Synthesis of [18F]fluoroacetaldehyde. Application to [ 18F]fluoroethylation of benzylamine under reductive alkylation conditions

Article abstract of DOI:10.1002/jlcr.1514

The radiosynthesis of a new [¹⁸F]fluoroalkylating agent, [ ¹⁸F]fluoroacetaldehyde, is described. It was produced using the Kornblum method by oxidation with dimethyl sulphoxide of 2-[¹⁸F] fluoroethyl p-toluenesulphonate ([¹⁸F]FETos). In these conditions the oxidation proceeds smoothly and rapidly to the selective conversion of tosyl esters of primary alcohols to aldehydes with no carboxylic acids being produced. The chemical identity of [¹⁸F]fluoroacetaldehyde was determined by comparing its chromatographic properties as well as those of its 2,4-dinitrophenylhydrazone (2,4-DNPH) derivative with those of, respectively, the standard fluoroacetaldehyde and its 2,4-DNPH derivative. Standard fluoroacetaldehyde was prepared by oxidation of fluoroethanol with pyridinium dichromate and characterized as its 2,4-DNPH derivative by mass spectrometry. To test its reactivity with amines under reductive alkylation conditions, [ ¹⁸F]fluoroacetaldehyde was reacted with benzylamine used as model substrate. The chemical identity of the resulting radiolabeled product was determined to be [¹⁸F]N-(2-fluoroethyl)-benzylamine by comparing its chromatographic properties with those of the synthesized standard N-(2-fluoroethyl)-benzylamine characterized by ¹⁹F and ¹H NMR spectroscopy and mass spectrometry. This new fluorine-18 labelled synthon may find applications in radiolabelling peptide, protein and antibody fragments as well as in aldol condensation or in the Mannich reaction. Copyright

Full text of DOI:10.1002/jlcr.1514

Research Article
Received 28 February 2007,
Revised 24 February 2008,
Accepted 29 February 2008
Published online in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1514
Synthesis of [18F]fluoroacetaldehyde.
Application to [18F]fluoroethylation of
benzylamine under reductive alkylation
conditions
Ã
C. Prenant,a J. Gillies,b J. Bailey,b G. Chimon,c N. Smith,b G. C. Jayson,d
and J. Zweitb
The radiosynthesis of a new [18F]fluoroalkylating agent, [18F]fluoroacetaldehyde, is described. It was produced using the
Kornblum method by oxidation with dimethyl sulphoxide of 2-[18F]fluoroethyl p-toluenesulphonate ([18F]FETos). In these
conditions the oxidation proceeds smoothly and rapidly to the selective conversion of tosyl esters of primary alcohols to
aldehydes with no carboxylic acids being produced. The chemical identity of [18F]fluoroacetaldehyde was determined by
comparing its chromatographic properties as well as those of its 2,4-dinitrophenylhydrazone (2,4-DNPH) derivative with
those of, respectively, the standard fluoroacetaldehyde and its 2,4-DNPH derivative. Standard fluoroacetaldehyde was
prepared by oxidation of fluoroethanol with pyridinium dichromate and characterized as its 2,4-DNPH derivative by mass
spectrometry. To test its reactivity with amines under reductive alkylation conditions, [18F]fluoroacetaldehyde was reacted
with benzylamine used as model substrate. The chemical identity of the resulting radiolabelled product was determined to
be [18F]N-(2-fluoroethyl)-benzylamine by comparing its chromatographic properties with those of the synthesized standard
N-(2-fluoroethyl)-benzylamine characterized by 19F and 1H NMR spectroscopy and mass spectrometry. This new fluorine-18
labelled synthon may find applications in radiolabelling peptide, protein and antibody fragments as well as in aldol
condensation or in the Mannich reaction.
Keywords: [18F]fluoroacetaldehyde; Kornblum oxidation; reductive alkylation; [18F]N-(2-fluoroethyl)-benzylamine
reactivity carbonyl compounds. Small aldehydes, formaldehyde
and acetaldehyde, are very effective reagents in reductive
Introduction
Radiolabelling, with fluorine-18, of amines by [18F]fluoroethyla-
tion is commonly carried out using [18F]FETos or 2-bromo-1-
[18F]fluoroethane.1–3 A procedure involving two steps has been
reported for the synthesis of [18F]N-(2-fluoroethyl)-anilines based
on direct nucleophilic substitution with [18F]fluoride ion in an N-
haloacetylaniline (halo = Cl or Br) followed by reduction of the
generated [18F]N-fluoroacetyl-aniline in situ.4
alkylation.8–10 Electron-withdrawing substituents in acetalde-
hyde, e.g. trifluoroacetaldehyde or difluoroacetaldehyde, in-
crease the chemical reactivity of the carbonyl carbon with
nucleophiles when compared with non-fluorinated acetalde-
hyde.11,12 For these reasons [18F]fluoroacetaldehyde was ex-
pected to be a good [18F]fluoroethylating agent for amines in
reductive alkylation conditions.
[18F]fluoroethylation using [18F]FETos or 2-bromo-1-[18F]fluor-
oethane requires an intermediate purification step of the
18F-fluoroethylating agents from their respective starting
materials ethylene di-p-toluenesulphonate and 1,2-dibro-
moethane using high-performance liquid chromatography
(HPLC) or a solid-phase extraction method. Furthermore these
reactions take place in organic, anhydrous, solvents (dimethyl-
formamide, dimethyl sulphoxide (DMSO) or acetonitrile). We
have developed a synthesis route to [18F]fluoroacetaldehyde as
an alternative to [18F]fluoroethylating agent for amines and for
its possible applications in radiolabelling peptides, proteins and
antibody fragments.
Alcohol oxidation in DMSO is widely used in synthetic organic
chemistry.13 The reaction requires a base and a hydroxyl
activating agent such as N,N0-dicyclohexylcarbodiimide,14 acetic
aWolfson Molecular Imaging Centre, The University of Manchester, 27 Palatine
Road, Manchester M20 3LJ, UK
bCancer Research-UK/University of Manchester Radiochemical Targeting and
Imaging Group, Paterson Institute for Cancer Research, Manchester M20 4BX, UK
cClinical Science Building, Human Pain Research Group, Hope Hospital, Eccles
Old Road, Salford M6 8HD, UK
dDepartment of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road,
Manchester M20 4BX, UK
Aldehydes and ketones are known to react with primary or
secondary amines in the presence of hydrogen or a hydrogena-
tion catalyst to produce N-alkylamines.5–7 These alkylations can
be carried out in water as the reaction solvent when using high-
*Correspondence to: C. Prenant, Wolfson Molecular Imaging Centre, The
University of Manchester, 27 Palatine Road, Manchester M20 3LJ, UK.
E-mail: christian.prenant@mmic.man.ac.uk
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Copyright r 2008 John Wiley & Sons, Ltd.

C. Prenant et al.
Figure 1. Alkyltosylate oxidation with DMSO (X = tosyl).
was not isolated but reacted further with DMSO at 1501C after
evaporation of acetonitrile. Because of the presence of excess
potassium carbonate used to convert [18F]HF to [18F]KF, the
addition of sodium bicarbonate, as described in the Kornblum
method, was not considered required for the oxidation of
[18F]FETos and pure DMSO was used instead. The reaction
mixture was set to distil immediately after addition of DMSO and
the distillate was collected into a vial containing 50 ml of water
kept at room temperature. According to the reaction mechan-
ism depicted in Figure 1, other products were expected to distil
with the radiolabelled aldehyde such as dimethyl sulphide,
glyoxal and DMSO vapour. Dimethyl sulphide, produced from
the reduction of DMSO during the reaction, is a volatile liquid
(boiling point = 381C) only slightly soluble in water (2.0% (w/w)
at 201C)31, only reactive with oxidizing agents and not expected
to interfere in the reaction of [18F]fluoroacetaldehyde with
amines in the presence of a reducing agent. Glyoxal was a
potential product of ethylene di-p-toluenesulphonate oxidation,
this reagent being used in excess for the production of
[18F]FETos. Glyoxal is a volatile liquid (boiling point = 511C),
readily soluble in water and which reacts with amines. Its
production and distillation with [18F]fluoroacetaldehyde would
compromise the use of the latter as an N-[18F]fluoroethylating
agent. HPLC analyses of the distillate showed no trace of glyoxal.
Furthermore, reaction of [18F]fluoroacetaldehyde with either
2,4-dinitrophenylhydrazine or benzylamine was not prevented.
Moreover, no precipitate was observed in the homo-
genous DMSO mixture; thus, decomposition of glyoxal or its
rearrangement to glycolic acid which boils at 1001C with
decomposition31 are possible explanations why glyoxal was not
found.
Figure 2. [18F]fluoroacetaldehyde radiosynthesis steps.
anhydride15 or a reagent for prior activation of DMSO such as
oxalyl chloride.16 In these gentle oxidation conditions primary
alcohols are converted to aldehydes with no carboxylic acids
being produced. In a similar way tosyl esters of primary alcohols
or primary alkyl halides are oxidized to aldehydes with DMSO in
conditions developed by Kornblum et al.17 Alkyltosylate oxida-
tion, using the Kornblum method, is carried out by treatment
with a sodium bicarbonate–DMSO mixture at a temperature
between 130 and 1501C for 3 min.18,19 The reaction proceeds via
an alkoxysulphonium ion intermediate (Figure 1).20,21 The
Kornblum method provided an attractive way to produce
[18F]fluoroacetaldehyde from the well-described synthon
[18F]FETos.22–25
A two-step synthesis route to [18F]fluoroacetaldehyde was
thus investigated (Figure 2). [18F]FETos obtained, in the first
step, by the reaction of ethylene di-p-toluenesulphonate with
potassium [18F]fluoride in the presence of Kryptofixs 222 was
oxidized by DMSO in the second step.
[18F]fluoroacetaldehyde has a lower boiling point than its
heavier chlorinated analogue chloroacetaldehyde (boiling
point = 85–861C) and it was expected that it would be easily
distilled. In fact [18F]fluoroacetaldehyde volatility allowed for a
continuous separation from the oxidation reaction by distilla-
tion. The distillate was analysed by HPLC with UV detection at
277 nm (lmax of the UV absorption of the acetaldehyde carbonyl,
To minimize the amount of distilled DMSO, the distillation
was carried out at 1501C for 4 min and carried on at 1301C for
another 4 min with a low flow rate of nitrogen as the carrier gas
(7–8 ml/min). Efficiency of trapping the radioactivity into water
Ã
in solution in water, due to the n-p electronic excitation).
[18F]fluoroacetaldehyde was characterized as the 2,4-dinitrophe-
nylhydrazone (2,4-DNPH) derivative and reacted with benzyla-
mine, used as model substrate, in order to test its reactivity with
amines under reductive alkylation conditions using sodium
cyanoborohydride26,27 as the reducing agent. Synthesis of the
resulting [18F]N-(2-fluoroethyl)-benzylamine has already been
reported by [18F]fluoroethylation of benzylamine using either of
the reagents [18F]FETos or 2-bromo-1-[18F]fluoroethane.3
was checked by connecting
a second vial, containing
tetrahydrofuran (THF) (0.3 ml), kept at around ꢀ101C (ice–al-
cohol), to the vent of the first one. The total radioactivity
distilled and trapped in the two vials accounted for 31–37%
(yield based on three experiments and decay corrected) of the
initial radioactivity as [18F]HF and more than 97% of the
distilled radioactivity was found in the water containing vial.
The radioactivity extracted by distillation and efficiently
Standard fluoroacetaldehyde was prepared following
a
method described by Moss et al.28 by oxidation of fluoroethanol
using pyridinium dichromate (PDC)29,30 and characterized as the
2,4-DNPH derivative.
trapped in
a small volume of water showed that the
radiolabelled, volatile product of the reaction was highly
hydrophilic. Such high hydrophilicity was expected from
fluoroacetaldehyde as electron-withdrawing substituents in-
crease solvation of the aldehyde under its more hydrophilic
hydrate form.
As the fraction of the distilled radioactivity trapped into THF
was not analysed, we cannot exclude the fact that a hydro-tosyl
elimination yielding [18F]vinylfluoride occurred; but as this
amount of radioactivity was low if [18F]vinylfluoride was
produced, it was only via a minor side reaction.
Results and discussion
18F]fluoroacetaldehyde preparation and 2,4-DNPH deriva-
tization
[
[18F]FETos produced by nucleophilic substitution of ethylene di-
p-toluenesulphonate with [18F]KF/Kryptofix 2.2.2 in acetonitrile
J. Label Compd. Radiopharm 2008, 51 262–267
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C. Prenant et al.
Figure 3. HPLC analysis of the distillate from the [18F]FETos oxidation reaction with DMSO, co-injection with standard fluoroacetaldehyde.
Figure 4. HPLC analysis of the reaction with 2,4-dinitrophenylhydrazine of the distillate from the [18F]FETos oxidation with DMSO.
A sample from the distillate trapped into water was analysed time and coelution with standard fluoroacetaldehyde-2,4-DNPH.
by HPLC under reverse-phase conditions. No UV detection was These HPLC analyses showed that [18F]fluoroacetaldehyde was
observed at 277 nm. The radio-HPLC trace showed a single peak the main component of the radioactivity distilled from the
with a retention time of 8.2 min that was identified as oxidation reaction.
[18F]fluoroacetaldehyde on the basis of both retention time
Radiosynthesis conditions for [18F]FETos production are
and coelution with standard fluoroacetaldehyde (Figure 3). described using acetonitrile as the reaction solvent.23–25 To
Under these HPLC conditions, glyoxal and DMSO had 6.1 and simplify the [18F]fluoroacetaldehyde synthesis procedure, we
10.2 min retention times, respectively.
tried using DMSO for both [18F]FETos production and oxidation
The distillate was reacted with 2,4-dinitrophenylhydrazine and steps by heating the reaction mixture at 901C, 8 min, for the first
a sample was analysed by HPLC with UV detection at 360 nm step and then at 1501C for the second step. We checked,
(Figure 4). The UV trace showed only one peak at 10.3 min, previously, using a Merck aldehyde colorimetric test kit, that no
which was the retention time of 2,4-dinitrophenylhydrazine. oxidation of ethylene di-p-toluenesulphonate with DMSO
Radio-HPLC trace showed a single peak that was identified as occurred below 1001C. Nevertheless, in our hands, the first-step
[18F]fluoroacetaldehyde-2,4-DNPH on the basis of both retention reaction of [18F]fluoride with ethylene di-p-toluenesulphonate to
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J. Label Compd. Radiopharm 2008, 51 262–267

C. Prenant et al.
Figure 5. HPLC analysis of the reaction mixture of [18F]fluoroacetaldehyde with benzylamine (traces a and b) Trace c: co-injection of N-(2-fluoroethyl)-benzylamine
standard with the reaction mixture.
produce [18F]FETos generated
acetonitrile, 75–88%, than in DMSO, 69–75%, for 8 min reaction
time (based on four experiments, analyses carried out by radio-
thin layer chromatography (radio-TLC)).
a slightly higher yield in
Experimental
Materials
Chemicals and solvents were purchased from Sigma-Aldrich
Company Ltd. (Gillingham, UK) and were used without further
purification. The aldehyde colorimetric test kit (formaldehyde
test) was purchased from Merck Chemicals Ltd. (Nottingham,
UK). HPLC solvents and a ready-to-use commercial cyanobor-
ohydride PBS solution (cyanoborohydride coupling buffer) were
obtained from Sigma. The coupling solution is made up of
0.02 M sodium phosphate, pH 7.5, containing 0.2 M sodium
chloride and 3.0 g/l sodium cyanoborohydride.
[18F]fluoride was produced via the 18O(p,n)18F nuclear
reaction by 16.4 MeV proton bombardment of an isotopically
enriched [18O] water target (95–97% H128O water enrichment)
using a GE PETtrace cyclotron at the Wolfson Molecular Imaging
Centre, Manchester, UK, or provided by the Douglas Cyclotron
Unit of the Clatterbridge Centre for Oncology, UK.
Reaction of
[
18F]fluoroacetaldehyde with benzylamine,
synthesis of [18F]N-(2-fluoroethyl)-benzylamine
The oxidation of [18F]FETos with DMSO is very fast and the
oxidation reaction mixture was distilled, as the reaction
proceeded as mentioned above, into a vial containing a solution
of benzylamine and sodium cyanoborohydride in a mixture of
phosphate-buffered saline (PBS) and acetonitrile. Acetonitrile
was used to increase the solubility of benzylamine in the
mixture. Radioactivity trapped into the benzylamine solution
was monitored and started to be detected and increased less
than 1 min after the temperature of the reactor had reached
1501C and was at its maximum after 7–8 min.
The alkylation reaction mixture was analysed by reverse-phase
HPLC after a 10 min reaction at 501C. The UV trace (Figure 5,
trace a) showed only benzylamine eluting at 8.5 min. The
radioactivity trace (Figure 5, trace b) showed three main
radioactive peaks: a first one at 5.0 min that was decreasing in
intensity as the [18F]fluoroethylation reaction proceeded and
was inferred to be unreacted [18F]fluoroacetaldehyde, a second
one at 5.8 min that was not identified and the third one at
13.5 min that coeluted with stable N-(2-fluoroethyl)-benzylamine
(Figure 5, trace c) and was thereby identified as [18F]N-(2-
fluoroethyl)-benzylamine. The radioactive fractions were col-
lected and the radioactivity measured. [18F]N-(2-fluoroethyl)-
benzylamine was produced with an overall radiochemical yield
of 17% (decay corrected).
Wheaton borosilicate screw-top V-vials, capacity 3.0 and 1 ml,
with open-top cap and PTFE-faced silicon septum from Aldrich
were used for the radiosyntheses.
TLC was performed on Fluka silica gel plates (20 ꢁ 20 cm,
250 mm thickness). Radio-TLC plates were analysed with an
instant phosphor imager (Packard).
Radioactivity was monitored using a Ratemeter Mini 900 from
Thermo Electron Corporation.
HPLC analyses of N-(2-fluoroethyl)-benzylamine and [18F]N-(2-
fluoroethyl)-benzylamine were carried out on a Varian ProStar
210 solvent delivery system equipped with a semi-preparative
C18 column (mBondapakTM, 10 mm particle size; 300 ꢁ 7.8 mm
i.d.; Waters Ltd., Elstree, UK). The eluate was monitored for
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C. Prenant et al.
absorbance (254 nm; model 325; Varian) and simultaneously for addition was complete, stirring was continued for 30 min.
radioactivity with a Bioscan PM Flow-count detector. Collected Potassium hydroxide (600 mg) was then added, and stirring
radioactive peaks were measured on a Capintec CRC-15R.
was continued until it was completely dissolved. The reaction
HPLC analyses of fluoroacetaldehyde, fluoroacetaldehyde-2,4- mixture was filtered through a PTFE membrane syringe filter,
DNPH, [18F]fluoroacetaldehyde and [18F]fluoroacetaldehyde-2,4- Acrodiscs, and the methanol evaporated with a rotary evapora-
DNPH were carried out on a Shimadzu prominence system tor at 501. The resulting oil was dissolved in chloroform and
operated using a LabLogic software Laura 3 and configured with purified on
a silica column. Elution with chloroform–2%
a CBM-20A controller, an LC-20AB solvent delivery system and a methanol–0.5% triethylamine followed by evaporation of the
SPD-20A absorbance detector. The system was equipped with a collected fraction afforded 0.743 g, 54% yield, of N-(2-fluor-
Luna C18, 5 mm particle size, 250 ꢁ 10 mm Phenomenex column. oethyl)-benzylamine as an oil. HPLC: water/acetonitrile (70:30 v/v)
Radioactivity was monitored with a radio-HPLC Bioscan Flow- with 0.1% triethylamine, flow rate: 6 ml/min, Rt = 13.2 min. ESI-MS:
count B-FC 3100 detector.
m/z = 154.18 [M1H]1. 1H NMR (CD3COCD3) d: 2.81 (dt, 2H,
1H NMR spectra were recorded on a Bruker DPX 400 MHz J = 25.7, 4.6Hz), 3.71 (s, 2H, ArCH2NH), 4.55 (dt, 2H, J = 47.1,
spectrometer Tetramethylsilane was used as internal reference. 4.7Hz), 7.25 (t, 1H, J = 6.8Hz), 7.33 (t, 1H, J = 7.1Hz), 7.43 (d, 2H,
19F NMR spectra were recorded on a Bruker DPX 200 MHz J = 7.3Hz). 19F-NMR (CD3COCD3) d: ꢀ144.84.
spectrometer.
Mass spectra (electrospray) of N-(2-fluoroethyl)-benzylamine
were acquired on a Micromass Quattro II LC/MS.
Radiochemistry
[18F]potassium fluoride
Mass spectra of fluoroacetaldehyde-2,4-DNPH were recorded
on a Shimadzu-Biotech Axima TOF-TOF MALDI instrument.
The aqueous [18F]fluoride solution (0.3–0.5 ml, 100–150 MBq)
was added to an open 3 ml conical vial containing potassium
carbonate (1.1 mg, 8 mmol) and Kryptofixs 222 (10 mg,
26.5 mmol). After addition of 1 ml of acetonitrile, the mixture
was dried under argon at 1101C. This drying step was repeated
twice with 1 ml of acetonitrile.
Synthesis of the standard compounds
Synthesis of fluoroacetaldehyde
Fluoroethanol (62 ml, 1 mmol) was added in one portion to the
magnetically stirred solution of PDC (576 mg, 1.5 mmol) in
anhydrous dichloromethane (1.5 ml). The mixture was left, under
stirring, at room temperature for 24 h. After removal of the
precipitate by filtration (syringe filter with PTFE membrane,
Acrodiscs), the reaction mixture was heated at 801C and the
volatiles were distilled into 1 ml of water. The aqueous phase
was then extracted from the distillate, presence of aldehyde was
checked using the Merck aldehyde colorimetric test kit and a
sample was analysed by HPLC (eluent: water, flow rate: 2 ml/
min) with UV detection at 277 nm. The HPLC trace showed a
single peak with a retention time of 8.0 min.
2-[18F]fluoroethyltosylate
To the dried Kryptofix/[18F]fluoride complex was added a
solution of ethylene di-p-toluenesulphonate, 5 mg (13.5 mmol)
in 0.3 ml acetonitrile, the vial was sealed and the mixture was
heated 8 min at 901C. [18F]fluoride was incorporated into 2-
[
chloroform–methanol, 96:4, Rf = 0.82).
18F]fluoroethyltosylate with 75–88% yield (radio-TLC:
[18F]fluoroacetaldehyde
The evaporation of the acetonitrile at 601C, under nitrogen, was
followed by addition of 0.2 ml of anhydrous DMSO and
[18F]fluoroacetaldehyde was distilled at 1501C for 4 min, carried
on at 1301C for another 4 min and conveyed by nitrogen
(7–8 ml/min) into water (50 ml) in a second reaction vial. A
sample was analysed by HPLC with UV detection at 277 nm
(eluent: water, flow rate: 2 ml/min, Rt = 8.2 min).
Synthesis of fluoroacetaldehyde-2,4-DNPH
To 0.5 ml of the aqueous fluoroacetaldehyde solution were
added 0.8 ml of 2,4-dinitrophenylhydrazine and phosphoric acid
solution (ꢂ0.2 M) and the mixture was left for 15 min at 901C.
Purification of the crude product was accomplished using HPLC
(eluent: acetonitrile/water 50:50, flow rate: 3 ml/min) with UV
detection at 360 nm. HPLC trace showed two main peaks at
10.4 min, retention time of 2,4-dinitrophenylhydrazine, and
24.5 min, the last one was collected and analysed by MALDI
mass spectrometry. A sample (1 ml) of the HPLC fraction was
pipetted onto the target plate and analysed without additional
matrix in both positive and negative mode: [M11]1 = 243.00
and [Mꢀ1]ꢀ = 241.23 (lit.28 M1 = 242.0451).
[18F]fluoroacetaldehyde-2,4-DNPH
A fraction of the distillate (30 ml) was added to a solution of 2,4-
dinitrophenylhydrazine (25 ml, ꢂ5 mmol) in ethanol (60 ml) and
the mixture was heated at 901C for 15 min. A sample was
analysed by HPLC with UV detection at 360 nm (eluent:
acetonitrile/water 50:50, flow rate: 3 ml/min, Rt = 24.8 min).
Synthesis of N-(2-fluoroethyl)-benzylamine
[18F]N-(2-fluoroethyl)-benzylamine
A solution of 1 g (10 mmol) of 2-fluoroethylamine hydrochloride
in 6 ml of methanol was prepared in a 25 ml round-bottom flask.
Potassium hydroxide (160 mg) was added in one portion to the
magnetically stirred solution. When it was completely dissolved,
0.92 ml (9 mmol) of benzaldehyde was added in one portion. The
resulting mixture was stirred at room temperature for 15min
before a solution of 200 mg (3.18mmol) of sodium cyanobor-
ohydride in 2 ml methanol was added dropwise. After the
[18F]fluoroacetaldehyde was trapped at room temperature in
80 ml of cyanoborohydride coupling buffer (sodium cyanobor-
ohydride content 3.8 mmol) to which 20 ml of a benzylamine
solution in acetonitrile (0.5 M) was added. The reaction mixture
was then heated for 10 min at 501C before being analysed by
HPLC (eluent: water/acetonitrile 70:30 with 0.1% triethylamine,
flow rate: 6 ml/min, Rt = 13.5 min).
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We have described a fast and simple procedure to produce
[18F]fluoroacetaldehyde in a two-step, one-pot reaction using
oxidation with DMSO of [18F]FETos. The [18F]labelled aldehyde
was extracted continuously by distillation from the reaction
mixture. The distilled radioactivity accounted for 31–37% (yield
based on three experiments and decay corrected) of the initial
radioactivity as aqueous [18F]HF and [18F]fluoroacetaldehyde
was inferred from HPLC analyses to be the main component of
the radioactivity distilled. It was characterized as the 2,4-DNPH
derivative as well as the product of the reaction with
benzylamine used as the model substrate to test [18F]fluoroa-
cetaldehyde reactivity with primary amines under reductive
alkylation conditions. This new [18F]fluoroethylating agent may
be useful for the generation of labelled peptides, proteins and
antibody fragments as it reacts in mild conditions, PBS and at a
low temperature. In addition to its use as a [18F]fluoroethylating
agent of amines [18F]fluoroacetaldehyde may find applications
in the Mannich reaction as well as in aldol condensations.
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Acknowledgement
¨
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