Use of 3-[18F]fluoropropanesulfonyl chloride as a prosthetic agent for the radiolabelling of amines: Investigation of precursor molecules, labelling conditions and enzymatic stability of the corresponding sulfonamides

Article abstract of DOI:10.3762/bjoc.9.115

3-[¹⁸F]Fluoropropanesulfonyl chloride, a recently proposed prosthetic agent for fluorine-18 labelling, was prepared in a two-step radiosynthesis via 3-[¹⁸F]fluoropropyl thiocyanate as an intermediate. Two benzenesulfonate-based radiolabelling precursors were prepared by various routes. Comparing the reactivities of 3-thiocyanatopropyl nosylate and the corresponding tosylate towards [¹⁸F]fluoride the former proved to be superior accounting for labelling yields of up to 85%. Conditions for a reliable transformation of 3-[¹⁸F]fluoropropyl thiocyanate to the corresponding sulfonyl chloride with the potential for automation have been identified. The reaction of 3-[¹⁸F]fluoropropanesulfonyl chloride with eight different aliphatic and aromatic amines was investigated and the identity of the resulting ¹⁸F-labelled sulfonamides was confirmed chromatographically by comparison with their nonradioactive counterparts. Even for weakly nucleophilic amines such as 4-nitroaniline the desired radiolabelled sulfonamides were accessible in satisfactory yields owing to systematic variation of the reaction conditions. With respect to the application of the ¹⁸F-fluoropropan-sulfonyl group to the labelling of compounds relevant as imaging agents for positron emission tomography (PET), the stability of N-(4-fluorophenyl)-3-fluoropropanesulfonamide against degradation catalysed by carboxylesterase was investigated and compared to that of the analogous fluoroacetamide.

Full text of DOI:10.3762/bjoc.9.115

Use of 3-[18F]fluoropropanesulfonyl chloride as a
prosthetic agent for the radiolabelling of amines:
Investigation of precursor molecules, labelling
conditions and enzymatic stability of the
corresponding sulfonamides
Reik Löser*1,2, Steffen Fischer3, Achim Hiller3, Martin Köckerling4,
Uta Funke3, Aurélie Maisonial3, Peter Brust3 and Jörg Steinbach1,2,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1002–1011.
1Institute of Radiopharmaceutical Cancer Research (formerly Institute
of Radiopharmacy), Helmholtz-Zentrum Dresden-Rossendorf (HZDR),
Bautzner Landstraße 400, 01328 Dresden, Germany, 2Department of
Chemistry and Food Chemistry, Technical University of Dresden,
Bergstraße 66c, 01062 Dresden, Germany, 3Institute of
Radiopharmaceutical Cancer Research, HZDR Research Site
Leipzig, Permoserstraße 15, 04318 Leipzig, Germany and 4Institute of
Chemistry, University of Rostock, Inorganic Solid-State Chemistry
Group, Albert-Einstein-Straße 3a, 18059 Rostock, Germany
doi:10.3762/bjoc.9.115
Received: 05 February 2013
Accepted: 26 April 2013
Published: 27 May 2013
This article is part of the Thematic Series "Synthetic probes for the study
of biological function".
Guest Editor: J. Aubé
Email:
Reik Löser* - r.loeser@hzdr.de
© 2013 Löser et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
fluorine-18; hydrolytic metabolism; prosthetic groups; radiochemistry;
sulfonamides
Abstract
3-[18F]Fluoropropanesulfonyl chloride, a recently proposed prosthetic agent for fluorine-18 labelling, was prepared in a two-step
radiosynthesis via 3-[18F]fluoropropyl thiocyanate as an intermediate. Two benzenesulfonate-based radiolabelling precursors were
prepared by various routes. Comparing the reactivities of 3-thiocyanatopropyl nosylate and the corresponding tosylate towards
[18F]fluoride the former proved to be superior accounting for labelling yields of up to 85%. Conditions for a reliable transformation
of 3-[18F]fluoropropyl thiocyanate to the corresponding sulfonyl chloride with the potential for automation have been identified.
The reaction of 3-[18F]fluoropropanesulfonyl chloride with eight different aliphatic and aromatic amines was investigated and the
identity of the resulting 18F-labelled sulfonamides was confirmed chromatographically by comparison with their nonradioactive
counterparts. Even for weakly nucleophilic amines such as 4-nitroaniline the desired radiolabelled sulfonamides were accessible in
satisfactory yields owing to systematic variation of the reaction conditions. With respect to the application of the 18F-fluoropropan-
sulfonyl group to the labelling of compounds relevant as imaging agents for positron emission tomography (PET), the stability of
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Beilstein J. Org. Chem. 2013, 9, 1002–1011.
N-(4-fluorophenyl)-3-fluoropropanesulfonamide against degradation catalysed by carboxylesterase was investigated and compared
to that of the analogous fluoroacetamide.
Introduction
The importance of molecular imaging, i.e., the characterisation variety of prosthetic groups were suggested and developed
and measurement of biological processes in living organisms at [5,6]. Their careful individual selection is critical for radio-
the molecular level using remote imaging detectors, for both tracer development as they often exert great influence on target
research and diagnostic purposes has considerably increased binding and/or stability in vivo. This is particularly valid when
over the recent years. The success of this interdisciplinary field PET imaging probes based on small molecules are considered.
depends substantially on the development of molecular probes
equipped with appropriate reporter groups [1].
Labelling based on the formation of carboxylic amides is an ap-
proach that allows convenient introduction of fluorine-18
Among the different imaging modalities, positron emission (Figure 1) [7,8], which applies especially to [18F]fluoroacet-
tomography (PET) stands out with regards to sensitivity and amides [9-15]. In several cases, [18F]fluoroacetamides were
quantitative image evaluation. PET is based on the application proven to be metabolically unstable due to hydrolytic cleavage
of molecules labelled with a positron-emitting radionuclide, [15-17]. As an alternative to acyl-based prosthetic groups the
which are termed radiotracers. Although such radionuclides are 3-[18F]fluoropropanesulfonyl group introduced by Li et al.
known for many elements, fluorine-18 can be considered as the attracted our interest [18]. Labelling with radiofluorine by
most suitable one for PET due to its intermediate half-life of sulfonamide formation seems to be intriguing not only because
109.8 min, its high content of β+-conversion (97%) and its of the inertness against the metabolic cleavage of the label but
rather low positron energy maximum of 640 keV [2].
also because of the polarity it can confer to the resulting tracer
molecule. This can be an advantage especially for radiotracers
From a chemical point of view, the introduction of fluorine-18 based on small molecules [19]. Therefore, we planned to estab-
into molecules that are able to address biomolecular targets in lish and to optimise the preparation of 3-[18F]fluoropropanesul-
vivo, requires a carefully developed methodology as the fonyl chloride in our labs and to study its reaction with a panel
carbon–fluorine bond is rather difficult to tie [3,4]. Further- of aliphatic and aromatic amines of varying reactivity. Particu-
more, as fluorine appears less frequently in biologically active lar attention was paid to the synthesis of precursor molecules
compounds, molecules that show the potential to interact with suitable for radiofluorination and nonradioactive reference com-
certain imaging targets have to be modified with fluorine. For pounds, as the information published in [18] is rather prelimi-
this purpose, generic groups that allow both derivatisation with nary in this regard. Furthermore, we aimed to extend 18F-
fluorine as well as convenient introduction of radiofluorine are fluoropropanesulfonylation to the labelling of aromatic amines.
often used. These groups are referred to as prosthetic groups in Additionally, the metabolic stability of 3-fluoropropanesulfon-
preparative radiochemistry. For labelling with fluorine-18, a amides was proven and comparatively assessed to that of analo-
Figure 1: Selection of prosthetic agents for 18F-labelling via acylation.
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Beilstein J. Org. Chem. 2013, 9, 1002–1011.
gous fluoroacetamides by degradation experiments with nucleophilic displacement of carbon-bound halogens with
carboxylesterase from pig liver. Preliminary results of this study sulfonates, which works best with alkyl iodides and silver salts
have been published previously as a conference abstract [20].
of sulfonic acids [23]. Therefore, the required 3-iodopropyl
thiocyanate (7) was synthesised by subjecting the corres-
ponding chloro-derivative 6 to the conditions of a Finkelstein
reaction. Unexpectedly, this led to a mixture containing 1,3-
diiodopropane and 1,3-dithiocyanatopropane beside 7, as
revealed by 1H NMR analysis. From this mixture, the desired
product 7 was isolated by distillation in a yield of 24%. Reduc-
tion of the amount of sodium iodide from 5 to 1.1 equivalents
did not result in a more favourable product distribution. The
course of this reaction becomes clear in the light of the pseudo-
halide concept: the thiocyanate functionality acts as a leaving
group towards attack by iodide forming 1,3-diiodopropane. The
thereby-released thiocyanate anion reacts with concomitantly
formed 7 to give 1,3-dithiocyanatopropane. The reversibility of
the iodide/thiocyanate displacement has been reported previ-
ously [24] and alkyl thiocyanates can be quantitatively trans-
formed under controlled conditions into the corresponding
iodides [25]. The preparation of compound 7 can be also
achieved by the transformation of alcohol 2 in an Appel-type
reaction, circumventing the problems encountered during the
Finkelstein reaction. Conversion of 7 with silver tosylate
proceeded smoothly leading to the desired tosylate 3. In
analogy, the nosylate 4 was obtained by reaction of the iodide 7
with silver nosylate, which was prepared according to a
published procedure [26]. Alternatively, 4 was obtained by
converting alcohol 2 with nosyl chloride. This procedure
resulted in lower yields but can be considered as more efficient,
as it is shorter by one step.
Results and Discussion
Synthesis of precursors and nonradioactive
reference compounds
The preparation of 18F-labelled sulfonyl chlorides is chal-
lenging as the chlorine atom in these electrophilic agents can be
exchanged by reaction with fluoride even in the presence of
water to form the corresponding sulfonyl fluorides [21]. Hence,
the sulfonyl chloride has to be generated by interconversion of a
different, less reactive sulfur-containing functional group after
radiofluorination. Sulfonyl chlorides can be generated by oxi-
dation with aqueous chlorine from a variety of organosulfur
species such as thiols, sulfides, disulfides, thioesters, isothio-
uronium salts, xanthates and thiocyanates [22]. The latter class
of organic sulfur compounds seems to be most advantageous, as
organic thiocyanates are easily accessible, sufficiently stable to
oxidation, and nonhygroscopic. Li et al. [18] decided to use a
propyl spacer between the fluorine-18 atom and the thiocyanate
moiety as radiofluorination by nucleophilic substitution
proceeds easier at aliphatic than at aromatic electrophilic
centres. In addition, the propyl spacer accounts for a balance
between the limited size of the prosthetic unit on the one hand
and the limited volatility of the radiofluorinated intermediates
on the other. Thus, the general approach presented in [18] to
generate 18F-labelled sulfonyl chlorides seems to be well-
conceived and was therefore adopted for our purposes.
Initially, the route described by Li et al. [18] was followed to
synthesise the tosylate precursor 3 (Scheme 1). As the tosyla- The synthesis of the 19F-based reference compounds started
tion of the alcohol 2 proceeded in low yields and led to side with the conversion of commercially available 1-fluoro-3-
products that were difficult to remove and impaired the reac- iodopropane (8) with potassium thiocyanate, analogous to the
tion with [18F]fluoride, an alternative procedure to afford 3 was preparation of 2 (Scheme 2). The key step was the transforma-
envisaged. Esters of sulfonic acids can be also prepared by tion of the thiocyano group of 9 to the chlorosulfonyl group
Scheme 1: Synthesis of radiofluorination precursors 3 and 4. Reagents and conditions: (a) KSCN, CH3OH, reflux; (b) TsCl, DIPEA, pyridine, CH2Cl2,
rt (for 3) or NsCl, K(CH3)3SiO, THF, rt (for 4); (c) KSCN, CH3OH, reflux; (d) NaI, acetone, reflux; (e) Ph3P, I2, imidazole, THF, rt; (f) silver tosylate (for
3) or silver nosylate (for 4), CH3CN, rt.
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Beilstein J. Org. Chem. 2013, 9, 1002–1011.
Scheme 2: Synthesis of 3-fluoropropanesulfonamide 11 via intermediary 3-fluoropropanesulfonyl chloride (10). Reagents and conditions: (a) KSCN,
CH3OH, reflux; (b) Cl2, H2O/AcOH, rt; (c) N-phenylpiperazine, triethylamine (TEA), CH2Cl2, reflux.
leading to 3-fluoropropanesulfonyl chloride (10). This func- side products that were identified as the corresponding N,N-
tional group interconversion using aqueous chlorine has been bissulfonylanilines 16a–18a. The double sulfonylation of
known for a long time [27] but has received little attention in aromatic amines under strongly basic conditions was described
synthetic organic chemistry. Following this approach, earlier [29]. This side reaction was most pronounced for the
Millington et al. were able to obtain the sulfonylating agent 10 reaction of 10 with 4-nitroaniline, which resulted in the forma-
by saturating an aqueous suspension of thiocyanate 9 with chlo- tion of 18a as the main product. Therefore, 10 was reacted with
rine gas [28]. In our hands, superior results were achieved when 4-nitroaniline in the presence of pyridine at room temperature
this transformation was carried out in a mixture of chlorine- resulting in the incomplete conversion to the mono-sulfony-
saturated water and acetic acid as cosolvent for 9. The desired lated product 18. This compound was obtained in the form of
intermediate was purified by vacuum distillation or trans- crystals suitable for X-ray diffraction analysis.
formed as crude product to the final 3-fluoropropanesulfon-
amides, as shown for compound 11. Alternatively, 10 was The molecular structure of 18 is shown in Figure 2A,
obtained commercially. The reaction of 10 with aliphatic confirming unambiguously its identity as N-(4-nitrophenyl)-3-
amines proceeded quantitatively and smoothly to the sulfon- fluoropropane-1-sulfonamide. Crystal data and structure refine-
amides 12–15 (Scheme 3). In contrast, its reaction with aniline ment parameters are collected in Table 1. The length of the S–N
derivatives required a longer time and led to the formation of bond in compound 18 is with 1.639(1) Å close to the average
Scheme 3: Synthesis of 3-fluoropropanesulfonamides 12–18. Reagents and conditions: (a) triethylamine (TEA), CH2Cl2, reflux (for 12–17) or pyri-
dine, CH2Cl2, rt (for 18).
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Beilstein J. Org. Chem. 2013, 9, 1002–1011.
Table 1: Crystal data and structure-refinement parameters for com-
pound 18.
Crystal data
Formula
C9H11FN2O4S
262.26 g·mol−1
173(2) K
Formula weight
Temperature
Wavelength
0.71073 Å
Crystal system
Space group
Unit cell dimensions
monoclinic
P21/n
a = 10.7639(7) Å
b = 5.2066(4) Å
c = 19.532(1) Å
β = 91.748(4)°
1094.1(1) Å3
4
Volume
Z
Density (calcd.)
Absorption coefficient
F(000)
1.592 g·cm−3
0.316 mm−1
544
Crystal size
Meas. Range, 2θmax
0.26 × 0.14 × 0.05 mm3
59.02
Refinement
Refinement method
Full-matrix least-
squares on F2
Data/restraints/param.
Goodness-of-fit on F2
Final R indices
3047 / 0 / 159
1.030
R1 = 0.0402
wR2 = 0.0952
R1 = 0.0613
wR2 = 0.1031
0.386/−0.328 e·Å−3
[I > 2σ(I)]
R indices (all data)
Largest diff. peak/hole
The orientation of the N1 lone electron pair is antiperiplanar to
the S1–C3 bond. Such conformational preferences have been
also observed for other sulfonamides and give rise to an optimal
nN-σ*S,C interaction [31]. Further notable features are the inter-
actions between the molecules in the crystal involving the
sulfonamide nitrogen. Together with the hydrogen attached to
this atom (H1C) it acts as a two-fold hydrogen-bond donor
towards the sulfonyl oxygen (O1) of a neighbouring molecule
with an O···H distance of 2.37(2) Å (N1···O1’: 3.015(2) Å) and
an N–H···O angle of 142(2)° (Figure 2B). The second contact of
the NH-group involves the fluorine atom (F1) of another neigh-
bouring molecule with an F···H distance of 2.70(2) Å (N1···F1’:
3.291(2) Å) and an N–H···F angle of 135(2)°, which can be
interpreted as weak hydrogen bond. Although covalently bound
fluorine is commonly considered as a poor hydrogen-bond
acceptor [33,34], it tends to participate in multipolar contacts
including hydrogen bonds [35], as observed herein. To our
knowledge, all sulfonamides shown in Scheme 2 and Scheme 3
have not been described so far.
Figure 2: (A) View of the molecular structure of sulfonamide 18 with
atom labelling scheme. Displacement ellipsoids are drawn at the 50%
probability level. (B) View of the arrangement of molecules in crystals
of sulfonamide 18 showing hydrogen-bond contacts of the amide
H-atom H1C.
value of 1.63(2) Å observed for sulfonamides [30]. Whereas the
nitrogen atom of carboxylic amides is typically trigonal planar,
that of sulfonamides tends to be pyramidalised [31,32]. This
phenomenon can be also observed for the molecular structure of
18 in the crystal. This is indicated by the fact that the sum of the
three valence angles around the sulfonamide nitrogen
(C4–N1–S1, C4–N1–H1C, and S1–N1–H1C) is equal to
348(4)°, which is significantly less than 360° for trigonal planar
geometry. Further evidence for pyramidalisation is provided by
the out-of-plane angle for S1 (sulfonamide sulfur atom) with
respect to the plane defined by the atoms N1, C4 and H1C,
which is 34(2)° compared to zero for the trigonal planar shape.
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Beilstein J. Org. Chem. 2013, 9, 1002–1011.
Radiochemistry
The sulfonate precursor molecules 3 and 4 were subjected to
nucleophilic substitution with [18F]fluoride. The reaction para-
meters (amount of precursor substance, solvent, volume,
temperature, time) were carefully optimised. The following
conditions were found to be optimal for the formation of radio-
labelled thiocyanate [18F]9: 2.5 to 3.0 mg of 3 or 4 in
0.3–0.5 mL of acetonitrile, 82 °C, 15 min. Thermal heating was
advantageous compared to microwave irradiation (up to 50 W
for 7 min, 75 °C (CH3CN), 100 °C (DMF)). Higher labelling
yields were achieved when the nosyl precursor 4 was used
instead of tosylate 3 (75–85% (n = 12) versus 45–55% (n = 9),
respectively; Figure 3). Notably, employing DMF as solvent
resulted in significantly lower yields.
Figure 4: Time course of the distillation of 3-[18F]fluoropropyl thio-
cyanate ([18F]9) in the argon stream. For calculation of the distillation
yield only the fraction of [18F]9 in the crude mixture is considered.
removed by passing the resulting solution through a Na2SO4-
filled cartridge.
3-[18F]Fluoropropanesulfonyl chloride ([18F]10) was reacted
with different primary and secondary aliphatic as well as prima-
ry aromatic amines (Scheme 4) at room temperature. The use of
dichloromethane as solvent was superior compared to mixtures
of acetonitrile and water. The reactions were carried out in the
absence of any additive or with stoichiometric amounts of
triethylamine (TEA) or 4-dimethylaminopyridine (DMAP) as
auxiliary bases (Table 2). The radiochemical yields of the 18F-
labelled sulfonamides [18F]11–[18F]15 derived from aliphatic
amines did not improve or even become attenuated upon addi-
tion of TEA or DMAP. Obviously, the aliphatic amines are
sufficiently nucleophilic to undergo sulfonylation readily within
short reaction times of 2–3 min. In contrast, the presence of
Figure 3: Dependence of the labelling yields of [18F]9 on the precursor
amount. Reactions of tosylate 3 and nosylate precursor 4 with [18F]F-
Kryptofix222-carbonate complex were carried out in 500 µL of acetoni-
trile at 82 °C for 15 min.
The crude reaction mixture containing [18F]9 was of sufficient these agents proved to be beneficial for the reaction of [18F]10
radiochemical purity to be subjected to the next step. Alter- with aniline and 4-fluoroaniline (Table 2 and Figure 5A) and
natively, it can be isolated by distillation at atmospheric pres- the well known acylation catalyst DMAP was somewhat advan-
sure in the argon stream at 80 °C and frozen out in a cooling tageous over TEA. Nevertheless, the radiochemical yields for
trap at −60 °C within 10 min and a recovery of 92% (Figure 4). the formation of the 4-nitroaniline-derived sulfonamide [18F]18
To transform the 18F-labelled thiocyanate [18F]9 into the corres- were below 10%, even in the presence of TEA and DMAP. This
ponding sulfonyl chloride [18F]10, [18F]9 was adsorbed by a can be attributed to the poor nucleophilicity of the amino group
C18-SPE-cartridge and repetitively treated with a saturated solu- of 4-nitroaniline which is by far lower than that of aniline and
tion of chlorine in water (prepared immediately before use). In 4-fluoroaniline. The difference in the nucleophilicity of these
this way 3-[18F]fluoropropanesulfonyl chloride ([18F]10) was three aromatic amines is reflected by the pKa values of their
obtained in radiochemical purities of 90–95% and overall corresponding ammonium ions decreasing from 4.65 over 4.58
decay-corrected radiochemical yields of 40–45%, within 70 min to 1.02 for 4-fluoroaniline, aniline, and 4-nitroaniline, respect-
of synthesis time. Attempts to obtain [18F]10 by using chlorine ively [36]. To achieve satisfactory conversion of the 18F-
generated in situ from calcium hypochlorite (in 2 M HCl) were labelled sulfonyl chloride [18F]10 with 4-nitroaniline, potas-
less efficient. After careful removal of excessive chlorine from sium trimethylsilanolate was tested as auxiliary base. This
the cartridge in the argon stream, we could isolate [18F]10 by reagent has good solubility in organic solvents and was
elution with dichloromethane, and the remaining water was suggested by Laganis and Chenard as equivalent for the O2− ion
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Beilstein J. Org. Chem. 2013, 9, 1002–1011.
Scheme 4: Radiosynthesis of 3-[18F]fluoropropanesulfonamides [18F]11–[18F]18. Reagents and conditions: (a) [18F]F−, Kryptofix222, K2CO3, CH3CN,
82 °C; (b) Cl2/H2O, C18-modified silica gel; (c) auxiliary base as specified in Table 2, CH2Cl2, rt.
Table 2: Reaction of [18F]10 with various aliphatic and aromatic amines (n ≥ 2). RCYs were determined by radio-TLC and refer to the fraction of the
product related to the total 18F-activity.
RCY (%)
18F-labelled
amine
no auxiliary base
TEA
DMAP
KOSiMe3
1:4a
sulfonamide
1:20a
1:2a
[18F]11
[18F]12
[18F]13
[18F]14
[18F]15
[18F]16
[18F]17
[18F]18
phenylpiperazine
piperidine
88–89
82–84
77–84
86
87
82
72–81
70–83
77–82
71
—
—
—
—
—
—
morpholine
76–82
74
—
—
—
benzylamine
cyclohexylamine
aniline
—
—
—
85
7
71
—
—
—
7
50
58
—
12–20
30–35
25–30
—
4-fluoroaniline
4-nitroaniline
4–8
<1
56
65
25
—
3
4–6
10–16
44–45
aRatio of potassium trimethylsilanolate to amine.
and is typically used to convert carboxylic esters to the corres- effect of potassium trimethylsilanolate on the sulfonylation
ponding potassium carboxylates under mild anhydrous condi- reaction could be a partial deprotonation of the 4-nitroaniline as
tions [37]. Its successful use for the acceleration of O-sulfonyla- the basicity of siloxides is comparable to that of alkoxides [39].
tions was recently described by Musachio et al. [38]. Conver- A pKa value of 21 has been reported for the amino group in
sion of [18F]10 with 4-nitroaniline in the presence of potassium 4-nitroaniline [40].
trimethylsilanolate led to the formation of the desired 18F-
labelled sulfonamide [18F]18 in radiochemical yields as high as Stability against enzymatic degradation
45%. Interestingly, a ratio of potassium trimethylsilanolate to Many compounds that are able to address biomolecular targets
4-nitroaniline of 1:20 was considerably more efficient than of interest for molecular imaging contain amino-substituted
ratios of 1:4 and 1:2 (Table 2 and Figure 5B). In this way, we aromatic and heteroaromatic moieties. For the convenient radio-
could even accomplish the labelling of weakly nucleophilic labelling of these molecules with fluorine-18 an 18F-fluoro-
amines such as 4-nitroaniline. The reason for the beneficial acetylation seems to be convenient from a chemical point of
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Beilstein J. Org. Chem. 2013, 9, 1002–1011.
Figure 5: Radio-HPLC chromatograms for the reaction of [18F]10 with (A) 4-fluoroaniline in the absence and presence of 4-N,N-dimethylaminopyri-
dine (DMAP) and triethylamine (TEA) and (B) 4-nitroaniline in the absence and presence of potassium trimethylsilanolate in varying amounts relative
to the nucleophile. The ordinates (counts of 18F-activity in arbitrary units) are omitted for clarity.
view. However, 18F-labelled aromatic fluoroacetamides turned Fluoroacetamide 19 was prepared by reacting 4-fluoroaniline
out to be unstable in vivo undergoing N-defluoroacetylation with fluoroacetyl chloride. The activity of the enzyme prepar-
[41]. Nothing has been stated regarding the enzymes catalysing ation was verified using the chromogenic standard substrate
this metabolic transformation but the involvement of 4-nitrophenyl butyrate in a spectrophotometric assay. The
carboxylesterase (EC 3.1.1.1) is probable even though the parti- concentrations of 17 and 19 were monitored by RP-HPLC.
cipation of other hydrolases cannot be excluded [42,43].
Carboxylesterase belongs to the large class of α/β serine hydro- As expected, sulfonamide 17 proved to be stable against de-
lases, is located in the lumen of the endoplasmic reticulum of gradation by carboxylesterase (Figure 6). Under the same
cells in many tissues, and is highly expressed in liver cells [44]. conditions, fluoroacetamide 19 underwent degradation with a
Beside its esterase activity the enzyme shows also amidase pseudo-first-order rate constant of 0.012 min−1 corresponding
activity towards amides with various acyl chains and plays a to a half-life of 58 min at an enzyme concentration of
prominent role in the hydrolytic metabolism of many drug
molecules including radiopharmaceuticals [45,46]. Notably, the
amidase activity of carboxylesterase is restricted to amides
derived from aromatic amines [47]. This catalytic activity is
crucial for the bioactivation of the acetanilide class of analgesic
agents represented by paracetamol as the most important
member [48]. Metabolic instability was also observed for ali-
phatic 18F-labelled fluoroacetamides [13,49]. Their fate seems
to be different from their aromatic counterparts in the way that
they undergo defluorination at the α-methylene group rather
than hydrolytic cleavage of the amide bond [13].
The metabolic hydrolysis of sulfonamide bonds has not been
reported so far. Thus, this type of chemical function can be
considered as metabolically inert [42]. To support this and to
assess the metabolic stability of 3-fluoropropanesulfonamides in
Figure 6: Time course of the carboxylesterase-catalysed degradation
comparison to their fluoroacetamide analogues, N-(4-fluoro-
phenyl)-3-fluoropropane-1-sulfonamide (17) and N-(4-fluoro-
phenyl)-fluoroacetamide (19, see Supporting Information
File 1) were exposed to pig-liver esterase (PLE), the porcine
homologue of carboxylesterase, in buffered aqueous solution.
of 3-fluoropropansulfonamide 17 (red) and fluoroacetamide 19 (blue).
The pseudo first-order rate constant for the decay of 19 was (0.012 ±
0.001) min−1 corresponding to a half-life of 57.8 min. Data points
represent average values from two measurements originating from two
independent experiments with SEM values less than 10% of the mean
values.
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Beilstein J. Org. Chem. 2013, 9, 1002–1011.
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Acknowledgements
We would like to thank Dr. Claudia Birkemeyer (University of
Leipzig) for HRMS measurements. The dedicated technical
assistance of Tina Spalholz, Peggy Wecke and Karin Landrock
is gratefully acknowledged. R.L. acknowledges financial
support by the Fonds der Chemischen Industrie.
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