2-, 3- and 4-[18F]fluoropyridine by no-carrier-added nucleophilic aromatic substitution with K[18F]F-K222 - A comparative study

Article abstract of DOI:10.1002/jlcr.730

Compared to homoaromatic and aliphatic nucleophilic radiofluorinations, only few references can be found in the literature describing nucleophilic substitutions with [¹⁸F]fluoride ion of heteroaromatic compounds such as pyridines and only reactions involving fluorination processes at the ortho-position (2-position) have been more intensively studied. In the present paper, the scope of the nucleophilic aromatic fluorinations at the meta- and paraposition of the pyridine ring with no-carrier-added [¹⁸F] fluoride ion as its activated K [¹⁸F]F-K₂₂₂ complex has been evaluated and compared to the nucleophilic aromatic fluorinations at the ortho-position in this pyridine series. The syntheses of 3- and 4- [ ¹⁸F]fluoropyridines were chosen as model reactions and compared to the radiosynthesis of 2-[¹⁸F]fluoropyridine. The parameters studied include the influence of the position of the leaving group at the pyridine ring, as well as the quantity of the precursor used, the type of activation (conventional heating, microwave irradiation), the solvent, the temperature and the reaction time. Using the corresponding nitro precursor, high yields were obtained at the 2-position (94% yield) using microwaves (100 W) for 2 min in DMSO. Good yields (up to 72%) were observed at the 4-position using the same conditions while practically no reaction was observed at the 3-position. About 60% yield was also obtained at both the 2- and 4-position using the corresponding nitro precursor at 145°C for 10 min in DMSO. Copyright

Full text of DOI:10.1002/jlcr.730

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 979–992.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.730
Research Article
2-, 3- and 4-[18F]Fluoropyridine by no-carrier-
added nucleophilic aromatic substitution with
K[18F]F-K222 – a comparative study
!
M. Karramkam, F. Hinnen, F. Vaufrey and F. Dolle*
! ! ! !
Service Hospitalier Frederic Joliot, Departement de Recherche Medicale,
! !
CEA/DSV 4 place du general Leclerc, F-91401 Orsay, France
Summary
Compared to homoaromatic and aliphatic nucleophilic radiofluorinations,
only few references can be found in the literature describing nucleophilic
substitutions with [18F]fluoride ion of heteroaromatic compounds such as
pyridines and only reactions involving fluorination processes at the ortho-
position (2-position) have been more intensively studied. In the present paper,
the scope of the nucleophilic aromatic fluorinations at the meta- and para-
position of the pyridine ring with no-carrier-added [18F]fluoride ion as its
activated K[18F]F-K222 complex has been evaluated and compared to the
nucleophilic aromatic fluorinations at the ortho-position in this pyridine series.
The syntheses of 3- and 4-[18F]fluoropyridines were chosen as model reactions
and compared to the radiosynthesis of 2-[18F]fluoropyridine. The parameters
studied include the influence of the position of the leaving group at the pyridine
ring, as well as the quantity of the precursor used, the type of activation
(conventional heating, microwave irradiation), the solvent, the temperature
and the reaction time. Using the corresponding nitro precursor, high yields
were obtained at the 2-position (94% yield) using microwaves (100 W) for
2 min in DMSO. Good yields (up to 72%) were observed at the 4-position
using the same conditions while practically no reaction was observed at the
3-position. About 60% yield was also obtained at both the 2- and 4-position
! !
*Correspondence to: Professor F. Dolle, Service Hospitalier Frederic Joliot, Departement de
Recherche Medicale, CEA/DSV 4 place du general Leclerc, F-91401 Orsay, France. E-mail:
!
!
! !
dolle@dsvidf.cea.fr
Copyright # 2003 John Wiley & Sons, Ltd.
Received 9 April 2003
Accepted 7 May 2003

980
M. KARRAMKAM ET AL.
using the corresponding nitro precursor at 1458C for 10 min in DMSO.
Copyright # 2003 John Wiley & Sons, Ltd.
Key Words: labelling, fluorine-18, fluoropyridine, nucleophilic aromatic
substitution, microwaves.
Introduction
Nucleophilic substitution by means of cyclotron-produced, no-carrier-
added [18F]fluoride ion is the method of choice for the synthesis of
radioligands labelled with fluorine-18 (half life : 110 min) of high specific
activity for Positron Emission Tomography.1,2
Compared to homoaromatic and aliphatic nucleophilic radiofluor-
inations, only few references can be found in the literature describing
nucleophilic substitutions with [18F]fluoride ion of heteroaromatic
compounds such as pyridines and only reactions involving fluorination
processes at the ortho-position (2-position) have been more intensively
studied.
The earliest examples for the synthesis of 2-[18F]fluoropyridine
derivatives using nucleophilic aromatic substitution with [18F]fluoride
ion are : (a) the preparation of 6-[18F]fluoronicotinic acid diethylamide3
([18F]-1) in up to 40% decay-corrected radiochemical yield from the
corresponding 2-chloropyridine derivative and [18F]fluoride ion as its
cesium salt, in acetamide at 2008C; (b) the preparation of 6- and 2-
[18F]fluoronicotine4 ([18F]-2,3) in 30 – 40% decay-corrected radio-
chemical yield in DMSO at 2108C for 30 min from the corresponding
2-bromopyridine derivatives and [18F]fluoride ion as its cesium salt.
More recently, potent nicotinic acetylcholine receptor ligands,
norchlorofluoroepibatidine
(4,
( ꢀ )-exo-2-(6-fluoro-3-pyridyl)-7-
azabicyclo [2.2.1]heptane) as well as 2- and 6-fluoro-A-85380 (5, 2-
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2-,3- AND 4-[18F] FLUOROPYRIDINE
981
fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine; 6, 6-fluoro-3-[2(S)-2-azeti-
dinylmethoxy]pyridine) were labelled with fluorine-18 on the pyridine
ring. [18F]Norchlorofluoroepibatidine ([18F]-4) was first synthesized
implying a nucleophilic aromatic bromo-to-fluoro substitution5–8 (in
DMSO, at 180–1908C for 10–15 min, 15–26% decay-corrected radio-
chemical yield) using the activated K[18F]F-K222 complex.9 It was also
obtained from the corresponding 2-trimethylammonium pyridine
derivative with a similar nucleophilic fluorination step (in DMSO
containing the K[18F]F-K222 complex, at 1208C for 10 min, 70% decay-
corrected radiochemical yield).10–12 2-[18F]F-A-85380 ([18F]-5) was first
synthesized by nucleophilic aromatic nitro-to-fluoro substitution in
DMSO using the activated K[18F]F-K222 complex by conventional
heating at 1508C for 20 minutes or by microwave activation at 100 W for
1 min (50–60% decay-corrected radiochemical yield).13 It was also
obtained in 20% decay-corrected radiochemical yield by nucleophilic
aromatic bromo-to-fluoro substitution in DMSO by conventional
heating at 1508C for 20 min14 and by nucleophilic aromatic trimethyl-
ammonium-to-fluoro substitution in DMSO by conventional heating at
1458C for 2 min or by microwave activation at 100 W for 1 min (70%
decay-corrected radiochemical yield).15 6-[18F]F-A-85380 ([18F]-6) was
synthesized by nucleophilic aromatic nitro-to-fluoro substitution in
DMSO using the activated K[18F]F-K222 complex by conventional
heating at 1508C for 20 min (16–24% decay-corrected radiochemical
yield).16,17 It was also obtained in 38–48% decay-corrected radio-
chemical yield by nucleophilic aromatic trimethylammonium-to-fluoro
substitution in DMSO by conventional heating at 1508C for 5 min.18
Finally, the scope of these nucleophilic heteroaromatic fluorinations
of the pyridine ring at the 2-position with no-carrier-added [18F]fluoride
ion as its activated K[18F]F-K222 complex was evaluated using the
synthesis of 2-[18F]fluoropyridine ([18F]-7a) as a model reaction.19
The parameters studied included the influence of the leaving group in
the 2-position of the pyridine ring (-Cl, -Br, -I, -NO2 and -N+Me3), the
quantity of the precursor used, the type of activation (conventional
heating, microwave irradiation and ultrasonication), the solvent, the
temperature and the reaction time.
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M. KARRAMKAM ET AL.
Concerning the influence of the leaving group, 2-chloro- and 2-
bromopyridine gave moderate to good fluorine-18 incorporation yields
while 2-nitro- and especially 2-trimethylammonium pyridine gave excellent
incorporation yields. Noteworthy, 2-iodopyridine was almost unreactive.
As expected, the incorporation yield increased with the quantity of
precursor used : high yields were observed from about 7 mmol of precursor.
Using conventional heating and regardless of the substituent in the 2-
position of the pyridine ring, the best yields for the radiosynthesis of 2-
[18F]fluoropyridine ([18F]-7a) were obtained when the temperature of the
reaction was 1808C and the solvent DMSO. The decay-corrected yields for
the 2-nitro- and the 2-trimethylammonium pyridine precursors were 77 and
88%, respectively, after only 5 min of reaction and were similar to those
observed at 1508C for longer reaction times. At 1208C, neither the 2-
chloro- nor the 2-bromopyridine gave any incorporation. Using microwave
irradiations, excellent incorporation yields (96%) were observed for the 2-
trimethylammonium leaving group from 1 min of reaction at 100 W in
DMSO. Concerning the 2-chloro-, 2-bromo- and 2-nitropyridine, the use
of 100 W microwave irradiation for 2 min gave yields comparable to those
obtained for 10 min of conventional heating at 1808C, 22, 71 and 88%,
respectively. No radioactivity incorporation at all could be detected when
ultrasound was applied, even with long reaction time and high power.
Heteroaromatic nucleophilic substitutions of the pyridine ring at the
para-position (4-position) has, to our knowledge never been reported
whereas substitution at the meta-position (3-position) was only reported
once. The only example of a radiosynthesis of a meta-[18F]fluoropyridine
derivative is the preparation of N-(2-aminoethyl)-5-[18F]fluoropyridine-
2-carboxamide ([18F]-8), as a potential MAO-B imaging radiotracer,20
implying a nucleophilic aromatic nitro-to-fluoro sub-stitution (in
DMSO, at 1358C for 20 min, 35% decay-corrected radiochemical yield)
using the activated K[18F]F-K222 complex. As illustrated within this
paper, this reaction can better be classified together with those
conventional nucleophilic aromatic substitutions implying a strong
electron-withdrawing group para to the leaving group.
In the present paper, the scope of these nucleophilic aromatic
fluorinations at the meta- and para-position of the pyridine ring with
Copyright # 2003 John Wiley & Sons, Ltd.
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2-,3- AND 4-[18F] FLUOROPYRIDINE
983
no-carrier-added [18F]fluoride ion as its activated K[18F]F-K222 complex
has been evaluated and compared to the nucleophilic aromatic
fluorinations at the ortho-position in this pyridine series. The syntheses
of 3- and 4-[18F]fluoropyridines ([18F]-7b,7c) were chosen as model
reactions and compared to the radiosynthesis of 2-[18F]fluoropyridine
([18F]-7a). The parameters studied include the influence of the position
of the leaving group at the pyridine ring, as well as the quantity of the
precursor used, the type of activation (conventional heating, microwave
irradiation), the solvent, the temperature and the reaction time.
Results and discussion
Chemistry
Synthesis of 2-, 3- and 4-nitropyridine as precursors for labelling : 2-
Nitropyridine (9a) was prepared from 2-aminopyridine in a mixture of
concentrated sulphuric acid and 30% aqueous hydrogen peroxide at
08C in 55% yield, using a slight modification of literature proce-
dures.19,21 3-and 4-Nitropyridine (9b and 9c) were prepared from the
corresponding 3- and 4-aminopyridines using similar conditions to
those described above in 62 and 51% yield, respectively.
Unfortunately, the corresponding pyridyltrimethylammonium tri-
fluoromethanesulfonates could not all be prepared and therefore
compared as precursors for labelling. Using protocoles adapted for
the preparation of these trimethylammonium salts,15,19,22,23 (2-pyridyl)-
trimethylammonium trifluoromethanesulfonate (10a) could be prepared
in 35% non-optimized yield from the corresponding 2-dimethylamino-
pyridine in toluene at room temperature containing 1.1 equivalent of
methyl trifluoromethanesulfonate.
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M. KARRAMKAM ET AL.
Noteworthy, starting from 3- or 4-dimethylaminopyridine using
similar conditions (toluene containing 1.1 equivalent of methyl
trifluoromethanesulfonate), at room temperature or lower (08C,
ꢁ208C or ꢁ788C), only the corresponding 3- and 4-dimethylamino-l-
methylpyridinium trifluoromethanesulfonates (11b and 11c) were
obtained (37–40% yield). The desired (3-pyridyl)-trimethylammonium-
and (4-pyridyl)-trimethylammonium trifluoromethanesulfonates (10b
and 10c) were not observed. With 2-dimethylaminopyridine using the
same conditions that are described above (toluene containing 1.1
equivalent of methyl trifluoromethanesulfonate), heating at 808C is
needed in order to obtain the 2-dimethylamino-l-methylpyridinium
trifluoromethanesulfonate (11a). Under these conditions, the (2-
pyridyl)-trimethylammonium trifluoromethanesulfonate is still present
1
(ratio 11a and 10a : 4/1, determined using H NMR).
Radiochemistry
K[18F]F-K222 complex was prepared from cyclotron-produced, no-
carrier-added [18F]fluoride ion batches (specific radioactivity : 5 Ci/mmol
at end of bombardment (EOB); typical batch : 550–650 mCi (20.3–24.0
GBq) of [18F]fluoride ion at EOB).
In a first set of experiments, the influence of the reaction time and
position of the nitro function as leaving group in the pyridine ring were
studied. A DMSO solution (600 ml) containing 17 mmol of 2-, 3- or 4-
nitropyridine as precursor for labelling (9a-c) was transferred to 30–60
mCi (EOB, 1.11 – 2.22 GBq) of the dried K[18F]F-K222 complex in a
reaction vial (Vacutainer1 tube). The tube (not sealed) was then placed
in a heating block for 1 – 15 min at 1458C without stirring the contents.
As shown in Table 1, the 2-nitro-derivative (9a) was reactive under
the conditions described above (conventional heating, 1458C). The yield
of 2-[18F]fluoropyridine ([18F]-7a) increased with the reaction time up to
10 min, and then decreased. High incorporation yields were observed
from 2 to 10 min of reaction (60–66% yield). These data are in
accordance with already published results.19 The 4-nitro-derivative (9c)
Copyright # 2003 John Wiley & Sons, Ltd.
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2-,3- AND 4-[18F] FLUOROPYRIDINE
985
Table 1. Yields of 2-[18F]fluoro-, 3-[18F]fluoro- and 4-[18F]fluoropyridine ([18F]-
7a-c) using conventional heating at 1458C or microwave activation at 100 W:
Influence of the reaction timea
Heating 1458C
Microwaves 100 W
10
Reaction time (min)
0.50 20
50
100
150 0.50
20
ortho
meta
para
16
0
15
60
0
47
64
0
52
66
1
60
38
1
43
40
0
30
81
1
65
94
2
72
a Conditions : precursor : 17 mmol ; K[18F]F-K222 complex : 30–60 mCi (EOB, 1.11 – 2.22 GBq)
Solvent: DMSO (600 mL); heating block for 1 – 15 min at 1458C or microwave oven (100 W) for 0.5
– 2 min ; no stirring. Indicated yields are the average of three independent runs.
was also reactive under the conditions described above. As shown for 2-
[18F]fluoropyridine ([18F]-7a), the yield of 4-[18F]fluoropyridine ([18F]-
7c) increased with the reaction time up to 10 min (47–60%), and then
decreased. In each run, the remaining radioactivity at the end of the
experiment was measured and 85% – 95% of the initial radioactivity
placed in the vessel was still present. The decrease in the radiochemical
yield with time was therefore not attributed to volatiles but to
decomposition of the formed 2- and 4-[18F]fluoropyridine ([18F]-
7a/7c). The 3-nitro-derivative (9b) was unreactive and only 1% of 3-
[18F]fluoropyridine ([18F]-7b) could be observed.
Results similar to those shown in Table 1 were obtained for all three
precursors (9a-c) when the above protocol was modified. The K[18F]F-
K222 complex was first dissolved in 600 ml of DMSO and then added to a
reaction vial containing 17 mmol of the precursor 9a-c. Finally, the
reaction vial was tightly sealed and placed in a heating block for 1 to
15 min at 1458C without stirring the contents.
In another set of experiments, the influence of the reaction time and
the position of the nitro function as leaving group in the pyridine ring
was studied using microwave activation. A DMSO solution (600 ml)
containing 17 mmol of 2-, 3- or 4-nitropyridine as precursor for labelling
(9a-c) was transferred to 30–60 mCi (EOB, 1.11 – 2.22 GBq) of the dried
K[18F]F-K222 complex in a reaction vial (Vacutainer1 tube). The tube
(not sealed) was then placed in a dedicated microwave oven and
irradiated (100 W).
As shown in Table 1, the 2-nitro-derivative (9a) was highly reactive
under the conditions described above (microwave activation, 100 W).
High incorporation yields were observed at 100 W from 1 minute of
reaction (81% yield) to 2 minutes of reaction (94% yield). These data
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M. KARRAMKAM ET AL.
are in accordance with already published results.19 The 4-nitro-
derivative (9c) was also reactive under the conditions described above
and up to 72% yield was obtained, hi both cases, the yield of 2- and 4-
[18F]fluoropyridine ([18F]-7a/7c) increased with the reaction time up to
2 minutes. The 3-nitro-derivative (9b) was unreactive and only 1–2% of
3-[18F]fluoropyridine ([18F]-7b) could be observed.
In a last set of experiments, the influence of the nature of the leaving
group at the 3-position and in particular the absence of reactivity
towards nucleophilic hetero-aromatic substitution was shortly investi-
gated using another precursor for labelling, 3-bromopyridine. A DMSO
solution (600 ml) containing 17 mmol or more (up to 100 mmol) of 3-
bromopyridine as precursor for labelling was transferred to 30–60 mCi
(EOB, 1.11 – 2.22 GBq) of the dried K[18F]F-K222 complex in a reaction
vial (Vacutainer1 tube). The tube (not sealed) was then placed in a
dedicated microwave oven and irradiated (100 W) or placed in a heating
block for 1–15 min at 1458C without stirring the contents. Alternatively,
the K[18F]F-K222 complex was first dissolved in 600 ml of DMSO and
then added to a reaction vial containing the 3-bromo derivative. The
reaction vial was tightly sealed and placed in a heating block for up to
60 min at 170–2008C without stirring. With 3-bromopyridine as
precursor for labelling, the influence of the solvent was also studied
using DMF, acetonitrile and a mixture of DMSO/H2O (95:5 v:v).
Whatever the conditions used, the 3-bromo-derivative was completely
unreactive and the desired 3-[18F]fiuoropyridine ([18F]-7b) could not be
detected.
Conclusion
The scope of the nucleophilic aromatic radiofluorination at the meta-
and para-position of the pyridine ring with no-carrier-added [18F]fluor-
ide ion as its activated K[18F]F-K222 complex has been evaluated and
compared to the nucleophilic aromatic radiofluorination at the ortho-
position in the pyridine series. Using the corresponding nitro precursor,
high yields were obtained at the 2-position (94% yield) using
microwaves (100 W) for 2 min in DMSO. Good yields (up to 72%)
were observed at the 4-position using the same conditions while
practically no reaction was observed at the 3-position. About 60% yield
was also obtained at both the 2- and 4-position using the corresponding
nitro precursor at 1458C for 10 min in DMSO.
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2-,3- AND 4-[18F] FLUOROPYRIDINE
987
Experimental
General
2- and 3-fluoropyridine, 2-, 3- and 4-aminopyridine, 2- and 4-
dimethylaminopyridine are commercially available and were purchased
from Aldrich, Fluka or Sigma France. 3-Dimethylaminopyridine was
available from Maybridge UK. 4-fluoropyridine can be synthesized
according to literature procedures.24–27 All other chemicals were
purchased from Aldrich, Fluka or Sigma France. All purchased
chemicals were used without further purification. TLC were run on
pre-coated plates of silicagel 60F254 (Merck). The compounds were
localized using a UV-lamp at 254 nm. Radioactive spots were detected
using a Berthold TraceMaster 20 automatic TLC linear analyser. Flash
chromatography was conducted on silicagel 63–200 mm (Merck) at 0.3
bars (Ar). NMR spectra were recorded on a Bruker AMX (300 MHz)
apparatus using the hydrogenated residue of the deuteriated solvents
(CD2Cl2, d = 5.32 ppm; DMSO-d6, d = 2.50 ppm) and/or TMS as
1
internal standards for H NMR as well as the deuteriated solvents
(CD2Cl2,
d = 53.8 ppm;
DMSO-d6,
d = 39.5 ppm;
CD3OD,
d = 49.3 ppm) and/or TMS as internal standards for 13C NMR. The
chemical shifts are reported in ppm, downfield from TMS (s, d, t, dd, b
for singlet, doublet, triplet, doublet of doublet and broad respectively).
The mass spectra (MS), DCI/NH+4 , were measured on a Nermag R10-
10 apparatus. Radiosyntheses using fluorine-18 were performed in a
7.5 cm-lead shielded cell using a computer assisted Zymate robot system
(Zymark corporation, USA). Microwave activation was performed with
a MicroWell 10 oven (2.45 GHz), Labwell AB, Sweden.
Chemistry
Nitropyridines:general procedure for the nitration of aminopyridi-
nes. 1.0 g (10.6 mmol, MW : 94.12) of the adequate aminopyridine were
dissolved in 10 ml of concentrated sulphuric acid and the resulting
solution was cooled to 08C using an ice-bath. To this solution was
added dropwise a cooled (58C) mixture of 30% aq hydrogen peroxide
(15 ml) in 30 ml of concentrated sulphuric acid while the temperature
was maintained below 158C. The solution was stirred at room
temperature overnight and then carefully basified with 3m aq KOH.
The resulting mixture was then filtered and extracted with EtOAc. The
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988
M. KARRAMKAM ET AL.
organic layers were combined, washed with water and brine, dried over
Na2SO4 and concentrated to dryness. The residue was chromato-
graphed on silica gel (heptane/EtOAc : 70/30 to 50/50) to give the
desired nitropyridine in moderate yields.
2-Nitropyridine. The procedure described above was used with 2-
aminopyridine and afforded, after chromatography, 2-nitropyridine as a
yellow solid (55%). 1H NMR (CD2Cl2, 298.0 K) : d : 8.66 (bdd, Japp
ꢂ
1.1 & 4.6 Hz, 1 H, H-6); 8.26 (d, J : 8.2 Hz, 1 H, H-3); 8.13 (td, J :
1.8 & 7.7 Hz, 1 H, H-4); 7.76 (ddd, J : 0.9 & 4.6 & 7.5 Hz, 1 H, H-5);
13C NMR (CD2Cl2, 298.0 K): d : 157.1 [C]; 149.2 [CH]; 140.3 [CH];
129.6 [CH]; 118.2 [CH]; MS (C5H4N2O2): 142 [M + NH+4 ];
125 [M + H+].
3-Nitropyridine. The procedure described above was used with 3-
aminopyridine and afforded, after chromatography, 3-nitropyridine as a
yellow solid (62%). 1H NMR (CD2Cl2, 298.0 K) : d : 9.41 (s, 1 H, H-2);
8.91 (bd, J : 4.5 Hz, 1 H, H-6); 8.47 (bd, J : 8.4 Hz, 1 H, H-4); 7.54 (dd,
J : 4.8 & 8.4 Hz, 1 H, H-5); 13C NMR (CD2Cl2, 298.0 K) : d : 155.3 [CH];
145.3 [CH]; 144.7 [C]; 131.3 [CH]; 124.2 [CH]; MS (C5H4N2O2) : 125
[M + H+].
4-Nitropyridine. The procedure described above was used with 4-
aminopyridine and afforded, after chromatography, 4-nitropyridine as a
yellow solid (51%). 1H NMR (CD2Cl2, 298.0 K): d : 8.94 (d, J : 4.8 Hz,
2 H, H-2,6); 8.01 (d, J : 4.8 Hz, 2 H, H-3,5); 13C NMR (CD2Cl2,
298.0 K) : d : 153.9 [2 ꢃ CH]; 152.5 [C]; 116.4 [2 ꢃ CH]; MS
(C5H4N2O2): 125 [M + H+].
General procedure for methylation of dimethylpyridines. To a solution of
0.5 g of the adequate dimethylaminopyridine (4.09 mmol, MW : 122.28)
in 10 ml of toluene was added 0.520 ml of methyl trifluoromethane-
sulfonate (4.50 mmol, MW : 167.11, d : 1.450, 1.1 eq). The solution was
stirred at room temperature or higher, but also 0, ꢁ20 or ꢁ788C for
60 min under an argon atmosphere. The precipitate was then filtered off,
washed with small portions of cold ether and dried under vacuum for
10 h.
(2-Pyridyl)-trimethylammonium trifluoromethanesulfonate. The pro-
cedure described above was used with 2-dimethylaminopyridine
(temperature : ambient) and afforded (2-pyridyl)-trimethylammonium
trifluoromethanesulfonate as
a
white solid (35%). 1H NMR
(CD2Cl2, 298.0 K) : d : 8.60 (d, J : 4.2 Hz, 1 H, H-6); 8.11 (t, J :
7.5 Hz, 1 H, H-4); 8.00 (d, J : 8.1 Hz, 1 H, H-3); 7.60 (t, J : 5.4 Hz, 1 H,
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2-,3- AND 4-[18F] FLUOROPYRIDINE
989
H-5); 3.68 (s, 9 H, CH3); 1 H NMR (DMSO-d6, 298.0 K) : d : 8.68 (bd,
J : 4.0 Hz, 1 H, H-6); 8.23 (td, J : 1.0 & 6.0 Hz, 1 H, H-4); 8.10
(d, J : 9.0 Hz, 1 H, H-3); 7.72 (dd, J : 6.0 & 9.0 Hz, 1 H, H-5); 3.60 (s,
9 H, CH3); 13C NMR (CD2Cl2, 298.0 K) : d : 156.8 [C]; 149.5 [CH];
141.7 [CH]; 126.9 [CH]; 121.2 [q, J : 319 Hz, CF3]; 114.9 [CH]; 55.7
[CH3].
2-Dimethylamino-l-methylpyridinium trifluoromethanesulfonate. The
procedure described above was used with 2-dimethylaminopyridine
(temperature used : 808C) and afforded 2-dimethylamino-1-methylam-
monium trifluoromethanesulfonate (contaminated with (2-pyridyl)-
trimethylammonium trifluoromethanesulfonate) as a white solid
1
(30%). H NMR (DMSO-d6, 298.0 K) : d : 8.40 (d, J :9.0 Hz, 1 H, H-
6); 8.16 (t, J : 9.0 Hz, 1 H, H-4); 7.53 (d, J : 9.0 Hz, 1 H, H-3); 7.31 (t, J :
9.0 Hz, 1 H, H-5); 4.02 (s, 3 H, CH3); 3.09 (s, 6 H, 2 ꢃ CH3).
3-Dimethylamino-l-methylpyridinium trifluoromethanesulfonate. The
procedure described above was used with 3-dimethylaminopyridine
(temperature used : room temperature, 0, ꢁ20 or ꢁ788C) and afforded
3-dimethylamino-l-methylpyridinium trifluoromethanesulfonate as a
1
white solid (40%). H NMR (CD2Cl2, 298.0 K) : d : 8.08 (s, 1 H, H-
2); 7.83 (d, J : 6.0 Hz, 1 H, H-6); 7.64 (td, J : 6.0 & 9.0 Hz, 1 H, H-5);
7.49 (dd, J : 2.0 & 9.0 Hz, 1 H, H-4); 4.34 (s, 3 H, CH3); 3.11 (s, 6 H,
2 ꢃ CH3).
4-Dimethylamino-l-methylpyridinium trifluoromethanesulfonate. The
procedure described above was used with 4-dimethylaminopyridine
(temperature used : room temperature, 0, ꢁ20 or ꢁ788C) and afforded
4-dimethylamino-l-methylpyridinium trifluoromethanesulfonate as a
1
white solid (37%). H NMR (CD2Cl2, 298.0 K) : d : 7.99 (d, J :
7.2 Hz, 2 H, H-2,6); 6.84 (d, J : 7.2 Hz, 2 H, H-3,4); 3.95 (s, 3 H, CH3);
3.21 (s, 6 H, 2 ꢃ CH3).
Radiochemistry
Radioisotope production. No-carrier-added aqueous [18F]fluoride ion
was produced on a CGR-MeV 520 cyclotron by irradiation of a 2 ml
water target using a 17 MeV proton beam on 95% enriched [18O]water
by the [18O(p,n)18F] nuclear reaction and was transferred to the
appropriate hot cell. Typical production : 550–650 mCi (20.3-24.0 GBq)
of [18F]Fꢁ at the end of bombardment for a 20 mA, 30 min (36,000 mC)
irradiation. A complete description of the target hardware and
operation can be found in references.8,15
Copyright # 2003 John Wiley & Sons, Ltd.
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990
M. KARRAMKAM ET AL.
Preparation of the K[18F]F-K222-complex. In order to recover and
recycle the [18O]water target, the 2 ml of aqueous [18F]fluoride from the
target were passed through an anion exchange resin (Sep-Pak1 Light
Waters AccellTM Plus QMA Cartridge, ionic form : chloride, washed
with 5 ml IM aq. NaHCO3 and then rinsed with 50 ml of water) by He
pressure (1.5–2.0 bar). Helium is blown through the column to extract
the last traces of [18O]water. The [18F]fluoride ion was then eluted from
the resin using 1.0 ml of a 4.5 mg/ml aqueous K2CO3 solution into a
Vacutainer1 tube. In order to distribute equally this activity over n
tubes (Vacutainer1 tube, n = 2–12), the quantity of K2CO3 was firstly
adjusted to n times 4.5 mg with a 50.0 mg/ml aqueous K2CO3 solution
and secondly, the total volume of the solution was adjusted to 2.0 ml
with water. This new aqueous [18F]fluoride solution was then equally
distributed over the n tubes each containing 12.0–15.0 mg of Krypto-
fix1222 (K222: 4,7,13,16,21,24-hexaoxa-l,10-diazabicyclo[8.8.8]hexaco-
sane). Finally, the volume of each fraction was adjusted to 1.0 ml with
water. The resulting solutions were then independently gently concen-
trated to dryness at 145–1508C under a nitrogen stream for 10 min to
give no-carrier-added K[18F]F-K222 complex as a white semi-solid
residue.
Preparation of [18F]fluoropyridines. General procedure using conven-
tional heating in a sealed reactor : The K[18F]F-K222 complex
(Vacutainer1 tube, on average 30 – 60 mCi (1.11 – 2.22 GBq, EOB,
representing 6–12 nmol)) was dissolved in 200 ml of a freshly distilled
solvent and transferred to a 5 ml pyrex1 reaction vial containing N mmol
of the precursor for labelling. The evaporation tube was rinsed twice
with 200 ml of solvent which was then added to the reaction mixture.
Resolubilization efficiencies were about 60–90% of the original
[18F]fluoride ion. The reaction vial was then tightly closed with a Teflon
cap and heated in a heating block at a temperature T and during a time t
without stirring the contents. The reaction vessel was then cooled using
an ice/water bath and the remaining radioactivity was measured. Eighty
five}Ninety five percent of the initial radioactivity placed in the vessel
was still present. The reaction mixture was then analyzed by radio-
chromatography. The reaction yield was calculated from the
TLC-radiochromatogram and defined as the radioactivity area of
[18F]fluoropyridines over total fluorine-18 radioactivity area ratio.
General procedure using conventional heating or microwave activation
in a non-sealed reactor : 600 ml of freshly distilled solvent containing
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 979–992

2-,3- AND 4-[18F] FLUOROPYRIDINE
991
N mmol of the precursor for labelling were directly added into-the
Vacutainer1 tube containing the dried K[18F]F-K222 complex (on
average 30 to 60 mCi (1.11 – 2.22 GBq, EOB, representing 6–12 nmol)).
The tube (not sealed) was then placed in a heating block at a
temperature T and during a time t or in a dedicated microwave oven
and irradiated (power W during a time t) without stirring the contents.
The remainder of the preparation used the same procedure as described
above.
Acknowledgements
The authors wish to thank the cyclotron operators Mr Daniel Gouel,
#
Mr Christophe Peronne and Mr Christophe Lechene for performing the
irradiations, as well as the Laboratoire d’Analyse, de Synthese et de
!
Speciation Organometallique (Ms Badia Amekraz) for recording the
!
MS spectra.
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