Synthesis of [18F]-labeled EF3 [2-(2-nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)-acetamide], a marker for PET detection of hypoxia

Article abstract of DOI:10.1016/S0968-0896(00)00279-0

[¹⁸F]-2-(2-Nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)-acetamide ([¹⁸F]-EF3) has been prepared, in 65% chemical yield and 5% radiochemical yield, by coupling 2,3,5,6-tetrafluorophenyl 2-(2-nitroimidazol-1-yl) acetate 1 with [¹⁸F]-3,3,3-trifluoropropylamine 7. This original radiolabelled key-synthon was obtained in 40% overall chemical yield by oxidative [¹⁸F]-fluorodesulfurization of ethyl N-phthalimido-3-aminopropane dithioate 4, followed by deprotection with hydrazine of the resulting [¹⁸F]-N-phthalimido-3,3,3-trifluoropropylamine 5. All the process was performed within 90min, from the [¹⁸F]-HF production in the cyclotron to the purification of the final target. Copyright

Full text of DOI:10.1016/S0968-0896(00)00279-0

Bioorganic & Medicinal Chemistry 9 (2001) 665±675
Synthesis of [18F]-Labeled EF3 [2-(2-Nitroimidazol-1-yl)-N-
(3,3,3-tri¯uoropropyl)-acetamide], a Marker for PET
Detection of Hypoxia
Olivier Josse,a,b Daniel Labar,b Benoit Georges,a,b Vincent Gregoirec
and Jacqueline Marchand-Brynaerta,*
a
Â
Unite de Chimie Organique et Medicinale, Universite catholique de Louvain, Batiment Lavoisier,
Â
Â
Ã
place L. Pasteur 1, B- 1348 Louvain-la-Neuve, Belgium
Universite catholique de Louvain, Laboratoire de Tomographie par Positron, chemin du Cyclotron 2, B- 1348 Louvain-la-Neuve, Belgium
b
Â
c
Â
Universite catholique de Louvain, Laboratoire de Radiobiologie, Hopital Universitaire Saint-Luc,
Ã
avenue Hippocrate 10, B- 1200 Bruxelles, Belgium
Received 25 August 2000; revised 19 October 2000; accepted 23 October 2000
AbstractÐ[18F]-2-(2-Nitroimidazol-1-yl)-N-(3,3,3-tri¯uoropropyl)-acetamide ([18F]-EF3) has been prepared, in 65% chemical yield and
5% radiochemical yield, by coupling 2,3,5,6-tetra¯uorophenyl 2-(2-nitroimidazol-1-yl) acetate 1 with [18F]-3,3,3-tri¯uoro-
propylamine 7. This original radiolabelled key-synthon was obtained in 40% overall chemical yield by oxidative [18F]-¯uor-
odesulfurization of ethyl N-phthalimido-3-aminopropane dithioate 4, followed by deprotection with hydrazine of the resulting
[18F]-N-phthalimido-3,3,3-tri¯uoropropylamine 5. All the process was performed within 90 min, from the [18F]-HF production in
the cyclotron to the puri®cation of the ®nal target. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
provides an unrivalled way of labelling hypoxic cells in
vivo.14 In this case, the marked cells can be detected by
immuno¯uorescence on tissue sections or by ¯ow cyto-
metry, using for both techniques speci®c antibodies.
A low oxygen concentration in solid tumor cells inevi-
tably increases the resistance to radiotherapy.1 There-
fore, the development of clinically useful methods for
measuring tissue hypoxia has been a focus of intensive
research,2 in view to provide prognostic information,
and indication to select for alternative therapies. Recent
progress in microelectrode techniques permitted to mea-
sure the oxygen partial pressure in tumors;3,4 however,
this method is invasive and has important limitations
considering its sensitivity and speci®city. An alternative
method is based on the use of hypoxia markers (chemi-
cal radiosensitizers)5,6 and detection by medical imaging
techniques, as recently reviewed.7À9 2-Nitroimidazole
derivatives constitute an important class of such markers,
exempli®ed with misonidazole, etanidazole, and erythro-
nitroimidazole (Scheme 1); their particular reductive
metabolism in hypoxic cells (with cytochrome P450
reductase) leads to the formation of intermediates which
can covalently bind to cellular macromolecules.10À13
Consequently, the bioreduction of 2-nitroimidazoles
Tagged with an appropriate radioactive isotope, the cell-
bound metabolites of 2-nitroimidazoles could also be
detected by nuclear medicine techniques. Thus, [18F]-
labelled 2-nitroimidazoles have been proposed to visualize
hypoxic cells by positron emission tomography (PET), a
non-invasive, highly sensitive, and short-time consum-
ing, medical imaging technique.15 Accordingly, [18F]-
¯uoromisonidazole,16À19 [18F]-¯uoroetanidazole,20 and
[18F]-¯uoroerythronitromidazole21,22 (Scheme 1) were
prepared, and used for the localisation and quanti®ca-
tion of hypoxia. However, these PET tracers, obtained
by replacing a methoxyl or hydroxyl group of the parent
radiosensitizers with [18F]-¯uorine, present di€erent
(bio)chemical properties regarding the corresponding
unlabelled compounds.
Some years ago, tri- and penta¯uorinated nitroimidazole
derivatives,23 called EF3 and EF5 respectively (Scheme
1), were synthesized. Comparatively to misonidazole,
the prototype of hypoxia-binding markers, these two
*Corresponding author. Tel.:+32-010-47-27-40; fax :+32-010-47-41-
68; e-mail: marchand@chor.ucl.ac.be
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(00)00279-0

666
O. Josse et al. / Bioorg. Med. Chem. 9 (2001) 665±675
Scheme 1.
compounds o€er several advantages:24,25 they have a
more speci®c binding to hypoxic cells,26 their binding
does not too much depend on the intracellular level of
reductase systems,27 their binding is oxygen-dependent,
and they present a reduced toxicity comparatively to
other chemical probes. Moreover, speci®c antibodies are
available against EF3-EF5 only, allowing the co-existing
control of hypoxia by biopsic measurements and imaging
techniques. In view of the high sensitiviy and speci®city
of these markers, the [18F]-¯uorine labelling of EF3 and
EF5 was examined to produce new PET tracers. Inter-
estingly, in this case, the unlabelled and labelled com-
pounds would have exactly the same properties.
synthetic equivalents could not be applied.31 The usual
reagent for [18F]-labelling of radiopharmaceuticals is
[18F]-potassium ¯uoride added with [2,2,2] kripto®x.32,33
This reagent has been used to prepare ethyl [18F]-tri-
¯uoroacetate from ethyl 2-bromo-2,2-di¯uoroacetate,34
and [18F]-2-tri¯uoromethyl-4,4-dimethyl-2-oxazoline from
2-bromo-2,2-di¯uoromethyl-4,4-dimethyl-2-oxazoline. 35
This nucleophilic substitution on CF2Br- precursors
with [18F]-FÀ requires hard conditions, and is limited to
speci®c compounds in which the competition with an
elimination reaction cannot occur. To our knowledge,
the two previous examples are the only ones described
in the literature concerning the [18F]-labelling of a tri-
¯uoromethyl group.
The [18F]-labelling of a per¯uoroalkyl moiety is a dicult
task because the classical nucleophilic displacement of a
leaving group by [18F]-¯uoride anion (as illustrated with
the synthesis of [18F]-EF128) cannot be readily applied.
Recently, the group of Koch succeeded in labelling EF5
by electrophilic addition of [18F]-F2 to 2-(2-nitroimida-
zol-1-yl)-N-(2,3,3-tri¯uoroallyl)-acetamide.29 In a parallel
course, we developed the oxidative ¯uorodesulfurization
method for the preparation of [18F]-EF3.30 The details
of this original way to produce [18F]-labelled tri¯uoro-
methylated compounds, in functionalized aliphatic series,
are described in this article. Our work led to the pre-
paration of an interesting labelled key-intermediate,
namely [18F]-3,3,3-tri¯uoropropylamine.
The direct transformation of a carboxylic acid into CF3
normally requires sulfur tetra¯uoride as the ¯uorinating
agent,36,37 a very strong and toxic reagent which would
not be easily labelled with [18F]-¯uorine. Recently, an
alternative solution has been brought to produce CF3
groups from carboxyl precursors, making use of sul-
phurated derivatives (orthothioesters38 and dithioesters)
treated with an HF-reagent in the presence of an oxi-
dant (halonium ions) (Scheme 2). This mild reaction,
called `oxidative desulfurization-¯uorination', has been
well developed by the group of Hiyama.39À46 However
the method appears to be limited to tri¯uoromethyl-
aromatic38,39 and conjugated44 derivatives, and to tri-
¯uoromethyl ethers40,45 (O-CF3) and amines41À43,46 (N-
CF3); no examples were disclosed in the aliphatic series,
with functionalized precursors, such as N-protected ami-
noacid derivatives. Nevertheless, we speculated that this
method would be well adapted for our purpose, because
high selectivity could result from the speci®c interaction
Strategy
As far as [18F]-labelling is concerned, tÀhe classical methods
+
ꢀ
of tri¯uoromethylation based on `CF3 ', `CF3 ', or `CF3 '

O. Josse et al. / Bioorg. Med. Chem. 9 (2001) 665±675
667
Scheme 2.
between the sulphurated precursor (soft nucleophile)
and the oxidant (soft electrophile), giving an intermediate
activated towards the substitution with ¯uoride. More-
over, the source of soft ¯uoride is an HF-reagent, such
as tetrabutylammonium dihydrogen tri¯uoride (TBA+
H2FÀ3 ),47 or pyridinium poly(hydrogen ¯uoride)48 (30%
pyridine±70% HF); such reagents are dramatically less
basic than potassium ¯uoride added with kripto®x, and
would thus limit the occurrence of side-reactions.
solution of TBA+H2F3À in dry dichloromethane. This
process, performed within 15 min, gave a solution of
TBA+H2F3À with 82% (decay corrected) of [18F] incor-
poration at the laboratory scale.50
The [18F]-poly(hydrogen ¯uoride) pyridinium was pre-
pared by eluting the [18F]-¯uoride trapped on the resin
with an aqueous solution of potassium carbonate. The
resulting solution of [18F]-KF was concentrated to dryness,
then treated with unlabeled48 (HF)nꢀ pyridinium. This
process, performed within 15 min, gave pure [18F]-
(HF)nꢀ pyridinium (Scheme 3) with 93% (decay cor-
rected) of [18F] incorporation at the laboratory scale.51
Several requirements have to be ful®lled for developing
the synthesis of [18F]-EF3 by oxidative ¯uorodesulfuriza-
tion: (i) the production of the appropriate [18F]-labeled
HF-reagents; (ii) the preparation of the required
dithioester precursors; (iii) the development of ¯uorina-
tion conditions in aliphatic series avoiding competitive
side-reactions, such as eliminations; (iv) the application
of the method to the production of [18F]-EF3 in the last
synthetic step, or via an advanced [18F]-labeled key-
intermediate; (v) the consideration of the half-life of
[18F]-¯uorine (110 min) to design short-time syntheses (a
maximum of 5 h, from the production of [18F]-HF in the
cyclotron to the puri®ed ®nal target is acceptable); (vi)
the production of [18F]-EF3 with good radiochemical
yields and appropriate activity for PET detection.
The capacity of these [18F]-reagents to label CF2 and CF3
groups in aromatic series has been previously estab-
lished.50,51
CF3-Labeling of an aliphatic model compound
Methyl undecanedithioate (Scheme 4) was obtained by
addition of carbon disul®de to 1-decylmagnesium bro-
mide, followed by reaction with iodomethane.
Treatment of methyl undecanedithioate with tetra-
butylammonium dihydrogen tri¯uoride in the presence of
1,3-dibromo-5,5-dimethylhydantoin (DBH) as the oxi-
dant (CH2Cl2, low temperature to room temperature;
excess of ¯uorinating agent) led to 1,1-di¯uoro-1-thio-
methylundecane resulting from uncomplete ¯uorination.
Similar results have been reported by Hiyama in the
case of aliphatic orthothioester precursors.52À54
Results
Production of the [18F]-labeled HF-reagents
[18F]-HF was produced at the cyclotron by irradiating
[18O]-enriched water with 16.5 MeV protons.49 The [18F]-
¯uoride was separated from the [18O]-enriched water by
trapping on an ion exchange resin. Organic solvents
(CH3CN and CH2Cl2) were passed through the resin to
remove all traces of water. Then [18F]-TBA+H2F3À was
obtained by ¯uorine exchange with unlabelled47
TBA+H2FÀ3 (Scheme 3): the resine was eluted with a
On the other hand, by using poly(hydrogen ¯uoride) pyr-
idinium as the ¯uorinating agent, complete substitution
occurred, and 1,1,1-tri¯uoroundecane was the major
product (Scheme 4); about 80% yield of tri¯uoro-
methylated compound could be isolated (column chro-
matography) when the dithioester precursor was treated
Scheme 3.

668
O. Josse et al. / Bioorg. Med. Chem. 9 (2001) 665±675
Scheme 4.
with 15 equiv of (HF)nꢀ pyridinium and 3.5 equiv of
DBH in CH2Cl2 at À78 ꢁC. Under such conditions,
electrophilic bromination of the aliphatic chain,52,53 and
elimination reactions54 were not observed.
activated dithioester moiety, followed by deprotonation
and degradation of the resulting cyclic-1,3-iminoether
(Scheme 5) under the oxidative ¯uorodesulfurization
conditions.
The process applied to [18F]-(HF)nꢀ pyridinium gave
[18F]-1,1,1-tri¯uoroundecane with a radiochemical yield
of 4.3% at the laboratory scale. Therefore, this method
of [18F]-per¯uorination was applied to the precursor 3
of EF3.
The related N-methyl precursor 3b has been similarly
prepared (Scheme 5) from the activated ester 1 and ethyl
3-(methylamino) propanedithioate 2b. Compound 2b
was obtained in six steps from 3-(methylamino) propio-
nitrile, according to the procedure we established for b-
alanine dithioester:56 the method is based on the
nucleophilic substitution of a thioacyl-N-phthalimide
intermediate with ethanethiol (Scheme 6).
Synthesis of [18F]-EF3: direct route
According to our previously established strategy, the
direct precursor of [18F]-EF3 is the dithioester 3a (R=
H) (Scheme 5). This compound could be obtained by
coupling the tetra¯uorophenyl ester55 1 of 2-(2-nitro-
imidazol-1-yl) acetic acid20 with ethyl 3-aminopropane-
dithioate 2a56 in acetonitrile at room temperature. After
chromatography on silica gel, the compound 3a was
isolated in 85% yield and well characterized as usual
(see Experimental).
The transformation of the N-methyl precursor 3b into
N-methyl EF3 also failed, whatever the experimental
conditions of ¯uorination could be. In both cases (pre-
cursors 3a and 3b), traces of [18F]-nitroimidazole deri-
vatives could not be detected in the crude mixtures by
radio-TLC (thin layer chromatography), when using
[18F]-labeled ¯uorinating agents in the synthetic process.
Consequently, another strategy was developed, based on
the production of [18F]-3,3,3-tri¯uoropropylamine as the
key-intermediate.
Treatment of the dithioester 3a with an excess of (HF)nꢀ
pyridinium in the presence of DBH, or N-iodosuccini-
mide (NIS) as the oxidant, gave untractable mixtures; the
same disappointing results were obtained with TBA+
H2FÀ3 and DBH or NIS. This could result from intra-
molecular nucleophilic attack of the amide function on the
Synthesis of [18F]-EF3: indirect route
The reaction of ethyl 3-aminopropane dithioate 2a (tri-
¯uoroacetate salt)56 with (HF)nꢀ pyridinium and DBH
Scheme 5.

O. Josse et al. / Bioorg. Med. Chem. 9 (2001) 665±675
669
Scheme 6.
gave less than 5% yield of isolated 3,3,3-tri¯uoropro-
pylamine (hydro¯uoride salt). The Boc-protected pre-
cursor,56 similarly treated, led to untractable mixtures.
Therefore, we selected the phthalimido group as the
protecting group susceptible to survive under the oxi-
dative ¯uorodesulfurization conditions.
the presence of DBH (4 equiv), in dichloromethane at
room temperature (Scheme 8). In the radiolabeling
process, we ®rst used 6 equiv of [18F]-(HF)nꢀpyridinium
(10 min) to produce the [18F]-labeled di¯uoro-inter-
mediate 6; then addition of 48equiv of unlabeled (HF)nꢀ
pyridinium (10 min) transformed [18F]-6 into [18F]-5. The
total reaction time, from 4 to N-phthalimido-[18F]-3,3,3-
tri¯uoropropylamine 5, was 30 min, including the pur-
i®cation by column chromatography on neutral alumina
with CH2Cl2 and the concentration of the solution. The
radiochemical yield, determined by radio-TLC was 5.6%
(decay corrected) at the laboratory scale.
The primary amine of 2a was readily transformed into
the corresponding phthalimide 4 by reaction with 2-
(methoxycarbonyl) benzoic acid activated by PyBOP,
followed by acid-catalyzed cyclization of the resulting
phthalamic ester57 (Scheme 7).
Pure N-phthalimido-3,3,3-tri¯uoropropylamine 5 could
be obtained in about 50% chemical yield by reacting 4
with a large excess of (HF)nꢀpyridinium (ꢂ50 equiv) in
The next step was the deprotection of the phthalimido
group of [18F]-5 to furnish [18F]-3,3,3-tri¯uoropropyl-
amine 7 (Scheme 9). Treatment of [18F]-5 with aqueous
Scheme 7.
Scheme 8.

670
O. Josse et al. / Bioorg. Med. Chem. 9 (2001) 665±675
Scheme 9.
Scheme 10.
hydrazine at 75 ꢁC led to the rapid formation of the free
amine [18F]-7 which was removed from water by distilla-
tion under an argon stream, and condensed into an ice-
cooled acetonitrile solution of 2,3,5,6-tetra¯uorophenyl
2-(2-nitroimidazol-1-yl) acetate 1 (Scheme 9) to give
[18F]-EF3 ([18F]-2-(2-nitroimidazol-1-yl)- N-(3,3,3-tri-
¯uoropropyl) acetamide) in about 70% chemical yield.
The duration of the process, from [18F]-5 to [18F]-EF3, was
40 min; 65% (decay corrected) of the initial radioactivity of
5 was recovered in the ®nal target, as determined by radio-
TLC. [18F]-EF3 prepared at the 10À2 mmol scale was iden-
ti®ed by comparison with an unlabeled authentic sample.
Conclusion
The successful synthesis of [18F]-EF3 relies upon the
rapid coupling reaction of the activated ester 1 of 2-(2-
nitroimidazol-1-yl)acetic acid with [18F]-3,3,3-tri¯uoro-
propylamine 7. This novel key-synthon would be useful
in other radiosyntheses.
The preparation of [18F]-3,3,3-tri¯uoropropylamine 7
was realized in three steps from ethyl N-phthalimido-3-
aminopropane dithioate 4, by oxidative [18F]-¯uoro-
desulfurization and hydrazinolysis of the resulting [18F]-
N - phthalimido -3,3,3- tri¯uoropropylamine 5, with an
overall chemical yield of about 40%, and within 60min
since the production of [18F]-HF in the cyclotron (Table 1).
At the laboratory scale (0.01 À 0.02mmol; [ 18F]-starting
activity <30 mCi), the radiochemical yield was of about
5% (Table 2, entries 1 and 2), giving a speci®c activity of
the free amine [18F]-7 of 58 mCi/mmol. In one experi-
ment (entry 3) using 880 mCi of [18F]-HF as labeling
source, we recovered 65 mCi of [18F]-5 (=76 mCi, decay
corrected), corresponding to a radiochemical yield of
8.6%, and a speci®c activity of 74 mCi/mmol. Compara-
tively to the synthesis of [18F]-EF5 actually made by
electrophilic per¯uorination,29 which gave a radiochemical
yield of about 10%, our results, based on nucleophilic
per¯uorination, appear quite similar.
Synthesis of unlabeled EF3
`Cold' EF3 was prepared, similarly to [18F]-EF3, by
condensing the `cold' amine 7 with the activated ester 1
(Scheme 9).
The preparation methods of 7 described in the literature
could not be easily applied, i.e. (i) the reaction of b-ala-
nine with SeF4 carried out in hydrogen ¯uoride;58 (ii)
the Curtius rearrangement of 4,4,4-tri¯uorobutyryl
azide obtained in situ from 4,4,4-tri¯uorobutyric acid.59
In our hands, this method gave only a few percent yields
of the hydrochloride salt of 7. Thus, we developed an
alternative two-step route, starting from 1-bromo-3,3,3-
tri¯uoropropane (Scheme 10, method iii): substitution
with potassium phthalimide in DMSO gave 5 which
phthalimido group was deprotected by reduction with
sodium borohydride in aqueous isopropanol.60 The
amine 7, recovered in 45% overall yield (as hydrochlo-
ride salt) reacted with 1 to quantitatively furnish EF3.
Extrapolation to the use of 1 Ci of [18F]-HF, as it should
be handled in an automatized system, would produce
about 15 mCi of puri®ed EF3 (injectable dose for one
patient); this value is more than enough for practical
application in detection and quanti®cation of hypoxia.

O. Josse et al. / Bioorg. Med. Chem. 9 (2001) 665±675
671
Table 1.
18F] Compound
[18F]-Poly(hydrogen ¯uoride)pyridinium. 96 mCi of [18F]-
HF in [18O]-water were deposited on the ion exchange
resin (BIO-RAD AG-1X8). After removal of [18O]-
water, the [18F]-¯uoride was eluted with an aqueous solu-
tion of K2CO3 (2.3 mg in 400mL). The solution was then
heated under argon ¯ow to remove water and give 81 mCi
of anhydrous [18F]-KF. Then, 9.2 mL of (HF)nꢀpyridinium
(corresponding to 0.32mmol of hydrogen ¯uoride) were
added so that all the radioactivity could be incorporated
in the per¯uorinating agent (93% decay corrected,
15 min).
[
Activity (d.c.)a
28 mCi
1.24 mCi (1.5 mCi) 0.021
0.982mCi (1.2mCi) 0.017
0.639 mCi (0.78 mCi) 0.011
mmol Chemical Process
yield(%) duration
(HF)nꢀpyridinium
Ft-amine 5
Free amine 7
EF3
20 min
50
80
65
30 min
10 min
30 min
ad.c.=Decay corrected.
Table 2.
Methyl undecanedithioate.61 To a solution of 1-decyl-
magnesium bromide, prepared from 1-bromodecane
(0.938 mL, 4.52mmol) and magnesium (0.115 g, 4.75
mmol) in THF (8 mL), was added, with ice cooling and
stirring, carbon disul®de (0.408 mL, 6.78 mmol). The
mixture was left overnight at room temperature. The
excess of magnesium was ®ltered o€ and the volatiles
were removed under vacuumn. The residue was dissolved
in dichloromethane (30 mL) and the dithiocarboxylate
was extracted with water (3Â15 mL). Iodomethane
(0.282 mL, 4.52 mmol) was added to the aqueous phase.
After 24 h of stirring, the solution was extracted with di-
chloromethane (3Â20 mL), dried (MgSO4) and ®ltered
on silica gel (hexane; Rf 0.06) to a€ord the dithioester as
Entry
[
18F]-(HF)n
Pyr. activity
[
18F]-5 activity
(d.c.)
Radiochemical
yielda
1
2
3
28 mCi
28 mCi
880 mCi
1.30 mCi (1.58)
1.00 mCi (1.22)
65 mCi (76)
5.6%
4.4%
8.6%
aActivity of isolated 5/activity of [18F] ¯uoride introduced.
All the process for [18F]-EF3 production (four steps)
could be easily performed within 90 min, from [18F] FÀ
production to ®nal puri®cation, giving the target mole-
cule in 26% overall chemical yield and about 5%
radiochemical yield.
1
a yellow liquid. Yield: 0.419 g (40%). H NMR (300
MHz, CDCl3) d=0.88 (t, 3H, J=6.6 Hz, CH3±(CH2)9±),
1.26 (m, 14H, CH3±(CH2)7), 1.83 (m, 2H, C8H17±CH2±
CH2±CS2±), 2.62 (s, 3H, ±CS2±CH3), 3.04 (t, 2H, J=
7.5 Hz, C8H17±CH2CH2±CS2±); IR (NaCl, ®lm: n=
2953, 2923, 2853, 1464, 1458, 1437, 1418, 1198, 956,
937, 906, 891 cmÀ1; MS (CI, CH4±N2O): m/z (%)=
233.1 ([M+H)+, 100), 217.1 (19.2), 185.0 (22.4), 141.1
(7.3), 112.9 (4.9).
Experimental
Solvents were dried before use. Reagents (from Acros,
Fluka or Aldrich) were used as purchased. Melting points
(uncorrected) were determined on an Electrothermal
apparatus. 1H (200 or 300 MHz) and 13C (50MHz) NMR
spectra were recorded on Varian Gemini 200 and 300
spectrometers; H (500 MHz) and 13C (125 MHz) spec-
1
tra were recorded on Bruker AM-500 and 19F
(282 MHz) on Varian Gemini 300 spectrometer. Che-
mical shifts are reported as d values (ppm) down®eld
from TMS. The mass spectra (FAB or CI modes) were
obtained on a Finnigan MAT TSQ-70 instrument. IR
spectra were obtained using a Biorad FTS 135 spectro-
meter calibrated with polystyrene. TLC were carried out
using silicagel 60 F254 (0.2mm, Merck) and spots were
visualised by UV. Silica gel 60, mesh size 0.04±0.063 mm
(Merck), was used for column chromatography. [18F]-
Fluoride was produced by the 18O(p,n)18F nuclear reac-
tion on an enriched [18O]-water target (2.0 mL) using the
IBA `Cyclone 30' cyclotron. Radio-TLC were mon-
itored with a Berthold TLC-Linear Analyser.
[18F]-1,1,1-tri¯uoroundecane. 1,3-Dibromo-5,5-dimethyl-
hydantoin (DBH) (73.9 mg, 0.25 mmol) was suspended
in dichloromethane (0.2mL) in a polyethylene ¯ask and
cooled to À70 ꢁC. [18F]-HFnꢀpyridinium (27.8 mL,
0.97 mmol of ¯uoride) was added to this suspension.
Then, a solution of methyl undecanedithioate (15 mg,
0.065 mmol) in dichloromethane (0.2mL) was slowly
introduced; the reaction mixture was allowed to warm
to 20 ꢁC and was stirred for 1 h. The crude mixture was
®ltered on neutral alumina and, after concentration, the
residue was puri®ed by ¯ash chromatography on silica
gel (hexane, Rf=0.8) to give labeled tri¯uoroundecane
(4.3% radiochemical yield) as a colourless liquid. 1H
NMR (300 MHz, CDCl3) d=0.88 (t, 3H, J=6.3 Hz,
CH3±(CH2)9±), 1.27 (m, 14H, CH3±(CH2)7±), 1.52(m,
2H, C8H17±CH2±CH2±CF3), 2.05 (m, 2H, C8H17±CH2±
CH2±CF3); 19F NMR (282 MHz, CDCl3/CFCl3) d=
À66.9 (t, J=10.6 Hz); MS (CI, CH4-N2O): m/z (%)=
210 ([M]ꢀ+, 10), 209 (36).
[18F]-Tetrabutylammonium
dihydrogen
tri¯uoride.
22.4 mCi of [18F]-HF in [18O]-water were deposited on
the ion exchange resin (BIO-RAD AG-1X8). After
removal of [18O]-water, the resin was rinsed with aceto-
nitrile (200 mL) followed by dichloromethane (200 mL).
Then, [18F]-¯uoride was eluted two times with a solution
of 25 mL TBAH2F3 (wt 82% in 1,2-dichloroethane) in
200 mL dichloromethane and a third time with solution
of 31 mL TBAH2F3 (wt 82% in 1,2-dichloroethane) in
200 mL dichloromethane. This process allowed the
recovery of 16 mCi of [18]-¯uoride in the form of [18F]-
TBAH2F3 (0.22 mmol) (82% decay corrected, 15 min).
2,3,5,6-Tetra¯uorophenyl tri¯uoroacetate.55 A solution
of 2,3,5,6-tetra¯uorophenol (3.045g, 18.33 mmol), tri-
¯uoroacetic anhydride (3.400mL, 24.07 mmol) and boron
tri¯uoride etherate (280mL, 2.21mmol) was re¯uxed for
24h. The volatiles were removed under vacuumn. Tri-
¯uoroacetic anhydride (3.40 mL, 24.07 mmol) and boron
tri¯uoride etherate (280 mL, 2.21 mmol) were added and

672
O. Josse et al. / Bioorg. Med. Chem. 9 (2001) 665±675
the mixture re¯uxed for another 24 h. This process was
repeated two times to allow a complete conversion of the
starting phenol. The ®nal mixture was concentrated under
N-(tert-Butoxycarbonyl)-N-methyl-ꢀ-thioalaninamide.
N-Boc-N-methyl-b-alaninamide (0.1 g, 0.49 mmol) and
Lawesson's Reagent (0.13 g, 0.32mmol) in THF (1 mL)
were stirred at 20 ꢁC for 21 h. After concentration, the
residue was puri®ed by ¯ash chromatography on silica
gel (EtOAc:hexane, 50:50; Rf=0.4) to yield the thio-
1
vacuumn and used as such for the next step. H NMR
(300MHz, CDCl3) d 7.15 (m, 1H); 19F NMR (282 MHz,
CDCl3/CFCl3) d=À74.2(s, 3F, ±C F3), À137.4 (m, 2F),
À152.6 (m, 2F).
amide (0.08 g, 80%) as a white solid. Mp 89±90 ꢁC; H
1
NMR (200 MHz, CDCl3) d=1.46 (s, 9H, t-C4H9), 2.88
(s, 3H, N-CH3), 3.05 (t, 2H, J=6.8 Hz, ±CH2±CSNH2),
3.58 (t, 2H, J=6.8 Hz, N-CH2-), 7.55 (br s, 1H, -
CSNH2), 8.65 (br s, 1H, ±CSNH2); 13C NMR (50 MHz,
CDCl3) d=28.2 [(CH3)3C], 34.7 (±CH2±CSNH2), 43.7
(N-CH3), 47.9 (N±CH2±), 80.1 [(CH3)3C], 156.0 (OC-
ONH), 207.1 (±CSNH2); IR (NaCl, ®lm): n=3307,
3175, 2977, 2930, 1674 (OCONH), 1483, 1456, 1429,
1396, 1365, 1165, 1136, 999; MS (CI, CH4-N2O): m/z
(%)=219.0 ([M+H]+, 18.3), 162.8 (79.6), 119.0 (100),
88.0 (21.2), 76.0 (30.0), 44.1 (14.6). Anal. calcd for
C9H18N2O2S: C 49.51, H 8.31, N 12.83, S 14.68. Found:
C 49.16, H 8.32, N 12.56, S 14.81.
2,3,5,6-Tetra¯uorophenyl 2-(2-nitroimidazol-1-yl)acetate
(1).20 2-(2-Nitroimidazol-1-yl)acetic acid20(0.375 g, 2.19
mmol) in acetonitrile (5mL) was neutralized with triethy-
lamine (0.306mL, 2.19mmol) before the addition of the
solution of tetra¯uorophenyl tri¯uoroacetate (0.680 mL,
2.63 mmol). The mixture was stirred overnight at 20 ꢁC.
After concentration, the residue was puri®ed by ¯ash
chromatography on silica gel (EtOAc-hexane, 50:50;
Rf=0.4) to yield 1 (0.489 g, 70%) as a pale yellow solid.
1H NMR (300 MHz, CDCl3) d=5.52(s, 2H, ±C H2±),
7.07 (m, 1H, ±C6HF4), 7.23 (d, 1H, J=0.9 Hz, imidazol-
H), 7.29 (d, 1H, J=0.9 Hz, imidazol-H); 19F NMR
(282 MHz, CDCl3/CFCl3) d=À76.4 (s, 3F, CF3), À138.2
(m, 2F), À152.7 (m, 2F); IR (NaCl, ®lm): n=3402, 1641
(CˆO), 1376, 1135; MS (FAB, MNBA): m/z (%)=
320.0 ([M+H]+, 19.3), 226.3 (37.5), 225.2 (44.6), 210.9
(100), 198.0 (10.0), 96.5 (26.6).
3-(N-tert-Butoxycarbonyl-N-methylamino)propanethioacyl
N-phthalimide. To a mixture of thioamide (2.320 g,
10.64 mmol) and K2CO3 (1.769 g, 12.77 mmol) in THF
(30 mL), cooled at 0 ꢁC, was added dropwise (within 4 h,
stirring under argon atmosphere) a solution of phtha-
loyl dichloride (1.84 mL, 12.7 mmol) in THF (30 mL).
After the addition was complete, the mixture was fur-
ther stirred for 4 h at 20 ꢁC, then poured into water
(50 mL) and extracted with EtOAc (3Â20 mL). Drying
over MgSO4, concentration and puri®cation by ¯ash
chromatography on silica gel (EtOAc:hexane 30:70;
Rf=0.78 for EtOAc:hexane 40:60) gave pure thioacyl
phthalimide as a red solid. Yield: 2.78 g (75%). Mp 112±
N-Methyl-ꢀ-alaninamide.62 3-(Methylamino)-propioni-
trile (3.4 mL, 36.4 mmol was slowly added to a suspen-
sion of KOH (6.0 g, 107.14 mmol) in t-BuOH (15 mL)
and heated for 60 min at 90 ꢁC. After cooling at 20 ꢁC,
the liquid phase was separated from the solid, cooled to
À15 ꢁC and treated with water (3 mL). Distillation
under vacuumn left a residue which was dissolved in
acetonitrile (50 mL), dried on MgSO4 and concentrated
to give N-methyl-b-alaninamide (2.6 g, 70%) as a white
solid. 1H NMR (200 MHz, CDCl3) d=2.38 (t, 2H,
J=6.0 Hz, ±CH2±CONH2), 2.44 (s, 3H, N±CH3), 2.85
(t, 2H, J=6.0 Hz, N±CH2±), 5.05 (br s, 1H, ±CONH2),
7.57 (brs, 1H, ±CONH2); IR (NaCl, ®lm): n=3365,
2954, 2806, 2456, 1652 (CˆO), 1457, 1236, 1143, 1108,
1035; MS (CI, CH4±N2O): m/z (%)=102.9 ([M+H]+,
28.7), 85.9 (5.0), 59.9 (38.3), 43.9 (100).
113 ꢁC; H NMR (200 MHz, CDCl3) d=1.37 (s, 9H, t-
1
C4H9), 2.87 (s, 3H, N-CH3), 3.61 (brt, 2H, ±CH2-
CSNPhth), 3.66 (brt, 2H, N±CH2±), 7.86 (m, 2Harom),
7.96 (m, 2Harom); 13C NMR (50 MHz, CDCl3) d=28.1
[(CH3)3C], 34.2(± CH2±CSNPhth), 46.7 (N±CH2±), 47.8
(N-CH3), 79.5 [(CH3)3C], 124.5, 130.7, 135.3, 155.8
(OCONH), 164.5 (Phth-CˆO), 209.3 (-CSNPhth); IR
(NaCl, ®lm): n=3457, 2971, 2942, 1790, 1732 (CˆO,
Ft), 1668 (OCONH), 1456, 1392, 1298, 1144, 1029, 872;
MS (FAB, MNBA): m/z (%)=349.0 ([M+H]+, 0.8),
274.2 (8.3), 249.1 (2.9), 218.0 (100), 206.1 (10.0), 160.2
(34.1), 148.2(9.1). Anal. calcd for C 17H20N2O4S: C
58.60, H 5.78, N 8.04, S 9.20. Found: C 58.39, H 5.72, N
7.92, S 9.00.
N-(tert-Butoxycarbonyl)-N-methyl-ꢀ-alaninamide. To a
solution of N-Methyl-b-alaninamide (2.5 g, 24.5 mmol)
and (Boc)2O (5.45 g, 25.0 mmol) in dichloromethane
(125 mL), was slowly added triethylamine (3.484 mL,
25.0 mmol). The mixture was re¯uxed for 40 h. After
cooling at 20 ꢁC, the solution was washed with water
(3Â20 mL) and brine (1Â20 mL). After drying (MgSO4)
and concentration, the productꢁwas obtained as a white
solid (4.2g, 85%). Mp 109±110 C; 1H NMR (200 MHz,
CDCl3) d=1.46 (s, 9H, t-C4H9), 2.49 (t, 2H, J=6.3 Hz,
±CH2±CONH2), 2.88 (s, 3H, N±CH3) 3.53 (t, 2H,
J=6.3 Hz, N±CH2±), 5.55 (br s, 1H, ±CONH2), 6.70 (br
s, 1H, ±CONH2); 13C NMR (50 MHz, CDCl3) d=28.4
[(CH3)3C], 34.7 (±CH2±CONH2), 45.2(N± CH3), 79.9
[(CH3)3C], 156.2(O CONH), 173.4 (±CONH2); IR
(NaCl, ®lm): n=3364, 3200, 2974, 2932, 1668 (CˆO),
1558, 1489, 1456, 1395, 1149; MS (CI, CH4-N2O): m/z
(%)=203.2 ([M+H]+, 0.7), 147.0 (8.7), 103.0 (100),
59.9 (8.3). Anal. calcd for C9H18N2O3: C 53.45, H 8.97,
N 13.85. Found: C 53.46, H 9.14, N 13.58.
Ethyl 3-(N-tert-butoxycarbonyl-N-methylamino)propane-
dithioate. To a cold (0 ꢁC) solution of thioacyl phthali-
mide (0.522 g, 1.50 mmol) in CH2Cl2 (5 mL), were added
dropwise successively (stirring under argon atmosphere)
ethanethiol (0.560 mL, 7.50 mmol) and triethylamine
(0.215 mL, 1.50 mmol). The solution was allowed to
reach 20 ꢁC within 1 h and left for another 1 h at 20 ꢁC.
After addition of 4 N NaOH (15 mL), the mixture was
rapidly extracted with CH2Cl2 (3Â15 mL). Drying over
MgSO4, concentration and puri®cation by ¯ash chro-
matography on silica gel (EtOAc:hexane 10:90; Rf=0.77
for EtOAc:hexane 30:70), gave pure dithioester as a
1
yellow oil. Yield: 0.315 g (80%). H NMR (200 MHz,
CDCl3) d=1.32(t, 3H, J=7.4 Hz), 1.46 (s, 9H, t±C4H9),

O. Josse et al. / Bioorg. Med. Chem. 9 (2001) 665±675
673
2.88 (s, 3H, N-CH3), 3.21 (q, 2H, J=7.4 Hz, ±SCH2
CH3), 3.23 (t, 2H, J=6.8 Hz, -CH2-CS2Et), 3.62( t, 2 H,
J=6.8 Hz, N±CH2±); 13C NMR (50 MHz, CDCl3)
d=11.9 (±SCH2CH3), 28.2 [(CH3)3C], 30.7 (±SCH2
CH3), 34.4 (±CH2±CS2Et), 49.8 (N±CH2±), 50.2(N-
CH3), 79.5 [(CH3)3C], 155.3 (OCONH), 235.0 (-CS2Et);
IR (NaCl, ®lm): n=2974, 2929, 1699 (OCONH), 1480,
1456, 1392, 1365, 1226, 1162, 1129, 914; MS (FAB,
MNBA): m/z (%)=264.2 ([M+H]+, 2.9), 208.0 (25.8),
189.1 (9.6), 175.3 (24.0), 164.1 (100), 146.2 (14.1), 133.1
(40.8), 121.0 (19.6), 103.9 (10.5), 87.8 (19.9). Anal. calcd
for C11H21NO2S2: C 50.16, H 8.03, N 5.32, S 24.34.
Found: C 50.36, H 8.02, N 5.37, S 24.55.
chromatography on silica gel (EtOAc; Rf=0.40) to give
1
a yellow oil (0.04 g, 76%). H NMR (500 MHz, CDCl3)
two rotamers, d=1.29 et 1.34 (t, 3H, J=7.3 Hz, ±CS2
CH2CH3), 3.00 and 3.13 (s, 3H, N±CH3), 3.19 and 3.26 (q,
2H, J=7.3 Hz, ±CS2CH2CH3), 3.22 and 3.34 (t, 2H,
J=7.0 Hz, ±CH2CS2Et), 3.82and 3.83 (t, 2H, J= 7.0 Hz,
N±CH2±CH2±), 5.19 and 5.30 (s, 2H, ±CH2±CONH±),
7.08 and 7.04 (d, 1H, J=1.2Hz, imidazol-H), 7.19 and
7.18 (d, 1H, J=1.2Hz, imidazol-H); 13C NMR (125MHz,
CDCl3) two rotamers, d=11.8 and 11.8 (SCH2CH3), 30.9
and 31.2(S CH2CH3), 35.6 and 33.6 (N-CH3), 48.6 and
48.8 (±CH2±CS2Et), 49.9 and 49.2(N- CH2-), 50.9 and 51.0
(±CH2±CO), 126.9 and 126.8 (CHimidazol), 127.7 and 127.7
(CHimidazol), 144.8 and 144.8 (C-NO2), 164.6 and 164.5
(CONMe), 232.8 and 234.4 (CS2Et); IR (NaCl, ®lm):
d=3121, 2971, 2932, 1779, 1667 (CˆO), 1493, 1371, 1206,
1160, 1053, 915, 842; MS (FAB, MNBA): m/z (%)=315.0
([M-H]À, 21.5), 253.0 (9.6), 183.0 (100), 136.1 (9.0), 126.0
(13.5), 112.0 (85.4), 96.0 (23.3). Anal. calcd for
C10H14N4O3S2: C 39.72, H 4.66, N 18.53, S 21.20. Found:
C 39.95, H 4.60, N 18.46, S 20.83.
Ethyl 3-(methylamino)propanedithioate (2b). The N-Boc
precursor (0.5 g, 1.91 mmol) was dissolved in cold (0 ꢁC)
tri¯uoroacetic acid (3 mL) and left 1 h (under argon
atmosphere). After evaporation under vacuum, the
residue was dissolved in CH2Cl2 (10 mL) and extracted
with water (4Â5 mL; HPLC grade). Lyophilization of
the aqueous phases gave pure 2b (tri¯uoroacetate salt)
as a yellow oil. Yield: 0.502g (95%). 1H NMR (200
MHz, CDCl3) d=1.32(t, 3H, J=7.4Hz), 2.73 (s, 3H, N-
CH3), 3.23 (q, 2H, J=7.4 Hz, ±SCH2CH3), 3.3±3.5 (m,
4H, N±CH2±CH2±CS2Et), 9.52(m, 2H, N H+2 ); 13C NMR
(50 MHz, D2O) d=12.2 (±SCH2CH3), 31.9 (±SCH2CH3),
34.0 (±CH2±CS2Et), 46.5 (N±CH2±), 49.2(N± CH3), 117.4
(CF3, JCÀF=290.5 Hz), 163.7 (CˆO, JCÀF=34.8 Hz),
235.2 (±CS2Et); IR (NaCl, ®lm): n=3025, 2797, 1674
(CˆO, carboxylate salt), 1456, 1423, 1202, 1134, 912;
MS (FAB, MNBA): m/z (%)=163.9 (M+, 100), 133.0
(26.0), 43.7 (41.2).
Ethyl 3-phthalimidopropanedithioate (4). To a suspen-
sion of PyBOP (3.095 g, 5.94 mmol) in THF (5 mL) was
added a solution of 2-(methoxycarbonyl)benzoic acid
(1.622 g, 5.94 mmol) in THF (5 mL) and triethylamine
(1.127 mL, 8.11 mmol). The mixture was stirred at 20 ꢁC
for 40 min; 2a (1.422 g, 5.41 mmol) was introduced in
one portion followed by a slow addition of triethyl-
amine (1.127 mL, 8.11 mmol). After stirring at 20 ꢁC for
3 h, a catalytic amount of p-TsOH was added before
re¯uxing overnight. After cooling at 20 ꢁC, the solution
was poured on aq sat. NaHCO3 (50 mL) and extracted
with EtOAc (3Â40 mL). The organic phase was dried
(MgSO4) and concentrated before puri®cation by ¯ash
chromatography on silica gel (EtOAc:hexane, 10:90,
Rf=0.27); 4 was then treated with tri¯uoroacetic anhy-
dride (5 mL) in dichloromethane (5 mL) to remove any
traces of water. Yield: 1.357 g (90%), yellow solid. mp:
N-[3-(Ethylthio)-3-thioxopropyl]-2-(2-nitroimidazol-1-yl)
acetamide (3a). General coupling procedure. Triethyla-
mine (0.022 mL, 0.16 mmol) was added slowly to a
solution of 1 (0.05 g, 0.16 mmol) and 2a (0.041 g,
0.16 mmol) in acetonitrile (1 mL). After stirring at 20 ꢁC
for 17 h, acetonitrile was removed under vacuum and
the residue puri®ed by ¯ash chromatography on silica gel
(EtOAc:hexane, 70:30; Rf=0.26) to give pure 3a (0.040g,
85%) as a yellow solid. Mp 131±132 ꢁC; 1H NMR
(500MHz, CDCl3) d=1.32(t, 3H, J=7.3 Hz, ±CS2
CH2CH3), 3.15 (t, 2H, J=5.8 Hz, ±CH2CS2Et), 3.22 (q,
2H, J=7.3Hz, ±CS2CH2CH3), 3.74 (dt, 2H, J=5.8 Hz et
5.8 Hz, NH±CH2±CH2±), 4.99 (s, 2H, ±CH2±CONH±),
6.41 (br t, 1H, J=5.8 Hz, ±CONH±), 7.14 (d, 1H, J=
1.2Hz, imidazol-H), 7.21 (d, 1H, J=1.2Hz, imidazol-
H); 13C NMR (125 MHz, CDCl3) d=11.9 (SCH2CH3),
30.8 (SCH2CH3), 39.2(CONH± CH2±), 49.4 (±CH2±
CS2Et), 52.2 (±CH2±CONH), 126.8 (CHimidazol), 128.6
(CHimidazol), 146.84 (C-NO2), 164.4 (CONH), 235.53
(CS2Et); IR (NaCl, ®lm): d=3318, 2987, 2930, 2872,
2431, 1662 (CˆO), 1559, 1534, 1482, 1420, 1368, 1342,
1290, 1216, 1166, 923; MS (CI, CH4-N2O): m/z (%)=
302.1 (M+, 31.6), 273.0 (100), 169.0 (5.0), 145.9 (9.1),
111.9 (18.9), 102.9 (26.6). Anal. calcd for C10H14N4
O3S2: C 39.72, H 4.66, N 18.53, S 21.20. Found: C
39.95, H 4.60, N 18.46, S 20.83.
82±83 ꢁC; H NMR (200 MHz, CDCl3) d=1.26 (t, 3H,
1
J=7.5 Hz, ±SCH2CH3), 3.18 (q, 2H, J=7.5 Hz, ±SCH2
CH3), 3.37 (t, 2H, J=7.0 Hz, ±CH2CS2Et), 4.14 (t, 2H,
J=7.0 Hz, N±CH2±), 7.70±7.75 (m, 2Harom), 7.83±7.90
(m, 2Harom); 13C NMR (50 MHz, CDCl3) d=11.9
(±SCH2CH3), 30.7 (SCH2CH3), 38.2(± CH2CS2Et), 49.1
(N±CH2±), 123.3, 132.0, 134.0, 168.0 (Phth-CˆO), 233.0
(CS2Et); IR (NaCl, ®lm): d=2972, 2930, 2861, 1772,
1713 (CˆO, Ft), 1466, 1436, 1393, 1357, 1185, 916; MS
(CI, CH4-N2O): m/z (%)=279.2 (MÀ, 4.9), 250.2 (24.1),
146.3 (100). Anal. Calc. for C13H13NO2S2: C 55.89, H
4.69, N 5.01. Found: C 56.02, H 4.62, N 4.84.
N-(3,3,3-tri¯uoropropyl)phthalimide (5). To a suspension
of potassium phthalimide (5.079 g, 27.42 mmol) in dry
DMSO (50 mL), was added 1-bromo-3,3,3-tri¯uoro-
propane (1.46 mL, 13.71 mmol) and the resulting mix-
ture was stirred for 6 h at 20 ꢁC. The excess of potassium
phthalimide was ®ltered o€, the solution poured on brine
(400 mL) and extracted with diethyl ether (3Â200 mL).
The combined organic phases were washed with brine
(3Â200 mL) and dried (MgSO4) before concentration.
The residue was puri®ed by ¯ash chromatography on
silica gel (EtOAc:hexane, 10:90; Rf=0.23) to a€ord 5
N-[3-Ethylpropanedithioate]-N-methyl-2-(2-nitroimidazol-
1-yl)acetamide (3b). The same general coupling proce-
dure was applied for 3b which was purifed by ¯ash

674
O. Josse et al. / Bioorg. Med. Chem. 9 (2001) 665±675
ꢁ
1
(1.882g, 56%) as a white solid. mp: 117±117.9 C; H
NMR (300 MHz, CDCl3) d=2.55 (tq, 2H, J=7.2Hz and
10.4 Hz, ±CH2±CF3), 3.97 (t, 2H, J=7.2Hz, N±C H2±),
7.70±7.80 (m, 2Harom), 7.83±7.91 (m, 2Harom); 19F NMR
(282 MHz, CDCl3/CFCl3) d=À66.1 (t, J=10.4 Hz);13C
NMR (50 MHz, CDCl3) d=31.2(q, JC-F=3.8 Hz, N-
CH2-), 32.2 (q, JCÀF=28.6 Hz, ±CH2±CF3), 123.4, 125.6
(q, JCÀF=273.5 Hz, ±CF3), 131.8, 134.2, 167.6 (Phth-
CˆO); IR (NaCl, ®lm): n=3464, 1703 (CˆO, Ft), 1464,
1386, 1335, 1251, 1185, 1141, 977; MS (CI, CH4±N2O):
m/z (%)=243.9 ([M+H]+, 20.8), 223.9 (13.7), 159.9
(100). Anal. Calc. for C11H8F3NO2: C 54.33, H 3.31, N
5.76. Found: C 54.50, H 3.25, N 5.72.
dissolved in N2H4ꢀÂH2O (1 mL) and heated at 75 ꢁC
under argon ¯ow for 10 min. The free amine was dis-
tilled into a ¯ask containing a solution of 1 (0.03 g,
0.09 mmol) in anhydrous acetonitrile (1 mL) cooled at
0 ꢁC; 80% of the radioactivity has been distilled as the
free amine (1.2mCi, d.c.; 0.017 mmol). Stirring the
mixture of 1 and labeled 5 at 20 ꢁC for 30 min allowed to
recover 65% of this radioactivity coupled to the 2-
nitroimidazole acetic acid as [18F]-EF3 (determined by
radio-TLC; EtOAc, Rf=0.30) (0.780 mCi; 0.011 mmol).
References and Notes
3,3,3-Tri¯uoropropylamine hydrochloride (7). To a solu-
tion of 5 (0.8 g, 3.29 mmol) in isopropanol (32mL)/water
(4.8 mL), was added NaBH4 (0.623 g, 16.48 mmol). The
mixture was strirred for 24 h at 20ꢁC. The solution was ice-
cooled before adding carefully AcOH (3.6 mL) and then
heated to 80 ꢁC for 2h. NaOH 4 N (32mL) was added to
the cooled mixture and the amine was distilled under an
argon ¯ow into a ¯ask containing HCl 5 N (10 mL, at
0 ꢁC), until no more product could be recovered. Eva-
poration of the solution yielded the hydrochloride of 7
(0.396 g, 80%) as a white solid. 1H NMR (200MHz, D2O)
d=2.82 (tq, 2H, J=10.4 Hz and 6.7 Hz, ±CH2±CH2±CF3),
3.50 (t, 2H, J=6.7 Hz, ±CH2±CH2±CF3); 19F NMR
(282 MHz, CDCl3/CFCl3) d=À66.9 (t J=10.4Hz); MS
(FAB, GLYC): m/z (%)=113.9 (M+, 100), 97.0 (16.5),
77.0 (92.1), 68.9 (11.2), 51.0 (12.5), 30.0 (33.7).
1. Hockel, M.; Schlenger, K.; Mitze, M.; Scha€er, U.; Vaupel,
P. Seminars in Radiation Oncology 1996, 6, 3.
2. Raleigh, J. A.; Dewhirst, M. W.; Thrall, D. E. Seminars in
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