Synthesis of novel halo and tosyloxy nortropane derivatives as efficient precursors for the one-step synthesis of the dopamine transporter PET ligand [18F]FECNT

Article abstract of DOI:10.1002/jlcr.3181

The fluorine-18 labeled nortropane derivative 2β-carbomethoxy-3β- (4-chlorophenyl)-8-(2-fluoroethyl)-nortropane (FECNT) is a dopamine transporter (DAT) ligand. Currently, it is considered as reference for positron emission tomography imaging. Herein, the synthesis of novel precursors (N-tosyloxy-, chloro-, and bromo- analogues) for one-step radiosynthesis of [ ¹⁸F]FECNT is reported. Using the N-mesyloxy- precursor in a one-step radiosynthesis, the crude [¹⁸F]FECNT was obtained with the radiolabeling yield of 45 ± 10%, confirming the practical efficiency of this approach in the design of novel precursors for labeling. Copyright

Full text of DOI:10.1002/jlcr.3181

Research Article
Received 19 September 2013,
Revised 10 December 2013,
Accepted 10 December 2013
Published online 5 February 2014 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3181
Synthesis of novel halo and tosyloxy
nortropane derivatives as efficient precursors
for the one-step synthesis of the dopamine
18
transporter PET ligand [ F]FECNT
a
a
b
b
*
J. Pijarowska-Kruszyna, A. W. Jaron, A. Kachniarz, K. Kasprzak,
A. Kowalska,b B. Malkowski,b S. Demphel,c F. Dollé,c and R. Mikolajczaka
The fluorine-18 labeled nortropane derivative 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane (FECNT) is
a dopamine transporter (DAT) ligand. Currently, it is considered as reference for positron emission tomography imaging.
Herein, the synthesis of novel precursors (N-tosyloxy-, chloro-, and bromo- analogues) for one-step radiosynthesis of [18F]
FECNT is reported. Using the N-mesyloxy- precursor in a one-step radiosynthesis, the crude [18F]FECNT was obtained with
the radiolabeling yield of 45 10%, confirming the practical efficiency of this approach in the design of novel precursors
for labeling.
Keywords: [18F]FECNT; precursors; one-step; radiofluorination
tropane precursor for labeling. Using the latter method, [18F]
FECNT was obtained in 33% decay-corrected yield and in total
synthesis time of 80 to 90 min.
The use of a mesylate as a leaving group in such a nucleophilic
substitution reaction (SN2) has some disadvantages. Mesylates
are rather hard to detect using ultraviolet (UV)-absorption, which
Introduction
2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl)-
nortropane (FECNT) is a dopamine transporter (DAT) ligand, first
reported by Goodman et al.1 Labeled with the positron-emitter
fluorine-18 (T1/2 =109.8min), this radiotracer has demonstrated
highly promising properties in positron emission tomography
may complicate the final HPLC purification of the radiotracer
(PET) studies in human. Indeed, the DAT is a presynaptically located
from its precursor-for-labeling and reaction side-products. In
protein responsible for the regulation of synaptic concentration of
addition, mesylates are often characterized by high reactivity
dopamine, and thus dopamine neurotransmission, in the brain.
and thus, limited long-term storage stability.
Deregulation of dopaminergic transmission in the basal ganglia is
Tosylates as well as halogens such as bromo- and chloro-
groups are also often reported leaving groups in [18F]fluorination
implicated in brain neurodegenerative disorders such as
Parkinson’s disease and psychiatric disorders,2–4 and as such, DAT
reaction. Tosylate is one of the most commonly used leaving
groups in SN2 reaction. [18F]fluoro-for-tosylate exchange
has been for several years a highly investigated target for
development of selective PET-tracers.
reactions usually work well under mild conditions. The tosylate
[18F]FECNT has high-binding affinity, low-nonspecific binding,
precursor and tosylated derivatives can be easily separated from
the [18F] products by HPLC purification with UV detection
and favorable kinetics towards the DAT compared with other
fluorine-18-labeled ligands.1,5,6 Moreover, high degree of test–
because of their high-UV absorption at 254 nm and differences
retest reproducibility and extremely high sensitivity of [18F]
in lipophilicity. However, one drawback of tosyloxy-containing
FECNT for imaging the DAT in PET studies were recently
structures is their limited shelf life. Bromo- group is another
demonstrated.7 However, the use of this radioligand as a clinical
marker for the state of the DAT system is highly dependent on
the robustness of the radiochemical process used for its
preparation, and this in particular in terms of efficiency and
speed. To date,1,8 [18F]FECNT has been synthesized in a two-step
chemical process, involving the preparation of 2-[18F]-fluoroethyl
tosylate or brosylate and subsequent N-(2-fluoroethyl) alkylation
of a dedicated nortropane moiety. These methods provided the
overall radiochemical yield of 21% and 16% (decay corrected) in
total time of 122 and 150 min, respectively. More recently, Chen
et al.9 reported that [18F]FECNT could be synthesized in one
aRadioisotope Centre POLATOM, National Centre for Nuclear Research, Andrzeja
Soltana 7, Otwock, Poland
bDepartment of Nuclear Medicine, Oncology Centre prof. Lukaszczyk Memorial
Hospital, Bydgoszcz, Poland
cCEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France
*Correspondence to: J. Pijarowska-Kruszyna, Radioisotope Centre POLATOM,
National Centre for Nuclear Research, Andrzeja Soltana 7, Otwock, Poland.
single chemical step by direct [18F]fluorination of N-mesyloxy E-mail: j.pijarowska@polatom.pl
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J. Pijarowska-Kruszyna et al.
possible leaving group, and bromo-bearing precursors for
On the basis of the latter result, we assumed that [18F]FECNT
fluorine-18-labeling have been described.11 Chloro- group is could analogously be synthesized at high yield, with high-
much less reactive, especially when compared with the tosyloxy- specific radioactivity and in relatively short time by direct
moiety and bromine atom, but provides a higher-stability of nucleophilic [18F]fluorination of the chloro- analog, and also the
compounds containing this halogen.12 Chloro- precursor has bromo- and tosyloxy- derivatives as precursors for labeling. Thus,
moreover been used for one-step radiosynthesis of another we report herein the synthesis of these novel derivatives. We
tropane-based DAT-radioligand, [18F]LBT-999.10
also described the synthesis of FECNT as standard and the
Scheme 1. One-step radiosynthesis of [18F]FECNT.
Scheme 2. (A) Synthesis of FECNT (8, standard compound) as well as the N-mesyloxy and N-tosyloxy nortropane (9 and 10 as precursors for labeling); (B) synthesis of
(2-fluoroethyl)-4-bromobenzenesulfonate (7).
J. Label Compd. Radiopharm 2014, 57 148–157
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J. Pijarowska-Kruszyna et al.
N-mesyloxy- derivative as precursor, followed by the development treatment at À78°C gave 70% yield of both C-2 epimers mixture
of novel, sensitive, and selective HPLC quality control methods. We (ratio C-2β 4a/C-2α4b: 7/3). The unwanted, biologically inactive
also investigated and compared by HPLC the preparation of FECNT α-isomer18,19 was separated by flash chromatography (diethyl
from the four precursors using non-radioactive fluoride, in order to ether/triethylamine, 9:1) on silica gel, followed by fractional
propose novel conditions for subsequent radiofluorination and to crystallization from hexane. In this manner, a total yield of β-isomer
confirm suitability of these precursors for radiopharmaceutical 4a of about 60% was obtained. 2β-Carbomethoxy-3β-
preparation. As a proof of concept, we also prepared [18F]FECNT (4-chlorophenyl)nortropane 5 was prepared by N-demethylation of
from the N-mesyloxy tropane precursor via
radiosynthetic process (Scheme 1).
a
one-step compound 4a. This reaction involved conversion of 4a to its 2,2,2-
trichloroethyl carbamate followed by reduction with zinc/acetic acid
mixture. Compound 5 was obtained in 59% yield and with purity
exceeding 99% (HPLC
– method B) after purification by
Results and discussion
Chemistry
crystallization from hexane according to previously described
procedures,13,15,17 with some modifications. The 2β-Carbomethoxy-
3β-(4-chlorophenyl)-8-(2-hydroxyethyl)nortropane 6 was prepared
by N-hydroxyethylation of 5 using 2-bromoethanol9 and was
obtained in 89% yield after purification by crystallization from
petroleum ether and with above 99% purity (HPLC – method A).
FECNT (8) as standard was prepared by direct N-(2-fluoroethyl)
alkylation of 5 with (2-fluoroethyl)-4-bromobenzenesulfonate
(7). The crude product was purified by recrystallization from
hexane and obtained in 71% yield and with purity exceeding
99% (HPLC – method A). Noteworthy, the synthesis of 7 from
2-fluoroethanol and 4-bromobenzenesulfonyl chloride was
already described by Voll et al.,8 but extremely low yields (5%)
were reported. Using anhydrous pyridine as acid neutralizer
(Scheme 2B) allowed to increase the yield up to 47%.
FECNT and precursors for labeling syntheses
FECNT as standard (8) as well as its tosyloxy-, mesyloxy-, chloro-,
and bromo- derivatives (9–12) were all prepared from cocaine
hydrochloride (1) as outlined in Schemes 2–4.
The critical intermediate, R-(À) anhydroecognine methyl ester
(3) was prepared as described previously13–15 from (À) cocaine
HCl (1) by (i) hydrolysis in 0.8 N HCl followed by (ii) dehydratation
with POCl3 and subsequent (iii) Fisher esterification with dry
MEOH (Scheme 2A). Compound 3 was obtained in 77% yield
after purification by distillation under reduced pressure.
2β-Carbomethoxy-3β-(4-chlorophenyl)tropane 4a was prepared
from 3 by treatment with (4-chlorophenyl)magnesium bromide
as previously reported by Caroll et al.16 and Goodmann et al.17
with minor modifications. Reaction of the Grignard reagent with
3 at À45°C in diethyl ether followed by trifluoroacetic acid
For the synthesis of the N-tosyloxy- derivative 9, two ways
were used. First, the alkylation of compound 5 with 1,2-
ethanediol di-(4-toluenesulfonate) (13) was used (Scheme 4).
Scheme 3. Synthesis of the chloro- and bromo- nortropane analogs (11 and 12 as alternative precursors for labeling).
Scheme 4. Synthesis of 1,2-di-[2β-carbomethoxy-3β-(4-chlorophenyl)nortropanyl]ethane (15).
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J. Pijarowska-Kruszyna et al.
Table 1. HPLC characteristic of FECNT and its derivatives
(Method A)
Compound
Retention
Known impurities
Retention
time (min)
time (min)
Number
(n = 10)
Number
(n = 10)
Resolutiona
8
11.6
5
7
6
6
6
10
6
10
11.2
15.8
11.3
11.3
11.3
12.4
11.3
12.4
1.6
12.4
15.7
6.7
7.6
1.3
9
10
11
15.3
12.4
12.6
Figure 1. HPLC typical analytical chromatogram (method C) of the N-mesyloxy-
derivative 10 reaction with fluoride (3 h, 80°C). Peak A, FECNT (8, Rt 2.26 min); peak
B, side-product (Rt 2.62 min).
12
12.7
8.3
2.0
aResolution was calculated in accordance with Ph. Eur.
requirements (monograph: 20246) between peak of analyzed
compound and known impurities (substrates or degradation
products).
confirmed by mass spectroscopy. Compounds 11 and 12 were
therefore prepared from the N-mesyloxy- derivative 10 by
nucleophilic substitution reaction using chloride and bromide,
respectively, and were obtained in 75% and 73% yield (Scheme 3).
Both halogenated compounds (11, 12) were obtained with purities
exceeding 98% (HPLC – method A).
The only recovered product from this reaction was compound
In conclusion, the four proposed precursors for labeling and
15 that could be isolated in 80% yield. Mass spectroscopy FECNT as standard were prepared in a few chemical steps from
analysis confirmed its structure as the 1,2-di-[2β-carbomethoxy- (À) cocaine HCl (1) in moderate overall yield: 12% for 9, 16%
3β-(4-chlorophenyl)nortropanyl]ethane. In the second method,9 for 10, 11% for 11 and 12, and 16% for 8. All synthesized
the tosylation reaction of alcohol 6 with p-toluenosulfonic compounds were characterized by mass spectroscopy, 1H and
anhydride gave compound 9 in 58% yield after purification using 13C NMR spectroscopy and m.p. measurement.
preparative HPLC described previously.
Robust HPLC methods were developed and used to separate
The N-mesyloxy- derivative 10 was prepared and purified as products from substrates. Purity of the compounds was determined
described previously but using methanesulfonic anhydride, by analytical HPLC method (method A) with values over 98% for all
and was obtained in 81% yield. Both sulfonates, that is, derivatives. The high purity obtained for the synthesized
compounds 9 and 10, were obtained with purities exceeding compounds permits direct use of these precursors for labeling
99% (HPLC – method A).
without further purification. The calculated resolution20 between
Synthesis of the chloro- derivative 11 was attempted by the peaks of obtained compounds and main impurities is presented
alkylation of 5 with (2-chloroethyl)-4-bromobenzenesulfonate in Table 1. For all analyzed compounds, the resolution from
(14) (Scheme 4), but only compound 15 could be isolated as impurities is higher than 1.3, while the Ph. Eur. requires min. 1.0.
Table 2. HPLC-determined, FECNT and its side-product synthesis yields
Yields (%) (n = 3)
Temp.
80°C
110°C
Time
Precursor
9 (ÀOTs)
10 (ÀOMs)
11 (ÀCl)
12 (ÀBr)
11 (ÀCl)
5 min
Ya
Yb
Ya
Yb
Ya
Yb
Ya
Yb
Ya
Yb
93.4
4.2
94.5
5.5
—
—
—
—
—
96.0
2.6
95.6
3.7
—
—
—
—
41.8
57.6
39.3
2.2
64.4
6.1
76.6
9.2
83.6
12.4
—
94.2
5.3
90.2
9.5
—
—
—
—
—
85.1
12.7
80.4
17.2
—
—
—
—
—
10 min
20 min
30 min
3 h
—
—
—
—
Ya: FECNT synthesis yield calculated as the ratio of the HPLC-peak area (method C) corresponding to FECNT (Rt 2.2 min) over the
sum of the HPLC-peak areas corresponding to the starting compound, FECNT, and side-product.
Yb: Side-product formation yield calculated as the ratio of the HPLC-peak area corresponding to the side-product (Rt 2.6 min) over
the sum of the HPLC-peak areas corresponding to the starting compound, FECNT, and side-product.
J. Label Compd. Radiopharm 2014, 57 148–157
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J. Pijarowska-Kruszyna et al.
The stability of all compounds was tested when stored at room FECNT from the four proposed precursors. The same amounts
temperature. FECNT as standard is stable under these conditions of substrates and the same temperature conditions were used
and can be stored for at least 36 months without decomposition, for all precursors in order to compare their reactivity. The
whereas all precursors decomposed and therefore should be synthesis of FECNT was carried out in one step in pressurized
stored in sealed vials at À20°C under inert gas atmosphere. At reaction vessels and preserving the conditions and reagents
least 6 months stability was confirmed by HPLC.
similar as in typical radiofluorination. The nucleophilic
substitution of the synthesized precursors was performed at
80°C using potassium fluoride, Kryptofix®222, and dry
acetonitrile as the solvent. Progress of the reaction was
monitored using HPLC (method C), which gave satisfactory
separation of FECNT from its precursors and side-products. The
FECNT preparation by nucleophilic substitution reaction from
(non-radioactive) fluoride
Pilot studies using non-radioactive fluoride were carried out to
investigate the initial conditions for one-step radiosynthesis of
Figure 2. Mass spectrum of the compound corresponding to peak A (Rt 2.26 min, Figure 1), confirming the identity of FECNT.
Figure 3. Mass spectrum of the compound corresponding to peak B (Rt 2.62 min, Figure 1), a side-product of the reaction with the same mass as FECNT.
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J. Pijarowska-Kruszyna et al.
identity of the desired fluorinated product was confirmed by
co-injection with FECNT standard (Rt 2.2 min), and all recorded
HPLC profiles were in accordance with the formation of FECNT.
For compounds 9, 10, and 12, the reaction time of 5 min at
80°C was sufficient to obtain FECNT in yields above 90%, as
measured by HPLC (method C). Using compound 11, the
reaction had to be carried out at 110°C to obtain similar yield
in the reaction time of 5 min. Fluorination yields obtained for
all runs are shown in Table 2.
We noticed, the same as Block et al.24, that the increase of the
substitution yields correlates with the following order of leaving
groups: Cl < Br < sulfonylates. The mesylate leaving group was a
bit more reactive than tosylate group, similar to the report by
Wester.25 Except for the latter precursor, reaction temperature
of 80°C seems to be optimal for sufficient fluorine incorporation
in these nucleophilic substitution reactions.21 The yield
decreased significantly at temperature lower than 80°C.
For all used precursors and reactions conditions, the formation
of more lipophilic side-product was observed; however, the
formation yield depended on the reaction time and
temperature. For the chlorinated derivate 11, it was the most
abundant because higher reaction temperature was required to
increase the fluorination yield.
Figure 5. A typical chromatogram (method C) of crude product [18F]FECNT ([18F]-8)
co-injected with non-radioactive standard. Top, UV (220 nm) detection; bottom,
radioactivity detection. This figure is available in color online at wileyonlinelibrary.
com/journal/jlcr
In order to isolate and identify this unexpected side-product,
the fluorination of compound 10 was performed at 80°C in the non-radioactive fluoride. The radiochemical yields of fluorine-18
reaction time extended to 3 h. In this way, the side-product incorporation, determined by HPLC (method B) and defined as
was formed in 58% yield. Results from this experiment are also the ratio of radioactivity HPLC area of [18F]FECNT to total
included in Table 2, and the typical HPLC analytical fluorine-18 radioactivity HPLC area, were about 45 10%
chromatogram is shown in Figure 1. HPLC purification was (n = 5). These yields are comparable with those (48 12%)
performed, and the fraction was collected at retention time reported by Chen et al.9
corresponding to FECNT as well as the fraction corresponding
The typical HPLC chromatograms of a crude [18F]FECNT are
to the side-product. Both compounds were extracted from the shown in Figures 4 and 5. The identity of [18F]FECNT was
HPLC solvents using a C18 Sep-Pak® cartridge and were analyzed confirmed by co-injection with non-radioactive standard. As
by mass spectrometry. As expected, the parent-ion [M + H]+ for demonstrated using HPLC (method C), the side-product was
peak A (Figure 2) lead to m/z value = 326, confirming the identity not observed.
of FECNT. Surprisingly, the same m/z value was also found for
The developed HPLC isocratic analysis method (method B) could
peak B (Figure 3), suggesting that the side-product could be be successfully used for the preparative purification of [18F]FECNT
the corresponding α-isomer. Indeed, such a structure may result from all precursors, degradation products, and fluorine-18 labeled
from α/β epimerization of the tropane ring at the C2 position21– side-product. Using these conditions, [18F]FECNT (Rt 7.9 min) was
23, leading to the formation of the thermodynamically more completely separated from compound 11 (Rt 11.2min) and
stable but undesired α-isomer.
compound 12 (Rt 12.0 min). [18F]FECNT was also efficiently
separated from derivative 5 (Rt 5.1min), a compound resulting
from the degradation of both the tosyloxy- and mesyloxy-
Radiochemistry
[18F]FECNT was synthesized from the N-mesyloxy- precursor 10 precursors (9 and 10) during the fluorination reaction.
using the one-step radiochemical process outlined in Scheme 1.
These results confirmed the usefulness of one-step
The [18F]fluorination reaction was carried out using the same radiosynthesis method for the preparation of fluorinated
conditions as described previously for the fluorination involving radiotracers, herein exemplified with [18F]FECNT.
Figure 4. Typical radioanalytical HPLC chromatogram (method B) of the reaction mixture corresponding to the preparation of [18F]FECNT. First peak, [18F]fluoride
(Rt 2.0–2.5 min); second peak, [18F]FECNT (Rt 7.5–8.0 min). Radiochemical yield of around 45% was obtained using 5 mg of the N-mesyloxy- derivate 10 as
precursor for labeling and at 80°C for 10 min. This figure is available in color online at wileyonlinelibrary.com/journal/jlcr
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J. Pijarowska-Kruszyna et al.
Technology 1200 series, USA) consisting of G311A quaternary
pump, DAD G1315D diode array detector, Gabi (Raytest, Germany)
radiodetector, and a Gina Star station (Raytest, Germany) software.
Chemical purity analyses of compounds 8, 9, 10, 11, and 12 were
performed using Phenomenex Luna C18(2) column (5μm,
250 × 4.6mm, 100 Å). Gradient method (method A) using the
following mobile phases was used: A: 0.1% TFA in water; B: 0.1%
TFA in acetonitrile/water (9:1). The gradient profile and timing
were as follows: (i) 0–10 min: linear gradient from 0% to 60% B;
(ii) 10–14 min: 60% B; and finally, (iii) 14–15 min: linear gradient
from 60% to 0% B. Flow rate of 1 mL/min and UV detection at
220 nm were used. Radiochemical yields were also determined
using the same column but applying isocratic method (method
B). In this case, the mobile phase consisted of MEOH/water mixture
(80:20), pH 8 (triethylamine, HCOOH). Flow rate of 1 mL/min and a
UV detection at 220 nm were used. Non-radioactive fluorination
reactions were monitored using a Waters Symmetry C18 column
(3.5μm, 50 × 4.6mm) and isocratic method (method C). The eluent
was 58:42 mixture of water containing 2% of low-UV PIC B7
reagent and acetonitrile/water (70:30) also containing 2% of low-
UV PIC B7 reagent. Flow rate of 2 mL/min and UV detection at
220 nm were used.
Conclusion
Non-radioactive FECNT as standard and four analogs as potential
precursors for the one-step radiosynthesis of [18F]FECNT were
prepared with good overall yields and high-chemical purities.
Improved purification and HPLC quality control procedures were
also developed for all compounds. In addition, the initial
parameters of the fluorination substitution reaction for the four
precursors were developed using non-radioactive fluoride, and
these procedures were confirmed in a one-step radiosynthesis
of [18F]FECNT from the N-mesyloxy- precursor for labeling. The
results presented will be a good starting point for the
implementation of the radiosynthesis of [18F]FECNT from other
precursors using automated synthesizers.
Experiment
Materials and methods
Materials. All reagents and solvents used in reactions were of
commercial quality and purchased from Sigma-Aldrich Co. (USA)
and POCH (Poland). Low-UV PIC B7 reagent, C18 Sep-Pak®
cartridges, and Sep-Pak® Light QMA cartridges were obtained from
Waters (USA). Solvents were dried as required. H and 13C NMR
1
spectra were recorded using Bruker 500MHz and Varian 600MHz
spectrometers. CDCl3 was used as solvent, and chemical shifts (δ)
were reported in parts per million relative to TMS as an internal
standard. Mass spectra were obtained on API 365PESciex
turboionspray tandem mass spectrometer (ESI method) and GCT
Premier Waters (FD-TOF) spectrometer (FD-method). m.p. were
determined using an OptiMelt (SRS) apparatus and are
uncorrected. Flash chromatography was used for routine
purification of reaction products using silica gel (Kieselgel 100,
230–400 mesh, Merck). Compound detection was accomplished
under UV or in an iodine chamber.
Chemistry
2β-Carbomethoxy-3β-(4-chlorophenyl)nortropane (5). 2β-Carbomethoxy-
3β-(4-chlorophenyl)tropane (4, 5 g, 17mmol) was dissolved in
2,2,2-trichloroethyl chloroformate (12.5mL, 93 mmol) and the
solution heated at 120°C for 2 h. The reaction mixture was then
cooled to room temperature and vacuum distilled to remove
unreacted 2,2,2-trichloroethyl chloroformate. The residue was
dissolved in 40 mL of 96% acetic acid and treated with zinc dust
(4g, 61 mmol). Then, the mixture was stirred at room temperature
for 16 h and filtered. The filtrate was adjusted to pH 7 with 25%
ammonium hydroxide, saturated with NaCl, and extracted once
with diethyl ether (50 mL) and four times with methylene chloride
(4× 50mL). The combined extracts were dried over anhydrous
MgSO4 and concentrated in vacuo to afford 3.5g (12 mmol) of
crude product. Purification by crystallization from hexane gave
compound 5 (2.8g, 9.5mmol, 59%) as a white solid and with a
purity >99% (HPLC, UV, 220nm). m.p.: 118–120°C (lit. 118–119°
C)12; MS: [M + H]+ = 280; 1H NMR (500 MHz, CDCl3) δ: 1.65–1.69
(m, 1H, H-4α), 1.71–1.83 (m, 2H, H-6α, H-7α), 2.13–2.17 (m, 1H, H-
[18F]Fluoride was prepared via the 18O(p,n)18F nuclear reaction
by irradiation of a 2.4 mL [18O]H2O (≥97% enriched, CIL (USA)
and ≥98% enriched, Rotem GmbH (Germany)) target on an
11 MeV negative-ion cyclotron RDS 111 (Siemens, USA). Typical
production of [18F]fluoride at the end of bombardment for
60 μA, 10–15 min irradiation: 10–15 GBq. All radiolabeling
reactions were conducted with the use of a multifunction
synthesizer SynChrom R&D (Raytest, Germany).
Preparative HPLC. Preparative HPLC was run on Gilson (USA) 6β), 2.20–2.50 (m, 1H, H-7β), 2.40–2.46 (td, 1H, H-4β), 2.75–2.77
system, consisting of a Gilson 306 pump, a Gilson 151 UV/VIS (m, 1H, H-2), 3.21–3.25 (m, 1H, H-3), 3.40 (s, 3H, O-CH3), 3.80–3.81
detector, a Gilson 506C controller system, and the Unipoint (m, 1H, H-5), 3.82–3.87 (m, 2H, H-1, N-H), 7.11–7.27 (m, 4H, ArCl);
software. Purification of compounds 9, 10, 11, and 12 was 13C NMR (500 MHz, CDCl3) δ: 27.2, 28.5, 33.1, 35.0, 50.3, 51.4, 53.5,
performed using Phenomenex Luna C18(2) column (15 μm, 56.2, 128.5 (2C), 128.7 (2C).
250 × 30 mm, 100 Å). A gradient method using the following
2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-hydroxyethyl)nortropane
two mobile phases was used: A: 0.1% TFA in water; B: 0.1%
(6). 2β-Carbomethoxy-3β-(4-chlorophenyl)nortropane (5, 0.56g,
TFA in acetonitrile/water (9:1). The gradient profile and timing
2 mmol) 2-bromoethanol (1.02 g, 8 mmol) and triethylamine
were identical for all purifications: (i) 0–10 min: linear gradient
(1.11 g, 11 mmol) were dissolved in acetonitrile (30 mL) and the
from 0% to 60% B, followed by (ii) 10–20 min: 60% B, and
resulting solution heated at 80°C for 5 h under argon atmosphere.
finally, (iii) 20–21 min: linear gradient from 60% to 0% B. A
The reaction mixture was then concentrated under reduced
maximum of 20 mg of each substance dissolved in acetonitrile
pressure to dryness and the residue dissolved in methylene
(1mL) was loaded onto the column. Flow rate of 15 mL/min and
chloride (30 mL). The solution was then washed with water
UV detection at 220 nm were used. Each purification run lasted
(30 mL), aqueous saturated NaHCO3 (30 mL), water again (30 mL),
35min.
and finally dried over anhydrous Na2SO4 for 12 h followed by
Analytical HPLC. Analytical HPLC was run on Shimadzu (USA) evaporation to dryness. The crude product (0.70 g) was purified
system consisting of LC-20AD pump, SPD-M20A diode array by crystallization from petroleum ether to afford 0.58 g of
detector, CBM-20A controller, and the LC Solution software. compound 6 (1.78 mmol, 89%) as colorless needles and with a
Radioanalytical HPLC was run on Agilent system (Agilent purity >99% (HPLC, UV, 220 nm). m.p.: 102–104°C; (lit. 103–104.5°C);
www.jlcr.org
Copyright © 2014 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2014, 57 148–157

J. Pijarowska-Kruszyna et al.
9 MS: [M + H]+ = 324; 1H NMR (500 MHz, CDCl3) δ: 1.65–1.69 (m, 1H, H- crystallization from acetonitrile to afford compound 15 (0.25 g,
4α), 1.71–1.83 (m, 2H, H-6α, H-7α), 2.13–2.17 (m, 1H, H-6β), 2.20– 0.43 mmol, 80%) as white solid and with purity >95% (HPLC,
2.50 (m, 1H, H-7β), 2.40–2.46 (td, 1H, H-4β), 2.75–2.77 (m, 1H, H- UV, 220 nm). m.p.: 225–231°C; MS: [M + H]+ = 585; 1H NMR
2), 3.21–3.25 (m, 1H, H-3), 3.40 (s, 3H, O-CH3), 3.80–3.81 (m, 1H, (500 MHz, CDCl3) δ: 1.56–1.79 (m, 6H, H-4α, H-6α, H-7α, H-4α’,
H-5), 3.82–3.87 (m, 2H, H-1, N-H), 7.11–7.27 (m, 4H, ArCl); 13C H-6α’, H-7α’), 2.07–2.11 (m, 2H, H-6β, H-6β’), 2.12–2.19 (m, 2H,
NMR (500 MHz, CDCl3) δ: 27.2, 28.5, 33.1, 35.0, 50.3, 51.4, 53.5, H-7β, H-7β’), 2.21–2.37 (m, 2H, CH2), 2.39–2.46 (m, 2H, CH2),
56.2, 128.5 (2C), 128.7 (2C).
2.47–2.51 (td, 2H, H-4β, H-4β’), 2.85–2.86 (m, 2H, H-2, H-2’),
2.94–3.03 (m, 2H, H-3, H-3’), 3.39 (m, 2H, H-5, H-5’), 3.49 (m, 6H,
O-CH3, O-CH3’), 3.68–3.76 (m, 2H, H-1, H-1’), 7.16–7.30 (m, 8H,
ArCl, ArCl’); 13C NMR (600 MHz, CDCl3) δ: 25.9 (2C), 26.0 (2C),
33.0 (2C), 33.7 (2C) 34.0 (2C), 51.4 (2C), 52.8 (2C), 53.8 (2C), 61.4
(2C), 63.7 (2C), 127.9 (4C), 128.7 (4C).
(2-Fluoroethyl)-4-bromobenzenesulfonate (7). A mixture of 2-
fluoroethanol (2.5 g, 39 mmol), anhydrous pyridine (15 mL), and
anhydrous THF (30 mL) under an argon atmosphere was cooled to
5°C using an ice/water bath. The solution of 4-bromobenzenesulfonyl
chloride in anhydrous THF (15mL) was added dropwise; the
reaction mixture was then allowed to warm to room temperature Method II. 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-hydroxyethyl)
and stirred for 2 days. After this time, water with ice (100mL) nortropane (6, 0.10 g, 0.31 mmol) was dissolved in anhydrous
was added to the reaction solution, which was then adjusted to methylene chloride (20 mL), and this solution was then added
pH 2 by addition of concentrated HCl. The product was then dropwise to a cooled (ice/water bath) solution of p-toluenesulfonic
extracted with methylene chloride (3× 100 mL). The combined anhydride (0.20 g, 0.62 mmol) in anhydrous methylene chloride
organic extracts were dried over anhydrous MgSO4, and (50 mL). The mixture was then heated at 45°C under argon
concentrated in vacuo to afford 7.1g (25 mmol, 58%) of crude atmosphere for 20h or until total disappearance of compound 6
product 7 as yellow oil. Purification by flash chromatography (HPLC-monitoring of the reaction). The crude product (0.12 g,
(hexane/EtOAc, 4:1) on silica gel gave compound 7 (5.7g, 20 mmol, 0.25 mmol, 82%) was then diluted in acetonitrile and purified
47%) as a white solid and with a purity >98% (HPLC, UV, 220 nm). by preparative HPLC. The fractions containing the desired
m.p.: 44–45°C (lit. 43.5–45°C);8 MS: [M+ Na]+ = 307; 1H NMR product were collected, combined and concentrated to dryness
(500 MHz, CDCl3) δ: 1.65–1.69 (m, 1H, H-4α), 1.71–1.83 (m, 2H, to afford compound 9 (85 mg, 0.18 mmol, 58%) as colorless oil
H-6α, H-7α), 2.13–2.17 (m, 1H, H-6β), 2.20–2.50 (m, 1H, H-7β), and with purity >99% (HPLC, UV, 220 nm). MS: [M + H]+ = 478;
2.40–2.46 (td, 1H, H-4β), 2.75–2.77 (m, 1H, H-2), 3.21–3.25 1H NMR (500 MHz, CDCl3) δ: 1.99–2.11 (m, 1H, H-4α), 2.15–2.24
(m, 1H, H-3), 3.40 (s, 3H, O-CH3), 3.80–3.81 (m, 1H, H-5), 3.82–3.87 (m, 2H, H-6α, H-7α), 2.49–2.55 (m, 4H, H-6β, CH3ÀAr (Ts)),
(m, 2H, H-1, N-H), 7.11–7.27 (m, 4H, ArBr); 13C NMR (500 MHz, 2.64–2.67 (m, 1H, H-7β), 2.89–2.94 (td, 1H, H-4β), 3.03–3.04 (m,
CDCl3) δ: 27.2, 28.5, 33.1, 35.0, 50.3, 51.4, 53.5, 56.2, 128.5 (2C), 1H, H-2), 3.40–3.46 (m, 4H, O-CH3, H-3), 3.58–3.62 (m, 1H, H-5),
128.7 (2C).
3.80–3.84 (m, 1H, H-1), 4.32–4.44 (m, 2H, CH2-N), 4.53–4.56
(m, 2H, O-CH2), 7.10–7.33 (m, 4H, ArCl), 7.38–7.82 (m, 4H, Ar
(Ts)); 13C NMR (500 MHz, CDCl3) δ: 21.7, 23.8, 24.6, 32.1, 34.0,
49.3, 51.9 (2C), 53.0, 64.0, 65.2, 128.1 (2C), 128.6 (2C), 129.1
(2C), 130.3 (2C).
2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane
(FECNT, 8). 2β-Carbomethoxy-3β-(4-chlorophenyl)nortropane (5,
0.25 g, 0.89 mmol) and (2-fluoroethyl)-4-bromobenzenesulfonate
(7, 0.3 g, 1.06 mmol) were dissolved in anhydrous acetonitrile
(3 mL), and Na2CO3 (0.3 mg, 2.9 mmol) was added. The solution
was heated at 130°C for 2 h using oil bath. The reaction mixture
was then cooled to room temperature, filtered, and
concentrated to dryness. The solid residue was finally purified
by crystallization from hexane to afford compound 8 (0.215 g,
0.66 mmol, 74%) as white solid and with purity >99% (HPLC,
UV, 220 nm). m.p.: 81–82°C; MS: [M + H]+ = 326; 1H NMR
(500 MHz, CDCl3) δ: 1.65–1.69 (m, 1H, H-4α), 1.71–1.83 (m, 2H,
H-6α, H-7α), 2.13–2.17 (m, 1H, H-6β), 2.20–2.50 (m, 1H, H-7β),
2.40–2.46 (td, 1H, H-4β), 2.75–2.77 (m, 1H, H-2), 3.21–3.25 (m,
1H, H-3), 3.40 (s, 3H, O-CH3), 3.80–3.81 (m, 1H, H-5), 3.82–3.87
(m, 2H, H-1, N-H), 7.11–7.27 (m, 4H, ArCl); 13C NMR (500 MHz,
CDCl3) δ: 27.2, 28.5, 33.1, 35.0, 50.3, 51.4, 53.5, 56.2, 128.5 (2C),
128.7 (2C).
2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-mesyloxyethyl)nortropane
(10). 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-hydroxyethyl)
nortropane (6, 100 mg, 0.31 mmol) was dissolved in anhydrous
methylene chloride (3 mL) and pyridine (0.59 g, 0.75 mmol)
was added. The mixture was then cooled (ice/water bath),
and a solution of methanesulfonic anhydride (0.10 g, 0.57 mmol)
in anhydrous dichloromethane (3 mL) was added dropwise.
The mixture was then heated at room temperature under
atmosphere of dry argon for 1.5 h or until total disappearance
of compound 6 (HPLC-monitoring of the reaction). Anhydrous
ether (5 mL) was then added to the reaction mixture. The oily
layer was separated, redissolved in dichloromethane (1 mL),
and diethyl ether (5 mL) was again added. This operation
was repeated twice. Finally, the oily layer was dried in
vacuum to give 0.14 g of 10 as colorless oil, which was then
redissolved in acetonitrile and purified by preparative HPLC.
The fractions containing the desired product were collected,
2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-tosyloxyethyl)
nortropane (9)
Method I [1,2-di-[2β-carbomethoxy-3β-(4-chlorophenyl)nortropanyl] combined and concentrated to dryness to afford compound
ethane (15)]. 2β-Carbomethoxy-3β-(4-chlorophenyl)nortropane 10 (100 mg, 0.25 mmol, 81%) as colorless oil and with purity
(5, 0.3 g, 1.07 mmol) and 1,2-ethanodiol di-(4-toluenosulfonate) >99% (HPLC, UV, 220 nm). MS: [M + H]+ = 402; 1H NMR
(13, 0.47 g, 1.26 mmol) were dissolved in anhydrous acetonitrile (600 MHz, CDCl3) δ: 2.00 (m, 1H, H-4α), 2.17–2.21 (m, 2H,
(5 mL). Then, Na2CO3 (0.3 mg, 2.9 mmol) was added, and the H-6α, H-7α), 2.51–2.63 (m, 2H, H-6β, H-7β), 3.04 (td, 1H,
mixture was heated at 130°C for 8 h using an oil bath. The H-4β), 3.18 (s, 3H, CH3-S), 3.40–3.44 (m, 4H, O-CH3, H-3), 3.58
reaction mixture was then cooled to room temperature, filtered, (m, 1H, H-5), 3.82 (m, 1H, H-1), 4.75 (m, 2H, CH2-N), 4.85
and washed with methylene chloride (2 × 2 mL) and diethyl (m, 2H, O-CH2), 7.10–7.33 (m, 4H, ArCl); 13C NMR (600 MHz,
ether (2 × 2 mL). The filtrate and combined washes were CDCl3) δ: 23.8, 25.0, 32.0, 34.0, 37.5, 49.3, 52.1, 52.9, 53.3,
concentrated to dryness, and the solid residue was purified by 63.8, 64.0, 128.6 (2C), 129.2 (2C).
J. Label Compd. Radiopharm 2014, 57 148–157
Copyright © 2014 John Wiley & Sons, Ltd.
www.jlcr.org

J. Pijarowska-Kruszyna et al.
2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-chloroethyl)nortropane (11). fluorination of compound 9, 10, 11, or 12 were carried out in
pressure vessels. For this, solutions containing the appropriated
Method I [1,2-di-[2β-carbomethoxy-3β-(4-chlorophenyl)nortropanyl]
precursor (1 mg, 2.1 μmol for 9, 2.5 μmol for 10, 2.9 μmol for
ethane (15)]. 2β-Carbomethoxy-3β-(4-chlorophenyl)nortropane
11, 2.7 μmol for 12), Kryptofix®222 (18 mg, 47.8 μmol) and KF
(5, 0.33g, 1.18mmol) and (2-chloroethyl)-4-bromobenzenesulfonate
(2.8 mg, 47.8 μmol) in dry acetonitrile (1 mL) were loaded into
(14, 0.425g, 1.42 mmol) were dissolved in anhydrous acetonitrile
dedicated glass vials which were then sealed with a stopper.
(5mL). Then, Na2CO3 (0.3mg, 2.9 mmol) was added, and the
The vials were then put into the pressure vessels and the
mixture was heated at 130°C for 2 h using an oil bath. The reaction
solutions heated at 80°C (for compound 9, 10, 11, and 12) and
mixture was then cooled to room temperature, filtered, and
110°C (for compound 11 only) using oil bath until total
washed with methylene chloride (2× 2 mL) and diethyl ether
disappearance of the starting material (HPLC-monitoring of the
(2× 2 mL). The filtrate and combined washes were concentrated
reaction). Reaction times were 5, 10, 20, or 30 min. Identity of
to dryness, and the solid residue was purified by crystallization
the reaction product, FECNT (8), was established by comparison
from acetonitrile to afford compound 15 (0.3g, 0.51 mmol, 86%)
with standard by HPLC.
as white solid and with purity >98% (HPLC, UV, 220 nm). Mp:
225–231°C; MS: [M+ H]+ = 585; 1H NMR (600 MHz, CDCl3) δ:
FECNT side-product formation and isolation. Syntheses were also
1.63–1.70 (m, 6H, H-4α, H-6α, H-7α, H-4α’, H-6α’, H-7α’), 2.00
(m, 2H, H-6β, H-6β’), 2.18 (m, 2H, H-7β, H-7β’), 2.21–2.22 (m, 2H,
CH2), 2.39–2.40 (m, 2H, CH2), 2.50–2.51 (td, 2H, H-4β, H-4β’),
2.85–2.86 (m, 2H, H-2, H-2’), 2.95 (m, 2H, H-3, H-3’), 3.39–3.40
(m, 2H, H-5, H-5’), 3.41–3.49 (m, 6H, O-CH3, O-CH3’), 3.68–3.69
(m, 2H, H-1, H-1’), 7.16–7.23 (m, 8H, ArCl, ArCl’); 13C NMR
(600 MHz, CDCl3) δ: 25.8 (2C), 26.0 (2C), 33.75 (2C), 34.0 (2C), 50.1
(2C), 52.8 (2C), 53.9 (2C), 61.4 (2C), 63.7 (2C), 128.0 (4C), 128.7 (4C).
carried out in pressure vessels, using the conditions described
previously for compound 10 but with a heating period of 3 h.
Samples were then cooled to room temperature and analyzed
by HPLC. The fractions at retention time corresponding to
FECNT and to the main side-product were collected separately.
These operations were repeated four times in order to obtain
sufficient materials for further analysis. Fractions isolated by
HPLC with the expected elution time were combined and
five-fold diluted with water. The resulting solution was drawn
through a C18 Sep-Pak® cartridge (pre-activated with 10 mL
of ethanol followed by 10 mL of water). The cartridge was then
rinsed with 20 mL of water to remove residual traces of
organic solvents and then rinsed with 0.5 mL of ethanol which
was collected separately. Most FECNT as well as the side-
product was then eluted with an additional 1.0 mL portion of
ethanol. These solutions were finally concentrated to dryness,
and their contents were characterized by mass spectrometry
(ESI method).
Method II. 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-mesyloxyethyl)
nortropane (10, 50mg, 0.12 mmol) was dissolved in MEOH
saturated with HCl (10 mL). The mixture was heated at 80°C using
an oil bath for 3 h or until total disappearance of compound 10
(HPLC-monitoring of the reaction). The reaction mixture was then
cooled to room temperature, concentrated to dryness and the
crude recovered product purified by preparative HPLC. The
fractions containing the desired product were collected,
combined, and concentrated to dryness to afford compound 11
(31 mg, 0.091 mmol, 75%) as colorless oil and with purity >98%
(HPLC, UV, 220nm). MS: [M+ H]+ = 342; 1H NMR (600 MHz, CDCl3)
δ: 2.08 (m, 1H, H-4α), 2.21 (m, 2H, H-6α, H-7α), 2.50–2.65 (m, 2H,
H-6β, H-7β), 2.85 (td, 1H, H-4β), 3.07 (m, 1H, H-2), 3.46–3.47 (m,
4H, O-CH3, H-3), 3.58–3.80 (m, 2H, CH2-Cl), 4.05 (m, 2H, CH2-N),
4.39 (m, 1H, H-5), 4.56 (m, 1H, H-1), 7.10–7.34 (m, 4H, ArCl); 13C
NMR (600 MHz, CDCl3) δ: 24.0, 25.0, 32.5, 34.0, 39.0, 53.0, 53.6,
63.1, 64.4, 128.5 (2C), 129.2 (2C).
Radiochemistry
The automated radiosynthesis of [18F]FECNT ([18F]-8) from
compound 10 was carried out using SynChrom synthesizer with
computer interface. First, 10–15 GBq of cyclotron-produced H
[18F]F in 2.4 mL of [18O]H2O was trapped on the QMA Sep-Pak®
cartridge followed by fluorine-18 elution using a solution
containing Kryptofix®222 (18 mg) in 0.8 mL of CH3CN and
K2CO3 (2.8 mg) in 0.2 mL of H2O. The resulting mixture was then
heated at 105°C for 10 min under flow of nitrogen (70 mL/min) in
order to evaporate solvents and to form the K[18F]F-
Kryptofix®222 complex. Then, 1 mL of CH3CN was added, and
the content of the vessel was heated at 105°C for additional
10 min to completely dry the [18F]fluoride complex. After cooling
below 50°C, the compound 10 (4–5 mg dissolved in 1 mL CH3CN)
was added, and the solution was heated at 80°C for 10 min. To
evaluate the [18F]fluorination yields, an aliquot of the reaction
mixture was diluted with some HPLC eluent and subjected to
analytical HPLC (method B and method C).
2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-bromoethyl)nortropane
(12). 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-mesyloxyethyl)
nortropane (10, 50mg, 0.12 mmol) was dissolved in MEOH
saturated with HBr (10 mL). The mixture was heated at 80°C using
oil bath for 3 h or until total disappearance of compound 10
(HPLC-monitoring of the reaction). The reaction mixture was then
cooled to room temperature, concentrated to dryness and the
crude recovered product purified by preparative HPLC. The
fractions containing the desired product were collected,
combined, and concentrated to dryness to afford compound 12
(33 mg, 0.090 mmol, 73%) as colorless oil and with purity >98%
(HPLC, UV, 220nm). MS: [M+ H]+ = 366; 1H NMR (500 MHz, CDCl3)
δ: 2.00–2.10 (m, 1H, H-4α), 2.15–2.31 (m, 2H, H-6α, H-7α),
2.61–2.78 (m, 2H, H-6β, H-7β), 2.91–2.97 (td, 1H, H-4β), 3.11–3.15
(m, 1H, H-2), 3.45–3.48 (m, 4H, O-CH3, H-3), 3.71–3.78 (m, 2H, CH2-Br),
3.94–4.42 (br, 2H, CH2-N), 4.53 (m, 1H, H-5), 5.02 (m, 1H, H-1),
7.14–7.34 (m, 4H, ArCl); 13C NMR (500 MHz, CDCl3) δ: 24.3, 25.2, 32.3,
34.2, 39.5, 49.3, 53.2, 54.6, 63.4, 64.7, 128.6 (2C), 129.2 (2C).
Acknowledgement
Work presented herein was supported in part by the FP6 European
Network of Excellence DiMI (Grant LSHB-CT-2005-512146).
Non-radioactive fluorination assays at the micromolar scale
Conflict of Interest
Preparation of FECNT (8) via nucleophilic substitution reactions
with fluoride. One-step syntheses of FECNT (8) by direct The authors did not report any conflict of interest.
www.jlcr.org
Copyright © 2014 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2014, 57 148–157

J. Pijarowska-Kruszyna et al.
[13] PC Meltzer, AY Liang, A Brownell, DF Elmaleh, BK Madras, J. Med.
Chem. 1993, 36, 855–862.
[14] RL Clarke, SJ Daum, AJ Gambino, MD Aceto, J Pearl, M Levitt, WR
Cumiskey, EF Bogado, J. Med. Chem. 1973, 16, 1261–1267.
[15] RA Millius, JK Saha, BK Madras, JL Neumeyer, J. Med. Chem. 1991, 34,
1728–1731.
[16] FI Caroll, Y Gao, MA Rahman, P Abraham, K Parham, AH Lewin, JW
Boja, MJ Kuhar, J. Med. Chem. 1991, 34, 2719–2725.
[17] MM Goodman, MP Kung, GW Kabalka, HF Kung, R Switzer, J. Med.
Chem. 1994, 37, 1535–1542.
References
[1] MM Goodman, CD Kilts, R Keil, B Shi, L Martarello, D Xing, JR Votaw,
TD Ely, P Lambert, MJ Owens, VM Camp, E Malveaux, JM Hoffman,
Nucl. Med. Biol. 2000, 27, 1–12.
[2] RD Badgaiyan, AJ Fischman, NM Alpert, Neuroimage 2009, 47,
2041–2045.
[3] H Bernheimer, W Birkmayer, O Hornykiewicz, K Jellinger, F Seitelberger,
J. Neurol. Sci. 1973, 20, 415–455.
[4] MF Ghesselet, JM Delfs, Trends Neurosci. 1996, 19, 417–422.
[5] M Honer, B Hengerer, M Blagoev, S Hintermann, P Waldmeier, PA [18] BK Madras, MA Fahey, J Bergman, DR Canfield, RD Spealman, J.
Schubiger, SM Ametamey, Nucl. Med. Biol. 2006, 33, 607–614.
[6] MR Davis, JR Votaw, JD Bremner, MG Byas-Smith, TL Faber, RJ Voll,
JM Hoffman, ST Grafton, CD Kilts, MM Goodman, J. Nucl. Med.
2003, 44, 855–861.
[7] G Masilamoni, JR Votaw, L Howell, RM Villalba, MM Goodman, JR Voll, J
Stehouwer, T Wichmann, Y Smith, Exp. Neurol. 2010, 226, 265–273.
[8] RJ Voll, J McConathy, MS Waldrep, RJ Crowe, MM Goodman, Appl.
Radiat. Isot. 2005, 63, 353–361.
[9] ZP Chen, PW Song, ML Xiao, YL Chun, T Jie, XC Guo, NL Shi, FZ Lian,
J Jian, Appl. Rad. Isot. 2008, 66, 1881–1885.
[10] F Dollé, J Helfenbein, F Hinnen, S Mavel, Z Mincheva, W Saba, MA
Schöllhorn-Peyronneau, H Valette, L Garreau, S Chalon, C Halldin,
JC Madelmont, JB Deloye, M Bottlaender, JL Gailliard, D Guilloteau,
Emond P, J. Label. Comp.Radiopharm. 2007, 50, 716–723.
Pharmacol. Exp. Ther. 1989, 251, 131–141.
[19] BK Madras, RD Spealman, MA Fahey, JL Neumeyer, JK Saha, RA
Millius, Mol. Pharmacol. 1989, 36, 518–524.
[20] Chromatographic separation techniques. European Pharmacopoeia
7th Ed. (monograph: 20246).
[21] T Chaly, V Dhawan, K Kazamuta, A Antonini, C Margouleff, JR Dahl,
A Belakhlef, D Margouleff, A Yee, S Wang, G Tamagnan, JL
Neumeyer, D R.L. Eidelberg, M.M Gooddman, Nucl. Med. Biol. 1996,
23, 999–1004.
[22] D Xing, P Chen, R Keil, CD Kilts, B Shi, VM Camp, G Malveaux, T Ely,
MJ Owens, J Votaw, M Davis, JM Hoffman, RA BaKay, T Subramanian,
RL Watts, MM Goodman, J. Med. Chem. 2000, 43, 639–648.
[23] F Wuest, M Berndt, K Strobel, J Hoff, X Peng, JL Neumeyer, R
Bergmann, Bioorg. Med. Chem. 2007, 15, 4522–4519.
[11] T Bourdier, CJR Fookes, TQ Pham, I Greguric, Katsifis A, J. Label. [24] Block D, Coenen H, Stöcklin G. J. Label. Compd. Radiopharm. 1987,
Compd. Radiopharm. 2008, 51, 369–373.
24, 1029–1042.
[12] H Qiao, L Zhu, BP Lieberman, Z Zha, K Plössl, HF Kung, Bioorg. Med. [25] HJ Wester, Munich Molecular Imaging Handbook Series, Pharmaceutical
Chem. Lett. 2012, 22, 4303–4306.
Radiochemistry I, SCINTOMICS, Fürstenfeldbruck, 2010, pp 30–31.
J. Label Compd. Radiopharm 2014, 57 148–157
Copyright © 2014 John Wiley & Sons, Ltd.
www.jlcr.org