An efficient one-step radiosynthesis of [18F]FE-PE2I, a PET radioligand for imaging of dopamine transporters

Article abstract of DOI:10.1002/jlcr.2927

The aim of this study was to develop a direct fluorination method for the preparation of [¹⁸F]-(E)-N-(3-iodoprop-2-enyl)-2β- carbofluoroethoxy-3β-(4'-methyl-phenyl)nortropane ([¹⁸F]FE-PE2I (VI). The synthesis procedure relies on the conventional Kryptofix-mediated nucleophilic ¹⁸F-substitution of the tosylate group in the precursor, TsOE-PE2I (V). Out of reaction conditions tested, the highest fluorination efficiency was obtained in dimethyl sulfoxide at 140°C. The reaction mixture was purified by semi-preparative HPLC, followed-up by a standard Sep-Pak SPE procedure. On average, 1.0 GBq of [¹⁸F]FE-PE2I was produced from 5-min irradiation at 35 μA (dimethyl sulfoxide, 5 min/140°C). Decay-uncorrected yield of the product after HPLC purification and formulation was in the order of 20%. Specific radioactivity of [¹⁸F]FE-PE2I at 15 min after EOS was 3.3-5.1 Ci/μmol (n = 3); radiochemical purity was >98% (n = 4). This direct nucleophilic fluorination strategy is well suited for the automation of the entire synthesis of [¹⁸F]FE-PE2I in a modern PET synthesizer for human PET application. In addition, the ¹⁸F- incorporation rate into TsOE-PE2I was evaluated using radio-thin layer chromatography (TLC) and radio-HPLC. The suggested HPLC method (ACE 5 C18-HL column and acetonitrile/0.1 M NH₄CO₂ (80:20)) was found to be suitable for evaluation of 'free' ¹⁸F-fluoride in the reaction mixture; in addition, this method allowed the detection of three radiolabelled by-products that were not discernable with the TLC approach. Therefore, we conclude that the HPLC approach may serve as a good alternative to traditional radio-TLC technique as it provides more detailed information about the fluorination process in the reaction kinetics or optimization studies. Copyright

Full text of DOI:10.1002/jlcr.2927

Research Article
Received 30 October 2011,
Revised 7 March 2012,
Accepted 5 April 2012
Published online 14 May 2012 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.2927
An efficient one-step radiosynthesis of [18F]
FE-PE2I, a PET radioligand for imaging of
dopamine transporters
a
a,b
Vladimir Stepanov, Raisa Krasikova, Liina Raus,c,d Olavi Loog,c
*
Jukka Hiltunen,c and Christer Halldina
The aim of this study was to develop a direct fluorination method for the preparation of [18F]-(E)-N-(3-iodoprop-2-enyl)-2b-
carbofluoroethoxy-3b-(4′-methyl-phenyl)nortropane ([18F]FE-PE2I (VI). The synthesis procedure relies on the conventional
Kryptofix-mediated nucleophilic 18F-substitution of the tosylate group in the precursor, TsOE-PE2I (V). Out of reaction
conditions tested, the highest fluorination efficiency was obtained in dimethyl sulfoxide at 140ꢀC. The reaction mixture
was purified by semi-preparative HPLC, followed-up by a standard Sep-Pak SPE procedure. On average, 1.0 GBq of [18F]FE-
PE2I was produced from 5-min irradiation at 35 mA (dimethyl sulfoxide, 5 min/140ꢀC). Decay-uncorrected yield of the
product after HPLC purification and formulation was in the order of 20%. Specific radioactivity of [18F]FE-PE2I at 15 min after
EOS was 3.3–5.1 Ci/mmol (n = 3); radiochemical purity was >98% (n = 4). This direct nucleophilic fluorination strategy is well
suited for the automation of the entire synthesis of [18F]FE-PE2I in a modern PET synthesizer for human PET application. In
addition, the 18F-incorporation rate into TsOE-PE2I was evaluated using radio-thin layer chromatography (TLC) and
radio-HPLC. The suggested HPLC method (ACE 5 C18-HL column and acetonitrile/0.1 M NH4CO2 (80:20)) was found to be
suitable for evaluation of ‘free’ 18F-fluoride in the reaction mixture; in addition, this method allowed the detection of three
radiolabelled by-products that were not discernable with the TLC approach. Therefore, we conclude that the HPLC approach
may serve as a good alternative to traditional radio-TLC technique as it provides more detailed information about the
fluorination process in the reaction kinetics or optimization studies.
Keywords: FE-PE2I; single-step; tosylate; dopamine transporter; PET chemistry; F-18
of the radiometabolite would make [18F]FE-PE2I more suitable
for the DAT quantification, because the radiometabolite is likely
Introduction
The dopamine transporter (DAT) is a transmembrane protein
to have some affinity for the DAT; in DAT-rich regions, kinetic
typically localized at the synaptic junctions and is responsible
analysis would require a four-tissue compartment model with
for the regulation of extracellular levels of dopamine. Molecular
imaging techniques allow evaluating the DAT density changes
in the progression of Parkinson’s disease and in the course of
eight rate constants, which would significantly complicate
quantification.9–11 Also, with [11C]PE2I, the late peak equilibrium
and slow kinetics result in long imaging times that can also pose
other various central nervous system disorders (for a recent
a problem in some circumstances, such as imaging patients with
review, see1). From several radioligands available for PET
imaging of DAT-binding sites in the brain, the tropane analog
N-(3-iodoprop-2E-enyl)-2b-carbomethoxy-3b-(4-methyl-phenyl)
nortropane labeled with carbon-11 ([11C]PE2I) is considered a ‘text-
book’ tracer because of its high affinity and specificity for DAT,
along with good blood–brain barrier penetration.2–7 The potential
limitations of [11C]PE2I for accurate in vivo quantification are
relatively slow kinetics with the late peak equilibrium and
formation of at least one radiometabolite that crosses the blood–
brain barrier.8 More recently, a fluorine-18 labeled analog of PE2I,
[18F]-(E)-N-(3-iodoprop-2-enyl)-2b-carbofluoroethoxy-3b-(4′-methyl-
phenyl)nortropane ([18F]FE-PE2I) has been developed9–11 (Figure 1).
The direct comparison between the [18F]FE-PE2I and [11C]PE2I
shows that [18F]FE-PE2I displays faster kinetics and more favor-
able metabolism than [11C]PE2I.11 The analyses with the input
function of the parent compound and its radiometabolite show
that the bias in BPND was much lower for [18F]FE-PE2I (<10% in
the caudate and putamen) than for [11C]PE2I (40–60% in the
Parkinson’s disease.11 Compared with carbon-11, the use of
fluorine-18 is advantageous for several reasons – lower positron
energy results in higher intrinsic resolution in the PET image,
whereas the relatively long half-life (110 min) allows for a
widespread clinical availability through remote-site delivery of
the radioligand from centralized cyclotron facilities. For the first
evaluation studies, the [18F]FE-PE2I was prepared via alkylation
of its acid precursor with [18F]fluoroethyl bromide in a two-step
aKarolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden
bInstitute of Human Brain, Russian Academy of Science, St.-Petersburg, Russia
cPharmaSynth AS, Tartu, Estonia
dInstitute of Chemistry, University of Tartu, Tartu, Estonia
*Correspondence to: Vladimir Stepanov, Department of Clinical Neuroscience,
Karolinska Institutet, Stockholm, Sweden.
caudate and putamen) and suggested that the lower formation E-mail: vladimir.stepanov@ki.se
J. Label Compd. Radiopharm 2012, 55 206–210
Copyright © 2012 John Wiley & Sons, Ltd.

V. Stepanov et al.
O
O
an automatic sample injector (Rheodyne-type) equipped with a 2 ml
loop; UV detector from Knauer, Smartline UV Detector 2500 and a
gamma-radioactivity PIN diode detector (Caroll & Ramsey Associates,
Berkeley, CA, USA) to monitor the effluent radioactivity. Radioanalytical
HPLC system included a pump (LaChrom Model L-7100, Merck-Hitachi),
UV detector (LaChrom model L-7400), a D-7000 interface and a Beckman
b-flow radiodetector (Model 170). ACE 5 C18-HL column (4.6 Â 250 mm)
was used for radiochemical purity determination and incorporation rate
analysis. The system was controlled by Merck-Hitachi Chromatography
Data Station Software D-7000 (version 4.1). Thin layer chromatography
(TLC) analyses were run on precoated Kiesel gel 60 F254 (Merck) glass
plates; radioactivity spots were detected using an automatic radio-TLC
scanner (Raytest GmBH, Germany).
11CH3
18F
I
N
I
N
O
O
1
2
Figure 1. Structures of [11C]PE2I (1) and [18F]FE-PE2I (2).
method.9,10 Despite an acceptable radiochemical yield (7%, EOS)
and good radiochemical purity (>95%), this two-step two-pot
synthesis procedure is considered to be practically inconvenient.
Direct nucleophilic radiofluorination is generally a better method
in the sense of both production yield and time, and is readily
adaptable into fully automated 18F-fluorination systems –
because a one-step synthesis can be implemented even in the
simplest commercially available module, whereas two-step reac-
tion with a distillation sequence would be difficult to implement.
In this paper, we report for the first time a direct fluorination
method for the preparation of [18F]FE-PE2I suitable for a rapid
and easy to automate production of the radioligand for use in
human studies. The synthesis procedure relies on conventional
Kryptofix-mediated nucleophilic 18F-substitution of TsO group
in a tosylated derivative of PE2I-TsOE-PE2I.
Preparation of TsOE-PE2I (2-(tosyloxy)ethyl-8-[(2E)-3-iodoprop-2-
en-1-yl]-3-(4-methyl-phenyl)-8-azabicyclo[3.2.1]octane-2-carbox-
ylate): V (Scheme 1)
This compound was prepared from desmethyl-PE2I in analogy (with and
addition of an extra synthetic step described in the following paragraph)
to a previously published method.12 Briefly, 40% tetrabutyl ammonium
hydroxide solution in H2O (0.518 g, 0.788 mmol) was added to the stirred
suspension of desmethyl-PE2I (III) (0.268 g, 0.652 mmol) in toluene (5 ml).
The mixture was stirred 10 min at room temperature and then concen-
trated at reduced pressure. Toluene (5 ml) was added to the residue,
and the solution was reconcentrated. The yellowish residue was then dis-
solved in CH3CN (8 ml) and the obtained solution was added dropwise
over the period of 35 min into the solution of 1,2-ethylditosylate (1.093
g, 2.95 mmol) in CH3CN (25 ml). After a 2-h reaction at room temperature,
the mixture was concentrated at reduced pressure. The residue was
purified sequentially by column chromatography using two different sys-
Experimental
Reagents and instrumentation
All reagents and solvents were acquired from Sigma-Aldrich, St. Louis,
MO, USA, and used as received without further purification. Acetonitrile tems: (i) EtOAc/hexane 2/1 + 2.5% Et3N; (ii) EtOAc/hexane 1/4 and EtOAc/
(for DNA synthesis, max 10 ppm H2O) was bought from Merck hexane 1/1 + 1% Et3N) to give after drying in vacuum tosylethyl-PE2I
(Darmstadt, Germany). Solid-phase extraction cartridges (Sep-Pak QMA (0.233 g, 0.382 mmol, 54%) as a colorless semi-solid. Purity of V by HPLC
light, Sep-Pak tC18 Plus) were purchased from Waters Corp., Milford,
MA, USA. Column chromatography was performed on silica gel (60 Å,
was 98%. TsOE-PE2I (V) is stable for significant periods if kept in the dark
and refrigerated – no difference in precursor purity and performance in
70–230 mesh, Sigma-Aldrich). NMR spectra were recorded on a Bruker the labeling procedure was observed after 9 months of storage. 1H
Avance II 200 spectrometer (Billerica, MA, USA) at 298 K using CDCl3 as
a solvent and tetramethylsilane as internal standard. HPLC analysis of
NMR (200 MHz, CDCl3) d ppm 1.55–2.15 (m, 5 H), 2.29 (s, 3 H), 2.46
(s, 3 H), 2.42–2.58 (m, 1 H), 2.60–3.07 (m, 4 H), 3.37 (br s, 1 H), 3.56 (br s,
TsOE-PE2I, FE-PE2I and related compounds were performed on a Waters 1 H), 4.00–4.15 (m, 4 H), 6.10–6.52 (m, 2 H), 7.09 (q, 4 H) (ABq, 4 H, ΔdAB
=
X-Bridge C18 column (4.6 Â 250 mm) with Kontron (Poway, CA, USA)
6.9 Hz, JAB = 8.6 Hz), 7.34 (d, 2 H, J = 8.0 Hz), 7.78 (d, 2 H, J = 8.4 Hz). 13C
HPLC system (UV absorbance at 220 nm) using CH3CN/0.1% TFA in H2O NMR (50 MHz, CDCl3) d ppm 21.0, 21.9, 25.9, 26.2, 33.6, 34.0, 52.6, 58.0,
50/50 or 60/40 as an eluent. Semi-preparative HPLC purification system 60.8, 61.0, 63.0, 67.9, 127.1, 128.0, 128.7, 129.9, 133.2, 135.4, 139.6, 144.5,
consisted of a pump (Knauer, Smartline Pump 100 (Berlin, Germany)),
144.9, 170.9.
Me
N
I
N
COOMe
OCOPh
8 steps
COOMe
II
dioxane/water, reflux
COOH
O
I
N
F
1) TBAH/toluene,
10 min/r.t.
I
N
O
IV
2) fluoroethyltosylate/DMF
1 h/70 °C
III
1) TBAH/toluene, 10 min/r.t.
2) 1,2-ethylditosylate/MeCN, 2 h/r.t.
O
I
N
OTs
O
V
Scheme 1. Route to the synthesis of tosylated precursor, TsOE-PE2I (V) and FE-PE2I (IV).
J. Label Compd. Radiopharm 2012, 55 206–210
Copyright © 2012 John Wiley & Sons, Ltd.
www.jlcr.org

V. Stepanov et al.
MeCN : 0.1M NH4CO2 80:20, flow 2 ml/min, UV 234 nm. The identity of 2
was confirmed by a co-injection with an authentic nonradioactive
standard, FE-PE2I (IV). The same HPLC conditions were used to monitor
the course of 18F-fluorination in optimization experiments; the samples
were taken at 5, 10, 15 and 25 min reaction times and analyzed also by
radio-TLC (EtOAc : Hexane 1:1).
Preparation of FE-PE2I (2-fluoroethyl 8-[(2E)-3-iodoprop-2-en-1-yl]-
3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate): IV
(Scheme 1)
This compound was prepared from desmethyl-PE2I in analogy (with
some modifications) to a previously published method.13 Briefly, 40%
tetrabutyl ammonium hydroxide solution in H2O (0.198 g, 0.305 mmol)
was added to the stirred suspension of desmethyl-PE2I (III) (0.102 g,
0.248 mmol) in toluene (2.5 ml). The mixture was stirred 20 min at room
temperature and then concentrated at reduced pressure. Toluene (1 ml)
was added to the residue, and the solution was reconcentrated. To the
yellowish residue were added dimethylformamide (DMF) (1 ml) and then
fluoroethyltosylate (1.093 g, 2.95 mmol) in DMF (0.5 ml). The mixture was
stirred for 15 min at room temperature and then for 1 h at 70ꢀC. After
cooling the reaction, the mixture was poured into a mixture of saturated
NaHCO3 solution (10 ml) and H2O (10 ml), and extracted with EtOAc
(20 ml + 2 Â 10 ml). The combined organic layers were washed with H2O
(20 ml) and brine (20 ml), dried over MgSO4 and concentrated at reduced
pressure. The residue was purified by column chromatography (EtOAc/
hexane 1/2) to give fluoroethyl-PE2I (0.085 g, 0.186 mmol, 75%) as
Results and discussion
Scheme 1 describes the synthesis of the tosylated precursor,
TsOE-PE2I (V). This compound was synthesized starting from
cocaine in eight steps (not all shown), with overall yield of
4.6% and purity of 97% (by HPLC) according to previously
published procedures for the desmethyl-PE2I with some modifi-
cations.12 The nonradioactive fluorinated analog IV was also
prepared in a similar way using a slightly modified published
method.13
Scheme 2 presents the radiosynthesis of [18F]FE-PE2I via
Kryptofix-mediated direct nucleophilic fluorination of tosylated
precursor V.
1
colorless oil. Purity of IV by HPLC was 98%. H NMR (200 MHz, CDCl3) d
ppm 1.55–2.15 (m, 5 H), 2.29 (s, 3 H), 2.48–2.60 (m, 1 H), 2.64–3.10 (m,
4 H), 3.41 (br s, 1 H), 3.68 (m, 1 H), 3.98–4.70 (m, 4 H), 6.14–6.58 (m, 2
H), 7.11 (q, 4 H) (4 H, ΔdAB = 13.3 Hz, JAB = 8.2 Hz). 13C NMR (50 MHz,
CDCl3) d ppm 21.0, 25.9, 26.1, 33.7, 34.1, 52.6, 58.1, 61.0, 62.5, 62.88,
62.92, 79.8, 83.2, 127.2, 128.7, 135.4, 139.7, 144.4, 171.1.
In optimization studies, radiofluorination of V was investigated
in three different solvents and various temperatures; the course
of the reaction was monitored at time intervals of 5, 10, 15 and
25min (Figure 2). In addition to radio-TLC analysis that is consid-
ered to be a general practice for evaluation of the 18F-incorporation
rates into precursor structure, we developed the HPLC method
allowing detection of unbounded [18F]fluoride as well as other
18F-labeleled products. With the use of the ACE 5 C18-HL column
and MeCN: 0.1M NH4CO2 (80:20) as a mobile phase, the desired
labeled product 2 (Rt 5.3min.) and three labeled by-products (not
identified) were well resolved (Figure 3). For the same sample of
reaction mixture, radio-TLC analysis showed the presence of only
two peaks: unbonded [18F]fluoride with Rf = 0.02 and the product
peak with Rf 0.7, which was not resolved from by-products
(Figure 4). Varying composition of TLC-developing solvent did
not result in the improved resolution.
Radiosynthesis of [18F]FE-PE2I (Scheme 2)
Aqueous [18F]fluoride was produced via the 18O(p,n)18F nuclear reaction
using a General Electric Medical Systems PETtrace cyclotron in a silver
fluorine-18 water target. The radionuclide was transferred from the tar-
get by means of helium flow (in a 1.5-ml bolus of [18O]H2O) and trapped
on a QMA light Sep-Pak cartridge (bicarbonate form) to remove [18O]
H2O. [18F]fluoride was then eluted into the reaction vessel using 2 ml of
acetonitrile/water (96/4 v/v) containing 9.8 mg of Kryptofix 2.2.2 and
1.8 mg of potassium carbonate. The solvents were evaporated by heating
at 140ꢀC under a stream of nitrogen (100 ml/min). With the use of this
method, azeotropic distillation with additional acetonitrile was not
required to produce reactive [18F]fluoride.14 To the dried [18F]fluoride,
complex 0.9–1.0 mg of V dissolved in 600 ml of solvent were added. The
reaction mixture was heated for 5 min at 90ꢀC (acetonitrile (MeCN)) or
140ꢀC (DMF, dimethyl sulfoxide (DMSO)) in the sealed 5-ml V-shaped
reaction vial without stirring. The reaction was quenched by addition of
1.5 ml of water. The crude product was injected directly onto semi-
preparative HPLC and purified on a Waters mBondapak C18 column
(10 m, 125 A, 7.8 Â 300 mm) under the following conditions: 0–5 min:
H2O, 4 ml/min; 6–25 min, MeCN : H2O : TEA 650:350:1, 6 ml/min, UV
230 nm. The desired fraction (Rt [18F]FE-PE2I 15–17 min) was collected into
a vial containing 50 ml of water and 70 mg of sodium ascorbate. The
resulting solution was pushed through Sep-Pak tC18 Plus Short cartridge
previously conditioned by rinsing it with 10 ml of ethanol and 15 ml of
water. After trapping of the product, the cartridge was rinsed with 10 ml
of distilled water, and the product was then eluted with 1.0 ml of EtOH
and collected in a sterile receiving vial prefilled with 8 ml of sterile
Phosphate buffered saline. Finally, the product was passed through a
sterile filter (0.22 mm pore size, Millipore) in a particle-free aseptic
environment. The [18F]FE-PE2I (2) was analyzed by analytical radio-HPLC
under following conditions: column ACE 5 C18-HL, 5 mm, 4.6 Â 250 mm,
From a direct comparison of two analytical techniques
(Table 1), we may conclude that the suggested HPLC method is
Figure 2. Fluorination efficiency of (V) under various reaction conditions.
O
O
18F
I
N
I
N
OTs
18F-/K2.2.2, DMSO
5 min, 140°C
O
O
V
VI
Scheme 2. Radiosynthesis of [18F]FE-PE2I.
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J. Label Compd. Radiopharm 2012, 55 206–210

V. Stepanov et al.
a suitable way for the evaluation of fluorination efficiency, allow- by-products detected via the HPLC analysis (Figure 3). It is
ing detection of all radiolabeled components presented in the noteworthy that the radiofluorination reaction works with a
reaction mixture. This method is very practical and fast, and it moderately low amount of precursor V (1 mg), as might be
is less laborious compared with radio-TLC. In our optimization demanded by a need to conserve expensive precursor in radio-
study, both methods showed similar trend in the efficiency of pharmaceutical production.
fluorination (Table 1). The incorporation rates were somewhat
On average, 1.0 GBq of [18F]FE-PE2I was produced from 5-min
overestimated with the use of radio-TLC because it was difficult irradiation at 35 mA (DMSO, 5 min/140ꢀC). Decay-uncorrected
to separate the target compound 2 from labeled by-products yield of the product after HPLC purification and formulation
that contributed to the peak area. From three different solvents, was in the order of 20%, with total synthesis time of 70 min.
the fluorination yields in MeCN at 90ꢀC were much lower than Specific radioactivity of [18F]FE-PE2I (15 min after EOS) was
that in DMSO or DMF at 140ꢀC. From the current results, the yield 3.3–5.1 Ci/mmol (n = 3), and radiochemical purity was >98%
in DMSO was slightly higher than in DMF; therefore, DMSO was (n = 4). No significant radiolysis of the product was observed
used as preferred solvent in preparative runs. The 5-min reaction after 2 h at room temperature in a formulation containing
time seemed to be optimal, giving the highest incorporation 11% v/v of ethanol in PBS.
rates. Radiochemical yields declined up to 20–30% for reaction
time of 20 min (Figure 2) because of the formation of fluorinated
Conclusions
The synthesis of radiolabelled analog of PE2I, [18F]FE-PE2I, via
direct 18F-nucleophilic substitution of the tosyl group of precur-
sor V with [18F]fluoride has been developed. The suggested
synthesis procedure provides the radioligand in good yield, high
purity and high specific radioactivity, and is well suited for the
automation of the entire synthesis process in the modern
synthesizers for human PET application. Compared with the
previously described procedures, the overall yield of the reaction
was improved more than 2 times – 20% vs 7% yield uncorrected
for decay, while the overall length of the synthesis was decreased
by 20–25%.9 The radio-HPLC method suggested within the
course of this work for evaluation of radiofluorination efficiency
of tosylated precursor V may serve as a good alternative to
traditional radio-TLC technique and provides more detailed
information about the fluorination process. This method may be
useful in the performance of the reaction kinetics or optimization
studies using various aliphatic substrates.
Figure 3. Representative chromatogram from the HPLC analysis of the products
from a nucleophilic fluorination of V in dimethyl sulfoxide, 5 min, 140ꢀC; co-injection
with reference IV.
Figure 4. Radio-TLC analysis of the products from a nucleophilic fluorination of V in dimethyl sulfoxide, 5 min, 140ꢀC.
Table 1. Results from the radiofluorinations of V in various solvents at 5 min reaction time
18F-incorporation rate (TLC)
% of product (HPLC)
ꢀ
Solvent
Reaction temperature, C
MeCN
DMSO
DMF
90
140
140
(20 Æ 6) (n = 3)
(73 Æ 7) (n = 4)
(66 Æ 11) (n = 3)
(24 Æ 8) (n = 2)
(61 Æ 7) (n = 6)
(55 Æ 8) (n = 3)
TLC, thin layer chromatography; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; MeCN, acetonitrile.
J. Label Compd. Radiopharm 2012, 55 206–210
Copyright © 2012 John Wiley & Sons, Ltd.
www.jlcr.org

V. Stepanov et al.
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Acknowledgements
We thank the staff of the Karolinska Institutet PET Centre for the
assistance in the conduction of the studies.
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Conflict of Interest
The authors did not report any conflict of interest.
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