Simplified synthesis of N-(3-[18F]fluoropropyl)- 2βcarbomethoxy-3β-(4-fluorophenyl)nortropane ([18F]β- CFT-FP) using [18F]fluoropropyl tosylate as the labelling reagent

Article abstract of DOI:10.1002/jlcr.943

A synthesis method has been developed for the labelling of N-(3-[ ¹⁸F]fluoropropyl)-2β-carbomethoxy-3β-(4-fluorophenyl) nortropane ([¹⁸F]β-CFT-FP), a potential radioligand for visualization of the dopamine transporters by positron em

Full text of DOI:10.1002/jlcr.943

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 463–471.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.943
Research Article
Simplified synthesis of N-(3-[18F]fluoropropyl)-2b-
carbomethoxy-3b-(4-fluorophenyl)nortropane
([18F]b-CFT-FP) using [18F]fluoropropyl tosylate as
the labelling reagent
Teija Koivula1,*, Outi Perhola1, Eeva-Liisa Kamarainen2, Tiina Lipponen1,
¨
¨
¨
Jouko Vepsalainen3 and Olof Solin1,4
¨
¨
1 Laboratory of Radiochemistry, Department of Chemistry, University of Helsinki,
P.O. Box 55, FI-00014, University of Helsinki, Finland
2 Division of Nuclear Medicine, Helsinki University Central Hospital, FI-00270
Helsinki, Finland
3 Department of Chemistry, University of Kuopio, P.O. Box 1627, FI-70210 Kuopio,
Finland
4 Turku PET Centre, P.O. Box 52, FI-20521 Turku, Finland
Summary
A synthesis method has been developed for the labelling of N-(3-[18F]fluoropropyl)-
2b-carbomethoxy-3b-(4-fluorophenyl)nortropane ([18F]b-CFT-FP), a potential radi-
oligand for visualization of the dopamine transporters by positron emission
tomography. The two-step synthesis includes preparation of [18F]fluoropropyl
tosylate and its use without purification in the fluoroalkylation of 2b-carbo-
methoxy-3b-(4-fluorophenyl)nortropane (nor-b-CFT). The final product is purified
by HPLC. Optimization of the two synthesis steps resulted in a greater than 30%
radiochemical yield of [18F]b-CFT-FP (decay corrected to end of bombardment). The
synthesis time including HPLC-purification was approximately 90 min. The radio-
chemical purity of the final product was higher than 99% and the specific radioactivity
at the end of synthesis was typically 20 GBq/mmol. In comparison to alkylation by
[18F]fluoropropyl bromide, the procedure described here results in an improved
overall radiochemical yield of [18F]b-CFT-FP in a shorter time. Copyright # 2005
John Wiley & Sons, Ltd.
*Correspondence to: Teija Koivula, Laboratory of Radiochemistry, Department of Chemistry, University
of Helsinki, P.O. Box 55 (A.I. Virtasen aukio 1), FI-00014, University of Helsinki, Finland.
E-mail: teija.s.koivula@helsinki.fi
Contract/grant sponsor: The Academy of Finland; contract/grant number: 201588
Contract/grant sponsor: Magnus Ehrnrooth Foundation
Copyright # 2005 John Wiley & Sons, Ltd.
Received 27 July 2004
Revised 18 February 2005
Accepted 19 February 2005

464
T. KOIVULA ET AL.
Key Words: fluorine-18; [18F]fluoropropyl tosylate; alkylation; [18F]b-CFT-FP;
cocaine analogue
Introduction
The in vivo imaging of dopamine transporters (DAT) is important when
monitoring neurological function in the brain. Several positron-emitting
radioligands labelled with 11C, 18F or 76Br have been developed for the
imaging of DAT by positron emission tomography (PET). These include 11C-
labelled nomifensine1 and methylphenidate,2 as well as the 18F-labelled
piperazine derivative named GBR 13119.3 [11C]Cocaine has also been
evaluated as a potential DAT radioligand.4 However, several of the labelled
analogues have proven to possess better physical and binding properties than
cocaine itself. Such radioligands are based on the phenyl tropane structure of
cocaine: typically compounds such as of 2b-carbomethoxy-3b-(4-fluorophe-
nyl)tropane (CFT or WIN 35,428) and its iodinated derivative b-CIT.5–11 In
fluoromethyl tropanes the phenyl group attached to the tropane ring is
fluoromethylated at either the para or ortho position.12,13
Several potential DAT ligands have also been developed by modifying the
original tropane structure of cocaine. There is a large number of analogues
where the bridging amino group is alkylated either with a fluoroethyl or a
fluoropropyl group, e.g. b-CIT-FE and b-CIT-FP [N-(3-fluoroethyl or
propyl)-2b-carbomethoxy-3b-(4-iodophenyl)nortropane] and also the corre-
sponding chlorinated and methylated compounds FECNT and FPCMT.14–23
Recent additions among these radioligands include prop-2-enyl- (PE2)24–26
and fluorobenzyl derivatives.27 In another class of tropanes the 2b-carboxy
group is modified to yield fluoroethyl ester28,29 or amide congeners.30 The
effect of adding substituent such as a fluoro-2-propoxy group to the 2b-
carboxy group has also been evaluated.31
18F-labelling procedures for alkylated tropane analogues are often two-step
methods beginning with the production of a labelling reagent, which is then
used for the 18F-fluoroalkylation of the nortropane precursor at the bridging
amino group of the tropane ring.16–23 This kind of synthesis methods have
been used previously in the production of several 18F-fluoropropylated cocaine
analogues, such as [18F]b-CIT-FP and [18F]FPCT.16–20,23 Labelling in most of
these syntheses is via [18F]fluoropropyl bromide.16,18,19 Separating this
labelling reagent from the 1,3-dibromopropane precursor requires a compli-
cated purification using a C-18 cartridge and subsequent distillation. The
successful synthesis of [18F]b-CIT-FP without intermediate purification was
reported by Kazumata et al.17 In their one-pot method an alternative
alkylating agent, [18F]fluoropropyl tosylate, was used.
We have previously prepared the 18F-labelled phenyl tropane analogue
N-(3-[18F]fluoropropyl)-2b-carbomethoxy-3b-(4-fluorophenyl)nortropane
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 463–471

SIMPLIFIED SYNTHESIS OF [18F]b-CFT-FP
465
[K/K2.2.2]+18F-
18F](CH2)3SO3
CH3
SO3
H3C
SO3 (CH2)3
CH3
[
CH3CN, 90˚C, 10 min
II
I
18
(CH )
F]
[
H
2
3
COOCH3
H
COOCH3
H
N
N
II
F
F
H
H
DMF, 135˚C, 25 min
IV
III
Figure 1. Radiolabelling of [18F]b-CFT-FP (IV) starting from [18F]fluoropropyl
tosylate (II) and nor-b-CFT (III)
([18F]b-CFT-FP) by a two-step synthesis using [18F]fluoropropyl bromide or
tosylate as the labelling reagent.19 Labelling with alkyl bromide resulted in a
higher radiochemical yield of [18F]b-CFT-FP than labelling with alkyl
tosylate. However, because of the protracted and complicated purification
step of [18F]fluoropropyl bromide we decided to develop further the approach
with [18F]fluoropropyl tosylate as the labelling reagent.
Here we report the development of a rapid two-step synthesis of [18F]b-
CFT-FP using [18F]fluoropropyl tosylate as the alkylating agent (Figure 1).
Preparation of [18F]fluoropropyl tosylate was studied in various chemical
conditions and the reagent was used without separate purification in the
labelling of 2b-carbomethoxy-3b-(4-fluorophenyl)nortropane (nor-b-CFT).
The 18F-fluoroalkylation reaction was optimized with respect to reaction time
and temperature as well as stochiometric conditions. The [18F]b-CFT-FP
obtained was then purified by HPLC.
Results and discussion
Preparation of [18F]fluoropropyl tosylate
The best average radiochemical yield in the preparation of [18F]fluoropropyl
tosylate was 61 Æ 4% (n=6) using 10 mg of 1,3-propanediol-di-p-tosylate
precursor in a volume of 0.5 ml of CH3CN and a 10 min reaction time.
Extending the reaction time or using higher concentration of precursor did not
have a significant effect on the radiochemical yield. In fact, contrary to
previously reported results,19 a lower amount of precursor (58 mg) lowered
the incorporation yield of [18F]fluoropropyl tosylate considerably, see
Figure 2. Similar results have also been reported by Block et al.32
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T. KOIVULA ET AL.
80
60
40
20
0
0
2
4
6
8
10
12
14
16
Amount of 1,3-propanediol-di-p -tosylate [mg]
Figure 2. Radiochemical incorporation yield of [18F]fluoropropyl tosylate (by
TLC) as a function of amount of 1,3-propanediol-di-p-tosylate. The solid line is a
sigmoidal fit to the experimental data points
Substitution of the tosylate precursor could proceed using either CH3CN or
DMF as a solvent. However, CH3CN was chosen considering the final
purification and formulation of [18F]b-CFT-FP. A heated ultrasonic bath and
a heated oil bath with magnetic stirring were found to promote the labelling
reaction equally well.
Commercial C-18 and SiO2 SPE cartridges have previously been used in the
purification of [18F]fluoroalkyl tosylate reagents.19,21 In our recent experience
neither of these cartridges separate [18F]fluoropropyl tosylate from 1,3-
propanediol-di-p-tosylate. Purification by this means has no effect on the
alkylation reaction and it was therefore excluded from the synthesis procedure.
This simplifies the method, increases the yield as the handling losses are
reduced and also shortens the overall synthesis time.
Preparation of [18F]b-CFT-FP
The most critical parameter in the 18F-fluoroalkylation of nor-b-CFT was the
amount of 1,3-propanediol-di-p-tosylate remaining after the first reaction step.
The unreacted precursor competes with the labelling reagent in the alkylation
of nor-b-CFT. An equivalent molar ratio of nor-b-CFT to 1,3-propanediol-di-
p-tosylate was needed to achieve maximum (90%, decay corrected)
incorporation of [18F]fluoropropyl tosylate into [18F]b-CFT-FP, see
Figure 3. On a molar basis 10 mg of 1,3-propanediol-di-p-tosylate corresponds
to approximately 7.5 mg of nor-b-CFT. The optimum reaction condition for
the alkylation was a reaction time of 25 min at 1358C. A lower reaction
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 463–471

SIMPLIFIED SYNTHESIS OF [18F]b-CFT-FP
467
100
80
60
40
20
0
0
0.5
1
1.5
2
2.5
3
Molar ratio of nor-ꢀ -CFT and 1,3-propanediol-di-p -tosylate
Figure 3. Relative yield of [18F]b-CFT-FP from [18F]fluoropropyl tosylate
(decay corrected) as a function of molar ratio of nor-b-CFT and 1,3-propanediol-
di-p-tosylate. The solid line is a sigmoidal fit to the experimental data points
temperature (908C) failed to produce [18F]b-CFT-FP. Raising the reaction
temperature (1508C) or prolonging reaction time over 25 min did not improve
the yield. The effect of a base (Cs2CO3) on the labelling reaction could not be
demonstrated.
[18F]b-CFT-FP was purified by HPLC. Under described conditions [18F]b-
CFT-FP eluted at 13–15 min and its inactive precursor nor-b-CFT at 8–
10 min. The radiochemical yield of the separated [18F]b-CFT-FP was 18 Æ 2%
(with decay correction to end of bombardment >30%) and the radiochemical
purity exceeded 99%.
The overall radiochemical yield of formulated [18F]b-CFT-FP at the end of
synthesis (EOS) was approximately 10%. The total synthesis including
formulation lasted about 105 min. The specific radioactivity of [18F]b-CFT-
FP at EOS was 15–30 GBq/mmol (400–800 Ci/mmol). The stability of the
product was confirmed for up to 8 h after EOS, at which time the
radiochemical purity of [18F]b-CFT-FP was >97%.
Experimental
Materials
1,3-Propanediol-di-p-tosylate was purchased from Aldrich. The inactive
precursor 2b-carbomethoxy-3b-(4-fluorophenyl)nortropane (nor-b-CFT) and
the reference standard for the product N-(3-fluoropropyl)-2b-carbomethoxy-
3b-(4-fluorophenyl)nortropane (b-CFT-FP) were synthesised as described
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T. KOIVULA ET AL.
earlier.19 Other reagents and chemicals were obtained from commercial
sources. HPLC-solvents were of HPLC gradient grade and other chemicals
were of analytical grade.
Production of [18F]fluoride
[18F]fluoride was produced at the Laboratory of Radiochemistry, University
of Helsinki with an IBA Cyclone 10/5 cyclotron using 10 MeV protons in the
18O(p,n)18F nuclear reaction on 18O-enriched water. The irradiated target
water was transferred through teflon tubing from the target chamber to the
laboratory.
Preparation of [18F]fluoropropyl tosylate
No-carrier-added (n.c.a.) aqueous [18F]fluoride was added to a solution of
Kryptofix-2.2.2 (15 mg, 40 mmol) and K2CO3 (3.0 mg, 22 mmol dissolved in
100 ml of H2O) in dry acetonitrile (800 ml). The reaction mixture was dried by
azeotropic distillation (1158C) with three 1 ml portions of CH3CN under a N2-
stream. 1,3-propanediol-di-p-tosylate (purity 98%) in 500 ml of dry CH3CN
was added to the dried residue. This solution was then heated in a closed vial
at 908C. The crude reaction mixture was subsequently cooled to room
temperature.
The radiochemical yield of [18F]fluoropropyl tosylate was investigated by
varying the following parameters: 2–15 mg (5–38 mmol) of precursor, and 10 or
20 min reaction time. The reaction mixture was heated either in an ultrasonic
bath or oil bath (reaction vial equipped with magnetic stirring). DMF was also
tested as a solvent with 10 mg of 1,3-propanediol-di-p-tosylate.
Preparation of [18F]b-CFT-FP
Three hundred microliters of dry DMF solution containing a variable amount
of nor-b-CFT precursor (2–20 mg, 7–69 mmol) with or without base, Cs2CO3,
was added into the cooled labelling reagent mixture. The reaction vial was
sealed and heated at 1358C varying the reaction time from 10 to 50 min.
Significantly lower (908C) and higher (1508C) reaction temperatures with
25 min heating time were also tested. The solution was subsequently cooled to
room temperature and 700 ml of HPLC-mobile phase was added.
Crude [18F]b-CFT-FP was purified by semi-preparative reversed-phase
HPLC on a Waters mBondapak1 C18 column (7.8 Â 300 mm, 10 mm) using
0.01 M H3PO4/CH3CN (80:20; v/v) as an eluent with flow rate of 4 ml/min.
The chromatographic system consisted of Merck-Hitachi L-7100 HPLC
pump, Rheodyne 7010 injector with 2 ml loop and LKB Bromma 2151 UV-
detector (l=254 nm) in series with NaI(Tl) crystal for radioactivity detection.
Copyright # 2005 John Wiley & Sons, Ltd.
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SIMPLIFIED SYNTHESIS OF [18F]b-CFT-FP
469
The collected product fraction was concentrated in vacuo and the residue was
dissolved in 2 ml of sterile saline.
Analysis of radiolabelled products
Radiochemical purity and stability of [18F]b-CFT-FP was analyzed by TLC
and reversed-phase HPLC. The identity of the product was confirmed by
comparing radiochromatograms of [18F]b-CFT-FP with the UV-chromato-
grams of non-labelled reference material. Analytical HPLC was also used to
determine the specific radioactivity of [18F]b-CFT-FP. A standard curve was
generated to calculate the mass of the final solution.
The analytical HPLC apparatus was comprised of a PC-controlled system
with Waters Millennium132 software, Waters 600E pump, Rheodyne 7125
injector with 100 ml loop, Waters photodiode array detector (PDA 996, range
190–400 nm) and NaI(Tl) crystal for radioactivity detection. A Waters
mBondapak1 C18 column (3.9 Â 300 mm, 10 mm) was eluted at a flow rate of
2 ml/min using a mixture of 0.01 M H3PO4 (A) and CH3CN (B) either in
isocratic (A/B: 80:20) or gradient mode. The gradient program consisted of
four steps: 0–7 min isocratic (A/B: 80:20); 7–17 min linear shift to A/B: 30:70;
17–20 min isocratic (A/B: 30:70); 20–25 min return to initial conditions (A/B:
80:20). Using these conditions (l=254 nm), nor-b-CFT, [18F]b-CFT-FP and
[18F]fluoropropyl tosylate eluted at approximately 4, 6, and 14 min,
respectively.
TLC was carried out using silica gel plates (60 F254, Merck) and hexane/
ether/TEA as the mobile phase. The eluent composition was 6.5:3.5:0.1 for the
labelling reagent (Rf=0.43) and 6.5:3.5:1 for the crude and final products
(Rf=0.73). UV visualization was accomplished with UV-lamp at 254 nm.
Radioactivity was detected with a Raytest MiniGita TLC-scanner (raytest
GmbH, Straubenhardt, Germany).
Conclusion
[18F]b-CFT-FP can be produced efficaciously from nor-b-CFT using
[18F]fluoropropyl tosylate as the fluoroalkylating agent. The synthesis
procedure is faster, simpler and results in a higher radiochemical yield of
[18F]b-CFT-FP when compared to the earlier two-step method using
[18F]fluoropropyl bromide.19 Optimized chromatographic purification of the
final product yields [18F]b-CFT-FP with good radiochemical and chemical
purities as well as reasonable specific radioactivity.
Acknowledgements
The authors thank Dr Kerttuli Helariutta and Mr Stewart Makkonen-Craig
for assistance with the fluorine-18 production and Mrs Maritta Salminkoski
for preparation of nor-b-CFT and b-CFT-FP. This work was supported by the
Copyright # 2005 John Wiley & Sons, Ltd.
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T. KOIVULA ET AL.
Academy of Finland. Teija Koivula is grateful to the Finnish Society of
Sciences and Letters for financial support from the Magnus Ehrnrooth
Foundation.
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