Copper-mediated reduction of 2-[18F]fluoroethyl azide to 2-[18F]fluoroethylamine

Article abstract of DOI:10.1002/jlcr.2945

¹⁸F-labelled fluoroalkylamines are attractive reagents for the preparation of positron emission tomography tracers containing amine, amide, and N-heterocyclic moieties. Herein, we report that 2-[¹⁸F] fluoroethylamine can be obtained from 2-[¹⁸F]fluoroethyl azide by reduction with elemental copper under acidic conditions. Azide to amine reduction was achieved in near quantitative analytical yields within 30 min by heating a solution of 2-[¹⁸F]fluoroethyl azide in the presence of copper wire and aqueous trifluoroacetic acid. Subsequent reaction of 2-[ ¹⁸F]fluoroethylamine with benzoyl chloride in the presence of triethylamine provided N-[¹⁸F]fluoroethyl benzamide in 63% decay-corrected radiochemical yield from 2-[¹⁸F]fluoroethyl azide. The utility of the Cu(0)/H⁺ azide reduction method was further exemplified by preparation of the potential GABA_A tracer 9H-β-carboline N-2-[¹⁸F]fluoroethylamide, which was obtained in 46% decay-corrected radiochemical yield by reaction of 2-[¹⁸F] fluoroethylamine with the corresponding 9H-β-carboline pentafluorophenyl ester. Copyright

Full text of DOI:10.1002/jlcr.2945

Research Article
Received 29 February 2012,
Revised 31 May 2012,
Accepted 15 June 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.2945
Copper-mediated reduction of 2-[18F]fluoroethyl
azide to 2-[18F]fluoroethylamine†
a{
b
b
Matthias Glaser,a,b Erik Årstad, Alessandra Gaeta, James Nairne,
*
William Trigg,b and Edward G. Robinsa,b}
18F-labelled fluoroalkylamines are attractive reagents for the preparation of positron emission tomography tracers containing
amine, amide, and N-heterocyclic moieties. Herein, we report that 2-[18F]fluoroethylamine can be obtained from
2-[18F]fluoroethyl azide by reduction with elemental copper under acidic conditions. Azide to amine reduction was achieved
in near quantitative analytical yields within 30min by heating a solution of 2-[18F]fluoroethyl azide in the presence of copper
wire and aqueous trifluoroacetic acid. Subsequent reaction of 2-[18F]fluoroethylamine with benzoyl chloride in the presence of
triethylamine provided N-[18F]fluoroethyl benzamide in 63% decay-corrected radiochemical yield from 2-[18F]fluoroethyl azide.
The utility of the Cu(0)/H+ azide reduction method was further exemplified by preparation of the potential GABAA tracer
9H-b-carboline N-2-[18F]fluoroethylamide, which was obtained in 46% decay-corrected radiochemical yield by reaction of
2-[18F]fluoroethylamine with the corresponding 9H-b-carboline pentafluorophenyl ester. Copyright © 2012 John Wiley & Sons, Ltd.
Keywords: PET; fluorine-18; azide; amine; copper catalysis; acylation
Introduction
Results and discussion
Fluorine-18 has near ideal decay properties (half-life 110 min) In order to indirectly identify the nature of the polar radioactive
for imaging with positron emission tomography (PET),1,2 side-product observed when treating azide [18F]1 with elemental
however, the limited scope of fluoride chemistry and the copper under acidic conditions, we first altered the reaction
tendency of H-bond donors to curb nucleophilic reactions with conditions to obtain the putative amine [18F]2 as major product.
[
18F]fluoride make the preparation of 18F-labelled PET tracers By heating a solution of azide [18F]1 in water and acetonitrile
challenging. Extensive efforts have therefore been made to (50% v/v) to 60 ꢀC in the presence of copper powder and
develop reagents for indirect labelling with 18F,3–9 yet access trifluoroacetic acid (5% v/v) for 15 min, we obtained the polar
to primary [18F]fluoroalkylamines remains limited.10,11 More side-product [18F]2 in 97% analytical radiochemical yield
recently, the traceless Staudinger ligation has been utilised to (Table 1, entry 3). Copper wire proved to be similarly efficient for
generate [18F]fluoroethylamides.12–14 During our previous work this reaction (Table 1, entry 9). Figure 1 shows the corresponding
to develop 2-[18F]fluoroethyl azide ([18F]1, Scheme 1) as a reagent HPLC profile. Subsequent reaction with benzoyl chloride in the
for the copper-catalysed azide–alkyne cycloaddition (CuCAAC, presence of excess triethylamine provided amide [18F]3 in 63%
click labelling),5,15 we observed formation of an unknown side- radiochemical yield (referring to azide [18F]1, see Table 2). An
product when azide [18F]1 was treated with copper powder analytical HPLC profile of the reaction mixture containing [18F]2
under acidic conditions. We have now identified this species is shown in Figure 2. Co-elution with the non-radioactive
as 2-[18F]fluoroethylamine ([18F]2) and modified the reaction reference compound 3 allowed us to confirm the identity of
conditions to obtain amine [18F]2 in near quantitative radiochemical
yield from 2-[18F]fluoroethyl azide ([18F]1). It should be noted that
aGE Healthcare, Medical Diagnostics, Hammersmith Hospital, London W12
ONN, UK
amine [18F]2 has previously been prepared using cumbersome and
low yielding protection–deprotection strategies.10 The method
bGE Healthcare, Medical Diagnostics, The Grove Centre, Amersham, HP7 9LL, UK
reported herein presents a more convenient and better yielding
route to amine [18F]2 for acylation, alkylation or cyclisation reactions.
*Correspondence to: Matthias Glaser, GE Healthcare, Medical Diagnostics,
Hammersmith Hospital, London W12 ONN, UK.
In addition, elemental copper is an attractive alternative to
organic reducing agents, such as phosphines, which lead to
formation of by-products that often are difficult to remove.16,17
Copper can also be applied in the form of a coiled wire, or poten-
tially as copper tubing, making it particularly suited for automation.
We have exemplified the utility of the Cu(0)/H+ azide reduction
method for preparation of the model compound N-[18F]fluoroethyl
benzamide ([18F]3), and 9H-b-carboline 2-[18F]fluoroethylamide
([18F]4) as a potential tracer for the GABAA receptor.18
E-mail: matthias.glaser@ge.com
† Parts of this article have been already presented at the 19th International Sym-
posium on Radiopharmaceutical Sciences, Amsterdam, The Netherlands, 28
August–2 September 2011.
{ Institute of Nuclear Medicine, University College London, London NW1 2BU, UK.
} Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and
Research (A*STAR), Singapore 138667.
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Copyright © 2012 John Wiley & Sons, Ltd.

M. Glaser et al.
Scheme 1. Preparation of 2-[18F]fluoroethylamine ([18F]2) and formation of acylation products [18F]3 and [18F]4. Reagents and conditions: (i) (a) K2CO3/Kryptofix, (b) 2-azidoethyl
tosylate, acetonitrile, 15 min at 80 ꢀC (c) distillation; (ii) H2O/10% TFA (v/v), copper powder or wire, 30min at 80ꢀC; (iii) BzCl/NEt3; (iv) 5/NEt3, 50min at 60ꢀC.
Table 1. Copper-mediated reduction of 2-[18F]fluoroethyl azide ([18F]1) to amine [18F]2
Volume of 1
(mL)a
Copper
catalyst
Reaction
time (min)
Reaction
Radiochemical
yield (%)b
No.
1
Additive
temperature (ꢀC)
50
50
Cu powder
(À200 mesh)
Cu powder
(À200 mesh)
Cu powder
(À200 mesh)
Cu wire
(ꢀ 0.25 mm)
Cu wire
(ꢀ 0.02 mm)
CuSO.45H2O
(5 mg,
H2O/5% TFA (v/v, 50 mL)
15
30
15
15
15
30
Room temperature
45
61
97
69
60
6
2
3
4
5
6
H2O/5% TFA (v/v, 50 mL)
H2O/5% TFA (v/v, 50 mL)
H2O/5% TFA (v/v, 100 mL)
H2O/5% TFA (v/v, 100 mL)
Room temperature
50
60
60
60
60
100
100
50
H2O (100 mL), ascorbic
acid (10.6 mg, 60 mmol),
HCl (37%, 50 mL)
H2O (100 mL), ascorbic
acid (10.6 mg, 60 mmol),
TFA (45 mL)
20 mmol)
7
8
55
55
CuSO.45H2O
(5 mg,
30
30
60
60
3
20 mmol)
CuI.P(OMe)3
(6.3 mg,
H2O (100 mL), TFA (45 mL)
28
20 mmol)
Cu wire
(ꢀ 0.1 mm)
Cu wire
(ꢀ 0.1 mm)
Cu wire
(ꢀ 0.1 mm)
Cu wire
(ꢀ 0.1 mm)
Cu wire
9
100
100
100
100
40
H2O/10% TFA (v/v, 100 mL)
H2O/17% HCl (v/v, 100 mL)
30
30
30
30
30
80
80
80
80
80
91 Æ 3c
12
10
11
12
13
H2O/20% H3PO4
(v/v, 100 mL)
H2O/20% H2SO4
(v/v, 100 mL)
H2O/10% MeSO3H
(v/v, 40 mL)
97
98
94
(ꢀ 0.1 mm)
aDistilled in MeCN.
bMeasured by analytical HPLC.
cn = 4.
the polar side-product as 2-[18F]fluoroethylamine ([18F]2). The reduc- acid, and methane sulfonic acid, which provided amine [18F]2 in
tion step was found to be equally efficient when trifluoroacetic acid analytical yields of 97%, 98%, and 94%, respectively. However, the
was replaced with other acids including phosphoric acid, sulfuric use of hydrochloric acid was found to be far less efficient and gave
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M. Glaser et al.
cps
cps
70000.0
7000.0
6000.0
5000.0
4000.0
3000.0
2000.0
1000.0
60000.0
50000.0
40000.0
30000.0
20000.0
10000.0
0.0
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3
2
1
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Figure 2. Semi-preparative HPLC of crude mixture from the reaction of amine
18F]2 and benzoyl chloride to produce amide [18F]3 (Top: radioactivity channel,
bottom: UV channel at 254 nm).
Figure 1. Analytical HPLC using semi-preparative system after reacting azide
18F]1 with aqueous TFA and copper wire at 60 ꢀC to form amine [18F]2 (Top:
radioactivity channel, bottom: UV channel at 254 nm).
[
[
amine [18F]2 in only 12% analytical radiochemical yield based on 2-
[18F]fluoroethyl azide ([18F]1). Table 1 gives a summary of our experi-
ments to optimize the radiochemical yield of [18F]2. The reaction
occurred only to a limited extent when using homogeneous systems
such as copper(II) sulfate/ascorbic acid, or iodo(trimethylphosphite)
copper(I) in the presence of acids (Table 1, entries 6–8). Scheme 2
outlines a potential mechanism for the Cu(0)/H+-mediated reduction
of azide [18F]1. We propose that protonation of the azide group leads
to attack by Cu(0), followed by release of nitrogen gas to yield amine
[18F]2 and formation of Cu(II) salts.
In our first experiments, we used copper powder for the
reduction of azide [18F]1 to amine [18F]2; however, although
the reduction step proceeded in excellent analytical yields, the
overall efficiency of the process was poor because of retention
Table 2. Formation of the amides [18F]3 and [18F]4 via one-pot reduction/acylation radiochemistry
Acylation reaction
Azide
reduction
Radiochemical
yield (%)c
a
No.
1
Compound
Reactants
Temperature (ꢀC)b
60
[18F]3
TFA
BzCl (19 mL, 162 mmol), NEt3
(79 mL, 649 mmol)
BzCl (19 mL, 162 mmol), NEt3
(79 mL, 649 mmol)
5 (4 mg, 10.6 mmol), DMF
(50 mL), NEt3 (27 mL, 227 mmol)d
5 (4 mg, 10.6 mmol), DMF
(50 mL), NEt3 (36 mL, 308 mmol)
5 (4 mg, 10.6 mmol), DMF
(50 mL), NEt3 (90 mL, 770 mmol)
63
47
16
46
2
3
4
5
[18F]3
[18F]4
[18F]4
[18F]4
TFA
Room temperature
TFA
80
80
80
MeSO3H
MeSO3H
e
40
a[18F]1 in MeCN (35–100 mL) added to equal volume of acid (10% v/v) over copper wire, followed by heating (30 min at 80 ꢀC).
bReaction time 15 min.
cIsolated radiochemical yield, decay-corrected referring to starting azide [18F]1.
dAzide reduction and acylation reaction in separate vials.
eMean value, n = 2.
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M. Glaser et al.
cps
70000.0
4
60000.0
50000.0
40000.0
30000.0
20000.0
10000.0
0.0
2
1
0:00
5:00
10:00
15:00
20:00mm:ss
Scheme 2. Proposed reaction mechanism for the Cu(0)/H+-mediated azide reduction.
mAU
2200.0
2000.0
1800.0
1600.0
1400.0
1200.0
1000.0
800.0
600.0
400.0
200.0
0.0
of amine [18F]2 on the copper powder. We also encountered
practical difficulties during the isolation of [18F]2 when removing
excess copper powder by filtration. The use of coiled copper wire
in the presence of aqueous methane sulfonic acid resolved these
issues and allowed us to develop an efficient and practical
method for Cu(0)/H+-mediated reduction of azide 1.
To investigate the suitability of the Cu(0)/H+-mediated
reduction of azide [18F]1 for preparation of PET tracers, we turned
our attention to carboline [18F]4 (Scheme 1), a potential tracer for
imaging of GABAA receptors.18,19 Our previous attempts to prepare
carboline [18F]4 by direct labelling of the corresponding tosylate
precursor with [18F]fluoride were unsuccessful, potentially because
of ring closure to yield an oxazoline moiety.20,21 Initially, we
transferred amine [18F]2 from the reduction vial into a second vial
for the acylation reaction. Subsequent addition of carboline
0:00
5:00
10:00
15:00
20:00mm:ss
Figure 3. Semi-preparative HPLC of the crude mixture from the reaction of amine
18F]2 with active ester 5 to produce amide [18F]4 (Top: radioactivity channel, bottom:
UV channel at 254nm).
[
pentafluorophenyl ester
5 and triethylamine provided the
carboline [18F]4 in an isolated radiochemical yield of 16%
be obtained from 2-[18F]fluoroethyl azide ([18F]1) by reduction with
elemental copper under acidic conditions. Conveniently, the
method can be used to obtain 2-[18F]fluoroethylamides from
2-[18F]fluoroethyl azide ([18F]1) in a one-pot procedure by reaction
of the intermediate amine [18F]2 with acyl chlorides or active
esters. Copper-mediated azide reduction is practical and high
yielding and offers an attractive alternative to the use of
phosphines or hydrogenation,22 which may be problematic to
incorporate in automated radiosyntheses. Finally, it may be
possible to extend the scope of the reaction to allow reduction
of other radiolabelled azides.
(decay-corrected and based on azide [18F]1, see Table 2).
Conveniently, when the two-step reaction sequence was carried
out in a one-pot procedure, the decay-corrected radiochemical yield
increased to 46% (based on azide [18F]1). It is plausible that the amine
[18F]2 can react with the ester 5 even when adsorbed on the surface
of elemental copper and that the superior radiochemical yield
observed for the one-pot procedure reflects increased availability
of the intermediate [18F]2. Figure 3 shows the semi-preparative radio
HPLC profile of the crude reaction mixture. However, as our aim was
to assess the feasibility of the copper-mediated reduction of azide
[18F]1 for PET tracer development, we have yet to attempt labelling
with high levels of radioactivity and to develop suitable separation
methods to obtain acylation products [18F]3 and [18F]4 free of
non-radioactive side-products. The model compound [18F]3 was
accompanied by a relatively low level of non-radioactive by-products,
whereas formation of [18F]4 led to a complex reaction mixture. Our
explorative studies suggest that the amount of non-radioactive
impurities that are formed in the reaction depends on the substrate
used, and that in some cases, purification of 2-[18F]fluoroethylamine
([18F]2) may be needed. Further studies are required to determine
the specific activity that can be obtained with the Cu(0)/H+ method
for azide reduction, as well as to explore the scope of the method
for other 18F-labelled azides.
Experimental
General
1H NMR spectra were recorded on JEOL Lambda (300 or 400 MHz)
spectrometers (Akishima, Tokyo, Japan). Chemical shifts (d) are reported in
parts per million downfield from the internal standard tetramethylsilane
(TMS). Mass spectra (ESI) analyses were carried out on a Finnigan
Surveyor MSQ with autosampler (Cambridge, MA, USA) and photodiode
array detector using a Phenomenex Gemini C18 column (Torrance, CA,
USA), 110 Å, 3 mm, 30 Â 3.00mm with a 5–95% acetonitrile/water gradient
over 3 minutes. All starting materials were obtained from commercial
sources and used without further purification. Flash chromatography was
performed using a Companion system (Presearch Ltd, Basingstoke, UK).
No-carrier-added aqueous [18F]fluoride was produced from the 18O(p,n)18F
reaction (PET trace cyclotron, GE Medical Systems, Waukesha, WI, USA) by
the irradiation of an isotopically enriched [18O]H2O target using a 16.4MeV
proton beam. The analytical radio HPLC comprised of a Beckman System
GoldW pump (Brea, CA, USA) [column Luna C18, 50 Â 4.6 mm, 3 mm, solvent
Conclusion
18F-labelled fluoroalkylamines are useful reagents for the pre-
paration of PET tracers containing amine, amide, and N-heterocyclic
moieties. Herein, we report that 2-[18F]fluoroethylamine ([18F]2) can A: water (0.1% TFA), solvent B: acetonitrile (0.1% TFA), flow 1 mL/min, gradient
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M. Glaser et al.
Preparation of 2-[18F]fluoroethylamine ([18F]2)
5–80% solvent B in 15 min, l = 254 nm]. The system was equipped with a
gamma detector (Bioscan Flow-count, FC3300 NaI PMT or FC3400 PIN diode)
and a UV detector (Linear UV–VIS 200). The semi-preparative radio HPLC used
a Phenomenex Onyx column, 100 Â 10 mm, solvent A: water (0.1% TFA),
solvent B: acetonitrile (0.1% TFA), flow rate 3 mL/min, gradient 5–80% solvent
B in 15min, l =254nm.
To a conical glass vial (Wheaton, 2 mL) was added a plug of copper wire
(0.1 mm, 90–110 mg), acid (100 mL, 20% in water), and 2-[18F]fluoroethyl azide
([18F]1) (100mL, 10–12 MBq, prepared as previously described23). The vial was
heated at 80 ꢀC for 30 min and an aliquot analyzed by HPLC. The product
peak eluted with the solvent front (tR =45s). 2-[18F]Fluoroethylamine ([18F]2)
was similarly prepared using 10% phosphoric acid, 10% sulfuric acid, or
10% methane sulfonic acid.
Preparation of N-fluoroethyl benzamide ([19F]3)
To
a stirring solution of 2-fluoroethylamino hydrochloride (273 mg,
Preparation of [18F]N-fluoroethyl benzamide ([18F]3)
2.74 mmol) and potassium carbonate (1.38 g, 10 mmol) in water (4mL) in
an ice bath was added benzoyl chloride (424mg, 3.02 mmol). The reaction
mixture was allowed to warm up to room temperature and the stirring
was continued overnight. After extraction into ethyl acetate, the product
was purified by flash chromatography using gradient elution with
hexane/ethyl acetate (10mL/min, linear gradient: 10–100% ethyl acetate
in 10 min). Yield: 294mg (64%), white solid, mp 38–43 ꢀC
A Wheaton vial (2 mL) was charged with coiled copper wire (0.1 mm, 185 mg),
2-[18F]fluoroethylazide (54 MBq) in acetonitrile (100 mL), and aqueous TFA
(100 mL, 10% v/v). The sealed vial was heated at 80 ꢀC for 30 min. After cooling
to room temperature, triethylamine (79 mL, 0.649 mmol) and benzoyl chloride
(19 mL, 0.162 mmol) were added. The vial was then heated at 60 ꢀC for 15min.
After quenching with water (0.2 mL) containing TFA (0.1% v/v), the reaction
mixture was injected into semi-preparative HPLC. The product [18F]3 was
isolated with a decay-corrected radiochemical yield of 63% based on starting
azide [18F]1. The radiochemical purity of the product was >99%.
1H NMR (CDCl3): d 3.75 (1H, m, NH-CH2), 3.81 (1H, m, NH-CH2), 4.56
(1H, t, J = 3.5 Hz, F-CH2), 4.65 (1H, t, J = 3.5 Hz, F-CH2), 6.51 (1H, m, NH),
7.48 (3 H, m, H-Ar), 7.79 (2H, m, H-Ar).
Preparation 9H-b-carboline-3-carboxylic acid pentafluorophenyl
ester (5)
Two-pot preparation of 9H-b-carboline-3-carboxylic acid (2-[18F]
fluoroethyl)amide ([18F]4)
9H-b-carboline-3-carboxylate ethyl ester (1 g, 4.4 mmol) was suspended
in THF (50 mL). Lithium hydroxide (106 mg, 4.4 mmol) was added,
followed by water (10 mL). The reaction mixture became a clear solution.
The mixture was stirred at room temperature until judged complete by
TLC. The precipitated solid was filtered off and dried in vacuo to give 1.1 g
of a colourless solid (quantitative).
2-[18F]fluoroethyl azide (63MBq) in acetonitrile (35mL) was added to a
Wheaton vial containing a plug of copper wire (0.1mm, 114 mg), followed
by a solution of TFA in water (10%, 45 mmol, 35mL). After heating for
30 min at 80 ꢀC, more acetonitrile (50 mL) was added and the reaction
solution transferred into another vial. Triethylamine (27mL, 227 mmol) was
added followed by a solution of active ester 5 (4 mg, 10.6 mmol) in DMF
(50 mL). The mixture was heated for 15min at 80ꢀC and filtered (Eppendorf
pipette tip with plug of tissue). The filter was rinsed with additional
acetonitrile (100mL). HPLC mobile phase (150mL) was added to the
combined filtrate. Purification of the crude reaction mixture was performed
by semi-preparative HPLC. The isolated and decay-corrected radiochemical
yield of title compound was 16% (referring to starting 2-[18F]fluoroethyl
azide). The radiochemical purity was >99%. The collected HPLC product
fraction was diluted with water (1mL) and loaded onto a SepPak-C18 light
cartridge that had been conditioned with ethanol (5mL) and water (10 mL).
The cartridge was flushed with water (5mL). The product was eluted with
ethanol in fractions of 0.1mL. The formulated title compound was obtained
in a total volume of 0.3mL with 3MBq. The formulation efficiency was 91%.
1H NMR (D6-DMSO): d 6.95 (1H, br t, 6-CH), 7.28 (1H, br t, 7-CH), 7.59
(1H, d, J = 7.5 Hz, 8-CH), 8.12 (1H, br d, 5-CH), 8.66 (1H, s, 4-CH), and 8.72
(1H, s, 1-CH).
Lithium 9H-b-carboline-3-carboxylate (460 mg, 2.2mmol) was treated
with thionyl chloride (5mL) and a catalytic amount of DMF was added.
The mixture heated at reflux for 3 h. The thionyl chloride was evaporated
and the residue dissolved in dry dichloromethane (10 mL) was added,
followed by a solution of pentafluorophenol (404mg, 2.2mmol) in
dichloromethane (5mL) and diisopropylethylamine (284 mg, 2.2mmol,
0.38 mL). The mixture was stirred at ambient temperature for 16h. The
precipitated solid was filtered off and dried in vacuo to give active ester 5.
1H NMR (D6-DMSO): d 7.51 (1H, t, J = 7.4 Hz, 6-CH), 7.84 (1H, t, J = 7.7 Hz,
7-CH), 7.92 (1H, d, J = 5.8 Hz, 8-CH), 8.70 (1H, d, J = 8.0 Hz, 5-CH), 9.25
(1H, s, 4-CH), and 9.42 (1H, s, 1-CH).
One-pot preparation of 9H-b-carboline-3-carboxylic acid (2-[18F]
fluoroethyl)amide ([18F]4)
19F NMR (282MHz) (D6-DMSO): d -162.3 (2F, t, JFF = 25.0 Hz, 3,5-CF), -157.8
(1F, t, JFF = 23.0Hz, 4-CF), and À153.4 (2F, d, JFF = 21.0 Hz, 2, 6-CF).
m/z 378.0 calcd for C18H7F5N2O2; found 379.0 (M + H)+.
A Wheaton vial (1 mL) was charged with a plug of copper wire (116 mg,
Goodfellow, Cat. No. CU005240/1), aqueous methanesulfonic acid
(100 mL, 14.8 mg, 0.154 mmol, 10% v/v), and 2-[18F]fluoroethylazide
(459 MBq) in acetonitrile (100 mL). After heating for 30 min at 80 ꢀC,
triethylamine (90 mL, 0.770mmol) was added. A solution of active ester 5
(4mg, 10.6mmol) in DMF (50mL) was added. The mixture was incubated
for 15 min at 80 ꢀC and subsequently diluted with acetonitrile (100mL).
The reaction solution was filtered (PTFE Acrodisc, 0.45 mm) and injected
onto the semi-preparative HPLC. The decay-corrected radiochemical yield
of the title compound with reference to 2-[18F]fluoroethyl azide was 46%.
The preparation time including formulation was 163 min.
Preparation of 9H-b-carboline-3-carboxylic acid (2-[19F]fluoroethyl)
amide ([19F]4)
Lithium 9H-b-carboline-3-carboxylate (150mg, 0.62 mmol) was suspended
in thionyl chloride (10 mL). A catalytic amount of dry DMF was added and
the reaction heated at reflux for 2 h. During this time, the solid dissolved.
The thionyl chloride was evaporated and the acid chloride was
used without further purification. The resulting acid chloride (150 mg,
0.62mmol) was dissolved in dichloromethane (50 mL). 2-Fluoroethylamine
hydrochloride (0.2g, 2.1mmol) and triethylamine (0.11 g, 1.1mmol) in
dichloromethane (10mL) were added and the mixture was stirred at room
temperature for 16 h. The solvent was evaporated and the residues
purified over silica gel (9:1 dichloromethane: methanol for 15 column
volumes followed by a gradient to 7:3 dichloromethane : methanol over
five column volumes).
Conflict of Interest
The authors did not report any conflict of interest.
HPLC Phenomenex Gemini 3 mm, water : acetonitrile 30–70% at 1 mL/min
over 30 min: tR =7.42min; 98%
References
1H NMR (D6-DMSO): d 3.68 (2H, dt, JHF = 25.5 Hz, JHH = 5.2Hz, CH2NH), 4.60
(2H, dt, JHF = 47.5Hz, JHH = 5.2Hz CH2F), 7.31 (1H, t, J= 7.3Hz, 6-CH), 7.60 (1H,
t, J= 7.5Hz, 7-CH), 7.68 (1H, d, J = 8.3Hz, 5-CH), 8.41 (1H, d, J = 7.6Hz, 8-CH),
8.85 (2H, m, 4-CH, NHCH2), 8.90 (1H, s, 1-CH), and 11.96 (1H, br s, CNHC).
m/z 257.1 calcd for C14H12FN3O; found 258.3 (M + H)+.
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J. Label Compd. Radiopharm 2012