
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
CF3
F
F
(14)
(15)
(13)
(16)
F
F
H
N
H
N
F
H
F
F
CF3(CF2)5
CF3(CF2)4CF3
O
O
F
F
F
F
F
(20)
(17)
(18)
(19)
Figure 1. Organofluorine compounds used in this study.
J. Label Compd. Radiopharm 2009, 52 504–511
Copyright r 2009 John Wiley & Sons, Ltd.
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E. Blom et al.
temperature was decreased to 75%, but heating at 1501C for
Pentafluorophenyl compounds containing an electron-with-
15 min decreased the incorporation yield to 40%. Further drawing group are susceptible to nucleophilic attack at room
investigation of this reaction showed that, upon heating and temperature, at reaction rates proportional to the electron-
during HPLC purification, one of the fluorine atoms was withdrawing strength of the group.26 Moderate incorporation
substituted by a hydroxyl group, (identified by GC-MS).
yields of compounds 8,27 10, and 1128,29 were obtained due to
The impact on incorporation yield of the number of fluorine their electron-withdrawing substituents. The exchange reaction
atoms present and their position in the substrate was explored did not occur with substrate 9, which has no fluorine atoms on
using compounds 2–7. The exchange reaction took place in the benzene ring. When 1,2,3,4,5-pentafluoro-6-(trifluoro-
DMSO at room temperature when more than one fluorine atom methyl)benzene (10) was used as precursor in the 18F-labelling
was present in the molecule (2 and 3), as shown in Table 1, but reaction (3.75 mM), labelled compound 15 was obtained in
not in the monofluorinated compounds 4–7. Compound 3 has 1371% (n = 2) yield, in addition to labelled compound 10
been evaluated as a binder to the oestrogen receptor by (7172 %, n = 2). Compound 15 was identified using co-elution
combined quantitative structure–activity relationship models in HPLC. This substitution reaction has previously been
and multilinear regression analyses.22
published.30 Compound 15 does not undergo any exchange
However, the incorporation yield of (4-fluorophenyl)(phenyl)- reaction at room temperature, so the fluorine exchange must
methanone23 (4), (2-fluorophenyl)(phenyl)methanone (6) and 1- take place before the substitution with a hydroxyl group.
(4-fluorophenyl)ethanone24 (7)was increased dramatically when
As expected, the reaction of [18F]fluoride with compounds
the exchange reaction was performed in DMSO at 1501C 12–15 gave no radiolabelled product at room temperature
(Table 2). The reactivity of these carbonyl-substituted aryl because of the electron-donating substituents. However,
fluorides decreased in the order para4ortho4meta, consistent labelled 16 was obtained at room temperature. The impact of
with an SNAr mechanism.25
microwave vs conventional heating on the incorporation of 18F
The scope and limitations of this method were explored in compounds 12–16 was explored, as shown in Table 4. The
further, using the activated and deactivated fluorobenzenes 18/19F exchange reaction was accelerated by increasing
8–16. The 18F-labelling syntheses were performed at various the temperature, using conventional or microwave heating.
concentrations at room temperature, as shown in Table 3.
The incorporation yields were very similar when the exchange of
these compounds with electron-donating substituents was
performed in either DMF or DMSO, for 15 min with conventional
heating or 1–5 min with microwave heating. The data presented
in Table 4 are from the reactions in DMF. The hydrogen bond-
donating groups present in compounds 12–15 and 17–18 are
also well known to reduce the reactivity.31
Table 1. Incorporation yields for the reactions of
compounds 2 and 3 with n.c.a. [18F]fluoridea,b
Precursor
Conc.c (mM)
Incorporationd(%)
Attempts to perform the labelling reaction at room tempera-
ture, using N-(pentafluorophenyl)benzamide (17), (pentafluor-
ophenyl)formamide (18), (tridecafluorohexyl)benzene (19) and
tetradecafluorohexane (20) in DMF were not successful. The
incorporation yields of 17 and 18 increased slightly when the
reaction was performed at higher temperature, for 15 min with
conventional heating or 1–5 min with microwave heating, as
shown in Table 5. The labelling reaction of compound 17 was
also performed in acetonitrile with microwave heating. This did,
2
2
3
3
0.93
0.46
28
6573
3378
7075
2275
7.5
aAll reactions were performed at least in duplicate.
bReaction conditions: 221C, 150 mL DMSO, 15 min.
cConcentration of precursor.
dIncorporation yield, determined from HPLC.
Table 3. Incorporation yields for reaction of compounds
8–16 with n.c.a. [18F]fluoridea,b
Table 2. Incorporation yields for reaction of compounds
4-7 with n.c.a. [18F]fluoridea,b
Precursor
Conc.c (mM)
Incorporationd (%)
Precursor
Conc.c (mM)
Incorporationd (%)
8
8
9
0.93
0.47
56
5772
2072
0
4
4
4
5
6
6
7
7
7
56
499
9771
9072
472
9071
2071
499
7.5
3.7
56
56
7.5
56
10
10
11
12
13
14
15
16
7.5
3.75
1.86
56
56
56
9174
7172
4775
0
0
0
0
7.5
3.7
9371
9171
56
56
4278
aAll reactions were performed at least in duplicate.
bReaction conditions: 1501C heating block, 150 mL DMSO,
15 min.
cConcentration of precursor.
dIncorporation yield, determined from HPLC.
aAll reactions were performed at least in duplicate.
bReaction conditions: 221C, 150 mL DMSO, 15 min.
cConcentration of precursor.
dIncorporation yield, determined from HPLC.
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J. Label Compd. Radiopharm 2009, 52 504–511

E. Blom et al.
Table 4. Incorporation yields for the reaction of compounds 12–16 with n.c.a. [18F]fluoride using a conventional heating block
(Con) or microwave heating (MW) at 1501Ca
Precursorb
Heating mode
Time (min)
Conc.c (mM)
Incorporationd (%)
12 (2)
12 (2)
12 (2)
12 (1)
12 (1)
12 (2)
12 (2)
13 (2)
13 (2)
13 (2)
13 (1)
14 (2)
14 (1)
14 (1)
15 (2)
15 (2)
15 (2)
15 (2)
16 (2)
16 (2)
16 (2)
Con
Con
MW
MW
MW
MW
MW
Con
Con
MW
MW
Con
MW
MW
Con
Con
MW
MW
Con
Con
Con
15
15
1
5
10
1
56
42
42
42
42
21
21
56
21
21
21
56
42
42
56
42
42
42
56
28
7.5
972
773
1371
20
20
773
1373
2372
873
371
14
5
15
15
1
5
15
1
0
0
0
5
15
15
1
671
271
0
471
7471
6774
3274
5
15
15
15
aReaction conditions: DMF (150 mL and 200 mL when the reaction mixture was heated with conventional heating block and
microwave, respectively).
bThe number in parentheses represents number of experiments.
cConcentration of precursor.
dIncorporation yield, determined from HPLC.
Table 5. Incorporation yields for the reaction of compounds 17 and 18 with n.c.a. [18F]fluoride using a conventional heating
block (Con) or microwave heating (MW) at 1501Ca,b
Precursor
Heating mode
Time (min)
Conc.c (mM)
Incorporationd (%)
17
17
17
17
18
18
18
18
Con
Con
MW
MW
Con
Con
MW
MW
15
15
1
56
42
42
42
56
42
42
42
872
472
271
4
371
171
1
5
15
15
1
5
3
aAll reactions were performed at least in duplicate.
bReaction conditions: DMF (150 mL and 200 mL when the reaction mixture was heated with conventional heating block and
microwave, respectively).
cConcentration of precursor.
dIncorporation yield, determined from HPLC.
however, not give any 18F incorporation. Solvents such as DMSO (21) and 3,4,5-trifluoro-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]-
or acetonitrile had no impact on the incorporation of 19 and 20. ethyl}-N-pyridin-2-ylbenzamide (22) were subjected to 18/19F
Starting with 5 mAh, the specific radioactivity of labelled exchange. Analogues of WAY-100635 labelled with 18F in
compounds 3 and 8 were 371 (n = 2) and 5 (n = 1) GBq/mmol, different positions on the benzoyl moiety have been prepared
respectively at end-of-synthesis.
previously.32–35 Nucleophilic aromatic substitution of a nitro
As an example of biologically active molecules that can be group with 18F is one method that has been used for
labelled by using the exchange strategy, two fluorine-containing labelling,32,34 and 18/19F exchange might be applicable if
analogues of WAY-100635, a radioligand for the 5-HT1A receptors there is no need for high specific radioactivity. The specific
for PET analysis in human brain, were used. 4-fluoro-N-{2-[4- radioactivity is thus lower, and its use is thus restricted
(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-pyridin-2-ylbenzamide (Figure 2).
J. Label Compd. Radiopharm 2009, 52 504–511
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E. Blom et al.
F
F
O
O
F
OCH3
N
F
OCH3
N
N
N
N
N
N
N
(21)
(22)
Figure 2. The two WAY-100635 analogues used in the exchange experiments.
Figure 3. HPLC chromatogram for analysis of compound 22 (UV and radio detector), byproduct at 7.1 min and product at 9.5 min (UV). This figure is available in colour
online at www.interscience.wiley.com/journal/jlcr.
Another radiolabelled product with lower lipophilicity was
formed by substitution of one fluorine atom with a hydroxyl
group in the labelling reaction (identified by LC-MS) in 2075%
(n = 2) yield (Figure 3). Any attempt to increase the amount of
radioactivity or reduce the amount of precursor to increase the
specific radioactivity resulted in no labelled product, and
consumption of the precursor. This could be due to radiolysis.
DMF, acetonitrile and DMSO were used as solvents in microwave
reactions. This did not give any differences in product
distribution or incorporation yields.
N
O
O
O
S
N
N
H
NH
Cl
O
Attempts were also made to label Lapatinib (23) (Figure 4),
which is a dual inhibitor of EGFR and HER2 tyrosine kinase
activity,36 by 18/19F exchange. Heating of the monofluorinated
compound together with [18F]fluoride at 1501C for 15 min, in
either DMF or DMSO, gave no labelled product. This confirms
previous observations that meta-substituted monofluorinated
compounds are not very reactive in nucleophilic aromatic
substitution.
F
(23)
Figure 4. Structure of Lapatinib.
When compound 21 (17.5 mM) was heated together with
Two other compounds which were labelled are 2,5,6,
n.c.a [18F]fluoride (E0.5 GBq) in DMF (200 mL) at 1501C for 7,8-pentafluoro-3-methylnaphthoquinone (24) and 1-(2,4-di-
15 min, the incorporation was 871% (n = 2) and the specific fluorophenyl)-3-(4-fluorophenyl)propan-1-one (25) (Figure 5).
radioactivity was 0.01 GBq/mmol. Performing the labelling Compound 24 is used as the precursor for a fluorinated
reaction using microwave heating in DMF, acetonitrile or DMSO analogue of Cpd
5
(2-(2-mercaptoethanol)-3-methyl-1,4-
did gave lower incorporation yield (1%) after 15 min reaction naphthoquinone) predicted to be a cell growth inhibitor by
time. Compound 22 (10.5 mM) was also reacted with n.c.a semi-empirical-calculations,37 and could not be labelled by the
[18F]fluoride (E1 GBq) in DMF (200 mL). The reaction mixture was exchange procedure in DMSO, even after heating at 1501C. On
stirred at room temperature for 15 min and the incorporation the other hand, when a mixture of acetonitrile and tert-butanol
yield was 1%. The reaction mixture was heated thereafter at was used as a solvent (with the precursor at a concentration of
1501C for 15 min, and the incorporation increased to 3573% 14 mM), the incorporation of [18F]fluoride was 8% after 15 min at
(n = 2) yield. Further heating at 1501C for 15 min did not increase room temperature. Heating at 1101C for 15 min did not increase
the incorporation. The specific radioactivity was 0.58 GBq/mmol. the incorporation. Reducing the concentration of 24 to 7.5 mM
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Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2009, 52 504–511

E. Blom et al.
formate (50%) were used as the mobile phase. Radioactivity
was measured in an ion chamber (Veenstra Instrumenten BV,
VDC-202). Microwave heating was performed in a SmithCrea-
torTM monomodal cavity (Biotage AB, Uppsala, Sweden). DMSO
O
F
F
O
O
F
CH3
F
F
F
F
˚
was dried over 4 A molecular sieves.
Retention times on HPLC for compounds 1– 25: = (1): 7.0 min,
(2): 6.8 min, (3): 6.3 min, (4): 5.7 min, (5): 5.8 min, (6): 5.4 min, (7):
4.5 min, (8): 5.5 min, (9): 5.8 min, (10): 5.5 min, (11): 5.0 min, (12):
5.2 min, (13): 6.0 min, (14): 3.7 min, (15): 3.5 min, (16): 6.0 min,
(17): 5.4 min, (18): 3.1 min, (19): 12.9 min, (20): 9.5 min, (21):
9.1 min, (22): 9.5 min, (23): 11.1 min, (24): 6.9 min, (25): 6.4 min.
F
(24)
(25)
Figure 5. 2,5,6,7,8-Pentafluoro-3-methylnaphthoquinone (24) and 1-(2,4-difluoro-
phenyl)-3-(4-fluorophenyl)propan-1-one (25).
Typical exchange procedure
Table 6. Incorporation yields for the reactions of
compound 25 with n.c.a. [18F]fluoridea,b
Precursor
The dried [K/K2.2.2.]118FÀ was dissolved in dry solvent and
added to a solution of the desired amount of precursor in a 1.5
mL pear-shaped vial. After reaction at the specified temperature
for the indicated time, the reaction mixture was analysed by
HPLC and the incorporation yield determined. In some cases the
reaction mixture was purified by semi-preparative HPLC for the
determination of specific radioactivity. Microwave experiments
Conc.c (mM)
28
14
Incorporationd (%)
7077
25
25
25
25
6075
1878
572
7.5
3.5
aAll reactions were performed at least in duplicate.
bReaction conditions: 1501C, 150 mL DMSO, 15 min.
cConcentration of precursor.
were conducted in
microwave vial.
a
200–1000 mL Smith Process VialTM
Compound 1 (byproduct identification): Pentafluorophenyl)
(phenyl)methanone (1) (0.100 g, 0.37 mmol) was dissolved in
5 mL DMSO and tetrabutylammonium fluoride (1.5 mL,
1.5 mmol, 1 M in THF) added and the reaction mixture was
heated at 1501C for 1 h. The crude product was purified by
semi-preparative HPLC and the more hydrofilic byproduct
analysed by GC-MS indicating that one fluorine atom had
been substituted by a hydroxyl group (Rt = 5.1 min). EI-MS:
dIncorporation yield, determined from HPLC.
decreased the incorporation to 4%. Compound 25 has inhibitory
activity for human 11-b-hydroxysteroid dehydrogenase type 1
enzyme (11bHSD1).38 It was labelled in DMSO at 1501C, as
shown in Table 6. The specific radioactivity was 1 GBq/mmol
when 14 mM of the compound was used, and the starting
radioactivity was n.c.a. 5.3 GBq [18F]fluoride.
ꢀ1
m/z 270 [M]
.
Compound 10 (byproduct identification): Labelled compound
co-eluted on HPLC UV/radio detector with compound 1530
(Rt = (10): 5.5, (15) 3.5 min).
Experimental
Compound 22 (byproduct identification): Compound 22
(0.005 g, 10.6 mmol) was heated at 1501C for 15 min in 0.1 ml
DMF with tetrabutylammonium fluoride (0.1 mL, 0.1 mmol, 1 M
in THF). The crude product was purified by semi-preparative
HPLC and the more hydrofilic byproduct analysed by LC-MS
indicating that one fluorine atom had been substituted by a
hydroxyl group (Rt = 7.1 min, (22) Rt = 9.5 min). ESI-MS: m/z 469
[M1H]1.
Radiosynthesis
General
No-carrier-added [18F]fluoride was produced at Uppsala Imanet
on a Scanditronix MC-17 cyclotron by the nuclear reaction
18O(p,n)18F in a target containing water 95% enriched in 18O
(Rotem Industries Ltd, Israel or Taiyo Nippon Sanso Corporation).
Synthia,39 an automated synthesis system, was used in the
handling of [18F]fluoride. The produced solution of [18F]fluoride
in water was transferred from the cyclotron target by an HPLC
pump and trapped on a QMA filter (ABX, advanced biochemical
compounds, pre-conditioned Sep-PAKs, Light QMA Cartridge
with CO23- as a counterion, Radeberg), and thereafter released
with a 2 mL solution of 96:4 (by volume, total volume 12 mL)
acetonitrile–water mixture containing 55.9 mg of Kryptofix 2.2.2
(K2.2.2) and 12.7 mg K2CO3. After the eluted 18F-Kryptofix/K2CO3
solution was dried under N2 (g) at 1101C, it was further dried
with 2 Â 1 mL dry acetonitrile. HPLC analyses of radiolabelled
compounds were performed with a VWR Hitachi Pump L-2130
and a VWR Hitachi UV Detector L-2400 UV detector in series with
Chemical synthesis
General
1H NMR, 13C NMR and 19F spectra were recorded on a Varian
Unity (1H at 400 MHz, 13C at 100 MHz and 19F at 376 MHz)
spectrometer using DMSO-d6 or CDCl3 as solvent (solvent peak
used as reference, except in the case of 19F, when CFCl3 was used
as a reference). All NMR experiments were conducted at 251C.
Thin-layer chromatography was performed on Merck silica gel
F-254 aluminium plates. Silica gel 60, particle size 0.040–0.063 mm
(Merck) was used for column chromatography. Liquid chromato-
graphy mass spectrometry (LC-MS) analyses were performed
using a Gilson HPLC and Finnigan AQA mass spectrometer, in ESI-
mode. Gas chromatography mass spectrometry (GC-MS) analyses
were performed using a Finnigan MAT GCQ mass spectrometer,
in EI-mode. Melting points were determined using a Bibby Sterlin,
Stuart Scientific Melting point apparatus SMP3. All chemicals were
obtained from commercial suppliers and used without further
a
Bioscan b1-flow detector.
A
Discoverys C18, Supelco,
25 cm  4.6 mm 5 mm HPLC column was used. The following
mobile phases were used: 25 mM KH2PO4 in water (A),
acetonitrile/water 50/7 (B). Program: 60–90 % (B) for 5 min,
then 90% for 10 min, flow rate 1.5 mL/min. For semipreparative
LC, an ACE 5C18HL 250 Â 10 mm 5 mm column was used at a
flow rate of 5 mL/min. Acetonitrile (50%) and 0.05 M ammonium
J. Label Compd. Radiopharm 2009, 52 504–511
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

E. Blom et al.
purification. N-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}pyridine- 45.9. 19F NMR (376 MHz, CDCl3, 251C) d = À133.6 (m, 2F), À157.1
2-amine (WAY-100634) was prepared as described previously.40 N-{3- (m, 1F). ESI-MS: m/z 471 [M1H]1.
Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6 -[5-({[2-(methylsulfonyl)ethyl]-
amino}methyl) - 2-furyl]quinazolin-4-amine (Lapatinib) was supplied
by GlaxoSmithKline.
Conclusion
Methyl(pentafluorophenyl)amine41 (13): Hexafluorobenzene
(5.035 g, 27.1 mmol) was dissolved in 40 mL propan-2-ol,
18/19F Exchange reactions were examined in various organo-
fluorine compounds, and the effect of solvent, temperature,
and methylamine (2.5 mL, 40% in H2O) was added. The reaction
conventional vs microwave heating, degree of fluorine load and
mixture was heated at 851C for 56 h, and then distilled
the presence of activating and deactivating groups on the
under reduced pressure to yield 13 as a colourless liquid
radiochemical yield was investigated. This study aimed to
1
(1.403 g, 26%). H NMR (CDCl3, 400 MHz, 251C) d = 3.05 (m, 3H).
understand the impact of fluorinated compounds in choosing
a labelling strategy, considering issues such as activated leaving
13C NMR (CDCl3, 100 MHz, 251C) d = 145.7 (m), 139.2 (m), 136.8
(m), 134.5 (m), 33.3 (m). 19F NMR (DMSO-d6, 376 MHz, 251C)
groups, matrix-supported substrates, catalysts, and work-up
protocols.
d = À161.5 (m, 2F), À166.0 (m, 2F), À176.6 (m, 1F). ESI-MS: m/z
198 [M1H]1.
N-(Pentafluorophenyl)benzamide42 (17): Pentafluoroaniline
Acknowledgement
(3.008 g, 16.4 mmol) was dissolved in 15 mL dry CH2Cl2 and
benzoyl chloride (3.458 g, 24.6 mmol) was added dropwise over
10 min. The mixture was stirred at room temperature for 16 h
under a nitrogen atmosphere, and then diluted with CHCl3,
washed with H2O, and concentrated under reduced pressure.
The residue was recrystallized from CHCl3/petroleum ether to
yield 17 as white crystals (0.280 g, 6%). M.p. 179–1801C. 1H NMR
(DMSO-d6, 400 MHz, 251C) d = 10.54 (bs, 1H), 8.03–7.98 (m, 2H),
7.69–7.63 (m, 1H), 7.60–7.54 (m, 2H). 13C NMR (DMSO-d6,
100 MHz, 251C) d = 165.4, 144.2 (m), 141.8 (m), 138.5 (m), 136.0
(m), 132.5, 132.3, 128.7, 127.9. 19F NMR (DMSO-d6, 376 MHz,
251C) d = À144.9 (m, 2F), À157.0 (m, 1F), À163.0 (m, 2F). ESI-MS:
m/z 288 [M1H]1.
Financial support from The Swedish Science Research Council
(BL) and the Juvenile Diabetes Research Foundation (JDRF) is
gratefully acknowledged. This work was conducted in collabora-
tion with Imanet, GE Healthcare.
References
[1] H. N. Wagner Jr, Z. Szabo, J. W. Buchanan (Eds.), Principles of
Nuclear Medicine, 2nd ed., WB Saunders Company, Philadelphia,
1995.
(Pentafluorophenyl)formamide43
(18):
Pentafluoroaniline
[2] B. L. Bailey, D. W. Townsend, P. E. Valk, M. N. Maisey (Eds.), Positron
Emission Tomography: Basic Science and Clinical Practise, Springer,
London, 2003.
[3] J. Czernin, M. E. Phelps, Annu. Rev. Med. 2002, 53, 89–112.
[4] W. C. Eckelman, Nucl. Med. Biol. 2002, 29, 777–782.
(3.005 g, 16.41 mmol) was dissolved in 30 mL p-xylene and, after
addition of 30 mL formic acid, the reaction mixture was heated
at 1001C for 67 h. The solvent was removed under reduced
pressure and the residue purified by column chromatography
(CH2Cl2) to yield 18 as white crystals (1.920 g, 56%). M.p.
99–1001C. 1H NMR (DMSO-d6, 400 MHz, 251C): d = 10.34 (bs, 1H),
8.38 (s, 1H). 13C NMR (DMSO-d6, 100 MHz, 251C) d = 156.0, 146.4
(m), 143.8 (m), 139.6 (m), 138.0 (m). 19F NMR (DMSO-d6, 376 MHz,
251C) d = À145.4 (d, J = 21.3 Hz, 2F), À158.3 (t, J = 23.3 Hz, 1F),
´
˚
¨
[5] M. Bergstro¨m, A. Grahnen, B. Langstrom, Eur. J. Pharmacol. 2003,
59, 357–366.
[6] R. A. Ferrieri, Production and Application of Synthetic Precursors
Labeled with Carbon-11 and Fluorine-18, in Handbook of Radio-
pharmaceuticals: Radiochemistry and Applications (Eds.: M. J. Welch,
C. S. Redvanly), Wiley, Chichester, UK, 2003, pp. 229–282.
ꢀ
À163.7 (m, 2F). EI-MS: m/z 211 [M] 1, 183.
˚
[7] B. Langstro¨m, O. Itsenko, O. Rahman, J. Label. Compd. Radiopharm.
2007, 50, 794–810.
4-Fluoro-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-pyri-
din-2-ylbenzamide (21): Procedure and spectral data are pub-
lished elsewhere.44
[8] W. Zhang, Tetrahedron 2003, 59, 4475–4489.
[9] D. P. Curran, Synlett 2001, 1488–1496.
[10] L. Pauling, The Nature of the Chemical Bond, Cornell University
Press, Ithaca, 1960.
3,4,5-Trifluoro-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-
pyridin-2-ylbenzamide (22): N-{2-[4-(2-Methoxyphenyl)piperazin-
1-yl]ethyl}pyridine-2-amine (0.075 g, 0.24 mmol) was dissolved
in 2 mL dry CH2Cl2. After cooling to 01C, triethylamine (0.05 mL,
0.36 mmol) and 3,4,5-trifluorobenzoyl chloride (0.047 mL,
0.36 mmol) was added dropwise. The reaction mixture was
heated to room temperature and stirred for 2 h under a nitrogen
atmosphere, and thereafter extracted with a 10% aqueous
solution of Na2CO3 and CH2Cl2. The organic phase was dried
with MgSO4 and concentrated under reduced pressure. A
colourless oil (0.090 g, 80%) was obtained after purification
using column chromatography (CH2Cl2/CH3OH 10:1). 1H NMR
(400 MHz, CDCl3, 251C) d = 8.42 (ddd, J = 0.8, 1.9, 4.9 Hz, 1H), 7.51
(dt, J = 1.9, 7.6 Hz, 1H), 7.11-7.07 (m, 1H), 6.99–6.81 (m, 7H), 4.22
(t, J = 6.6 Hz, 2H), 3.83 (s, 3H), 2.91 (m, 4H), 2.72 (t, J = 6.6 Hz, 2H),
2.62 (m, 4H). 13C NMR (100 MHz, CDCl3, 251C) d = 167.2, 155.8,
152.2, 150.6 (ddd, J = 3.5, 10.1, 251.2 Hz), 149.0, 141.3, 140.8 (dt,
J = 15.2, 256.5 Hz), 137.6, 132.1 (m), 122.8, 122.2, 121.6, 120.9,
118.0, 113.3 (dd, J = 6.5, 16.1 Hz), 111.2, 56.1, 55.3, 53.3, 50.6,
[11] A. Bondi, J. Phys. Chem. 1964, 68, 441–451.
¨
¨
[12] H.-J. Bohm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Muller,
U. Obst-Sander, M. Stahl, ChemBioChem. 2004, 5, 637–643.
[13] K. Mu¨ller, C. Faeh, F. Diederich, Science 2007, 317, 1881–1886.
[14] B. K. Park, N. R. Kitteringham, P. M. O’Neill, Annu. Rev. Pharmacol.
Toxicol. 2001, 41, 443–470.
[15] B. E. Smart, J. Fluorine Chem. 2001, 109, 3–11.
[16] N. R. Thompson, B. Tittle, Halogen Chem. 1967, 2, 369–398.
[17] M. F. A. Dove, D. B. Sowerby, Halogen Chem. 1967, 1, 41–132.
[18] F. Cacace, M. Speranza, A. P. Wolf, J. S. Fowler, J. Label. Compd.
Radiopharm. 1981, 18, 1721–1730.
[19] J. W. Babich, R. H. Rubin, W. A. Graham, R. A. Wilkingson, J. Vincent,
A. J. Fischman, Nucl. Med. Biol. 1996, 23, 995–998.
[20] O. Langer, M. Mitterhauser, M. Brunner, M. Zeitlinger, W. Wadsak,
B. X. Meyer, K. Kletter, M. Muller, Nucl. Med. Biol. 2003, 30, 285–291.
[21] S. E. Snyder, M. R. Kilbourn, Chemistry of Fluorine-18
Radiopharmaceuticals, in Handbook of Radiopharmaceuticals:
Radiochemistry and Applications (Eds.: M. J. Welch, C. S. Redvanly),
Wiley, Chichester, UK, 2003, pp. 195–227.
[22] Y. Akahori, M. Nakai, Y. Yakabe, M. Takatsuki, M. Mizutani,
M. Matsuo, Y. Shimohigashi, SAR and QSAR in Environ. Res. 2005,
16, 323–337.
www.jlcr.org
Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2009, 52 504–511

E. Blom et al.
[23] T. Ludwig, J. Ermert, H. H. Coenen, Nucl. Med. Biol. 2002, 29, [34] N. Ginovart, W. Hassoun, D. Le Bars, D. Weissmann, V. Leviel,
255–262.
[24] C.-Y. Shiue, M. Watanabe, A. P. Wolf, J. S. Fowler, P. Salvadori, [35] L. Lang, E. Jagoda, Y. Ma, M. B. Sassaman, W. C. Eckelman, Bioorg.
J. Label. Compd. Radiopharm. 1984, 21, 533–547. Med. Chem. 2006, 14, 3737–3748.
[25] F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry, Part A: [36] P. M. Harari, G. W. Allen, J. A. Bonner, J. Clin. Oncol. 2007, 25,
Synapse 2000, 35, 192–200.
Structure and Mechanism, 4th ed., Kluwer Academic/Plenum
Publishers, New York, 2000, pp. 590.
[26] J. Burdon, Tetrahedron 1965, 21, 3373–3380.
4057–4065.
[37] S. H. Ham, J. I. Choe, M.-F. Wang, V. Peyregne, B. I. Carr, Bioorg.
Med. Chem. 2004, 14, 4103–4105.
[27] F. Cacace, M. Speranza, A. P. Wolf, R. R. Macgregor, J. Fluorine [38] P. J. Barton, D. S. Clarke, C. D. Davies, R. B. Hargreaves, J. E. Pease,
Chem. 1982, 21, 145–158.
M. T. Rankine, Preparation of (hetero)aryl ketones as 11b HSD1
inhibitors. PCT Int. Appl. WO 2004011410, 2004.
[39] P. Bjurling, R. Reineck, G. Westerberg, A. Gee, J. Sutcliffe,
[28] K. Hashizume, H. Tamakawa, N. Hashimoto, Y. Miyake, Chem. Lett.
1997, 26, 109–110.
˚
¨
[29] L. W. Herman, A. J. Fischman, R. G. Tompkins, R. N. Hanson,
C. Byon, H. W. Strauss, D. R. Elmaleh, Nucl. Med. Biol. 1994, 21,
1005–1010.
B. Langstrom, Presented at Proceedings of the VIth Workshop
on Targetry and Target Chemistry, TRIUMF, Vancouver, Canada,
1995, 282–284.
[30] I. N. Rozhkov, N. D. Kuleshova, Bull. Acad. Sci. USSR Div. Chem. Sci. [40] Z.-P. Zhuang, M. P. Kung, H. F. Kung, J. Med. Chem. 1994, 37,
1976, 25, 1919–1923. 1406–1407.
[31] D. W. Kim, H.-J. Jeong, S. T. Lim, M.- H. Sohn, J. A. Katzenellenbogen, [41] V. E. Platonov, A. Haas, M. Schelvis, M. Lieb, K. V. Dvornikova,
D. Y. Chi, J. Org. Chem. 2008, 73, 957–962.
[32] D. Le Bars, C. Lemaire, N. Ginovart, A. Plenevaux, J. Aerts,
C. Brihaye, W. Hassoun, V. Leviel, P. Mekhsian, D. Weissmann,
O. I. Osina, Y. V. Gatilov, J. Fluorine Chem. 2001, 10, 131–139.
[42] H. Adams, J.-L. J. Blanco, G. Chessari, C. A. Hunter, C. M. R. Low,
J. M. Sanderson, J. G. Vinter, Chem. Eur. J. 2001, 7, 3494–3503.
J. F. Pujol, A. Luxen, D. Comar, Nucl. Med. Biol. 1998, 25, 343–350. [43] T. K. Traylor, D. Magde, J. Luo, K. N. Walda, D. Bandyopadhyay,
[33] L. Lang, E. Jagoda, B. Schmall, B. K. Vuong, H. R. Adams, G.-Z. Wu, V. S. Sharma, J. Am. Chem. Soc. 1992, 114, 9011–9017.
D. L. Nelson, R. E. Carson, W. C. Eckelman, J. Med. Chem. 1999, [44] O. Itsenko, E. Blom, B. Langstrom, T. Kihlberg, Eur. J. Org. Chem.
˚
¨
42, 1576–1586.
2007, 4337–4342.
J. Label Compd. Radiopharm 2009, 52 504–511
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org