Synthesis of 18F-labelled 2-(4′-fluorophenyl)-1,3-benzothiazole and evaluation as amyloid imaging agent in comparison with [11C]PIB

Article abstract of DOI:10.1016/j.bmcl.2008.12.069

2-(4′-[¹⁸F]fluorophenyl)-1,3-benzothiazole was synthesized as a fluorine-18 labelled derivative of the Pittsburg Compound-B (PIB), which has known affinity for amyloid β and promising characteristics as tracer for in vivo visualisation of amylo

Full text of DOI:10.1016/j.bmcl.2008.12.069

Bioorganic & Medicinal Chemistry Letters 19 (2009) 602–605
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
18
Synthesis of F-labelled 2-(40-fluorophenyl)-1,3-benzothiazole and evaluation
as amyloid imaging agent in comparison with [11C]PIB
a
b
a
c
b
K. Serdons a, , T. Verduyckt , D. Vanderghinste , J. Cleynhens , P. Borghgraef , P. Vermaelen ,
*
C. Terwinghe b, F. Van Leuven c, K. Van Laere b, H. Kung d, G. Bormans a, A. Verbruggen a
a Laboratory for Radiopharmacy, K.U.Leuven, Herestraat 49—bus 821, B-3000 Leuven, Belgium
b Nuclear Medicine, U.Z. Gasthuisberg, B-3000 Leuven, Belgium
c Laboratory of Experimental Genetics and Transgenesis, K.U.Leuven, B-3000 Leuven, Belgium
d Department of Radiology, University of Pennsylvania, Philadelphia, USA
a r t i c l e i n f o
a b s t r a c t
2-(40-[18F]fluorophenyl)-1,3-benzothiazole was synthesized as a fluorine-18 labelled derivative of the
Pittsburg Compound-B (PIB), which has known affinity for amyloid b and promising characteristics as tra-
cer for in vivo visualisation of amyloid deposits in patients suffering from Alzheimer’s disease (AD). Both
the nitro-precursor 2-(40-nitrophenyl)-1,3-benzothiazole and the non-radioactive reference compound
were synthesized using a 1-step synthesis pathway. Labelling was achieved by direct aromatic nucleo-
philic substitution of the nitro-precursor using [18F]fluoride by heating for 20 min at 150 °C and with a
radiochemical yield of 38%. The reference compound showed high affinity for amyloid in an in vitro com-
petition binding study using human AD brain homogenates (Ki = 9.0 nM) and fluorescence imaging of
incubated transgenic APP mouse brain slices confirmed binding to amyloid plaques. A biodistribution
study in normal mice showed a high brain uptake at 2 min pi (3.20% ID/g) followed by a fast washout
Article history:
Received 28 October 2008
Revised 16 December 2008
Accepted 16 December 2008
Available online 24 December 2008
Keywords:
Amyloid
Alzheimer
PIB
2-Phenylbenzothiazole
Fluor-18
(60 min pi: 0.21% ID/g). A dynamic lPET study was performed in a transgenic APP and normal WT mouse,
but, similar to [11C]PIB, no difference was seen in tracer retention between both kind of mice. The new
18F-labelled 2-phenylbenzothiazole showed excellent preclinical characteristics comparable with those
of the 11C-labelled PIB.
Ó 2008 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is a slowly progressive and fatal neu-
rodegenerative brain disorder associated with progressive episodic
memory loss and decrease of cognitive functions and characterized
by the presence of amyloid plaques and neurofibrillary tangles.1 As
the number of affected people, as well as the economical and social
impact, will increase in the future due to the increasing average life
span, the search for a radioactive tracer which allows in vivo diag-
nosis of AD in an early stage has become an important research ob-
ject during the last years.2 Several radioactive derivatives of
thioflavin-T (ThT, Fig. 1A), a conjugated fluorescent compound
used to stain amyloid plaques in vitro, have been reported as po-
tential diagnostic tracers for this purpose.3 The most promising
of all reported compounds seems to be the carbon-11 labelled 6-
OH-BTA or 6-hydroxy-2-(40-N-[11C]methylaminophenyl)-1,3-ben-
zothiazole, also known as Pittsburgh Compound-B (PIB, Fig. 1B).
PIB has already been tested intensively in several clinical studies
showing clear differences between AD, mild cognitive impairment
(MCI) and control subjects.4 However, this agent is labelled with
short-lived carbon-11 (t1/2 = 20.39 min), which limits its availabil-
ity to centres equipped with a cyclotron. This limitation may be
overcome by introducing a fluorine-18 label which has a longer
half-life (t1/2 = 109.8 min) and thus may provide a positron emis-
sion tomography (PET) tracer that is useful for a widespread clini-
cal application.
The aim of this study was the synthesis and biological evalua-
tion of a 18F-labelled derivative of ThT, useful for diagnosis of AD
using PET. For this purpose we developed 2-(40-[18F]fluoro-
phenyl)-1,3-benzothiazole (Fig. 1C). Its structure is based on that
of PIB, in which the amine group on the 2-phenyl ring is replaced
by a 18F-atom and no OH-group is present on the benzothiazole
part. No other substituents were introduced on the benzothiazole
part or the 2-phenyl ring. Mathis et al. recently reported another
18F-labelled PIB analogue and are evaluating this compound as po-
tential amyloid imaging agent.5
The precursor for radiolabelling, 2-(40-nitrophenyl)-1,3-benzo-
thiazole (1), was synthesized using polyphosphoric acid (PPA) fol-
lowing the procedure as described by Shi et al. with small
modifications with respect to temperature (150 °C instead of
220 °C as higher yields were obtained at lower temperature).6
1
was synthesized with a yield of 34%, starting from equal molar quan-
tities of 2-aminothiophenol and 4-nitrobenzoic acid (Scheme 1).
* Corresponding author. Tel.: +32 16330441; fax: +32 16330449.
E-mail address: kim.serdons@pharm.kuleuven.be (K. Serdons).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.069

K. Serdons et al. / Bioorg. Med. Chem. Lett. 19 (2009) 602–605
603
Figure 1. Structure of thioflavin-T (ThT, A), 6-hydroxy-2-(40-N-[11C]methylaminophenyl)-1,3-benzothiazole or PIB (B) and 2-(40-[18F]fluorophenyl)-1,3-benzothiazole (C).
Scheme 1. Synthesis of 2-(40-nitrophenyl)-1,3-benzothiazole (1).
The non-radioactive 2-(40-fluorophenyl)-1,3-benzothiazole (2)
was prepared in a yield of 55% starting from 2-aminothiophenol
and 4-fluorobenzoyl chloride (Scheme 2). A more convenient
method (Dean-Stark trap instead of PPA) was used to synthesize
2.7 The identity of the non-radioactive compounds was confirmed
by mass spectrometry (MS) and 1H NMR.8–10 As described in liter-
ature, both compounds have already been synthesized in different
ways.11,12
the nitro group and facilitate the exchange of the nitro group for a
fluorine-18 atom.14 In the case of 1, the presence of the benzothi-
azole in para position of the nitro group apparently also activates
the 40-nitro group as relatively high yields of the corresponding
2-(40-[18F]fluorophenyl)-1,3-benzothiazole were obtained. This
may allow the preparation of other similar compounds that can
be radiolabelled using the same procedure, if the corresponding
precursors can withstand the conditions of the nucleophilic substi-
tution reaction.15,16
A direct radiofluorination reaction was applied for aromatic
nucleophilic substitution of a fluorine-18 atom for the nitro group
of 1 (Scheme 3).13 A solution of 1 in anhydrous DMSO was heated
at 150 °C for 20 min in the presence of K2CO3, 18Fꢀ and 2.2.2-crypt-
and to achieve 2-(40-[18F]fluorophenyl)-1,3-benzothiazole ([18F]2)
with an average yield of 38% (not decay corrected, Fig. 2) and a spe-
The in vitro affinity of the new agent [18F]2 for amyloid b pla-
ques was determined by measuring the binding affinity of the ref-
erence compound 2 for post-mortem human brain homogenates of
AD patients.17 The Ki value, obtained from binding inhibition stud-
ies using [125I]IMPY as radioligand, was 9.0 2.0 nM. This affinity is
comparable to that of 11C-labelled PIB which has a Ki value of
2.8 0.5 nM in the same assay. We can assume that the newly
developed 2-(40-[18F]fluorophenyl)-1,3-benzothiazole binds to the
same binding sites in the amyloid b plaques as do [125I]IMPY and
cific activity of 48 19 GBq/l
mol. The separation of the 4’-[18F]flu-
oro and 40-nitro phenylbenzothiazole proved to be difficult but the
use of reversed-phase high-performance liquid chromatography
(RP-HPLC) with a mobile phase consisting of a mixture of ethanol,
tetrahydrofuran and 0.05 M ammonium acetate buffer made it
possible to separate the fluorine-18 labelled compound [18F]2 from
the nitro-precursor 1. The identity of the 18F-labelled 2-phen-
ylbenzothiazole [18F]2 was confirmed by co-injection of the non-
radioactive reference compound 2 on RP-HPLC and comparison of
the retention times. This radiolabelling is an example of a direct
aromatic nucleophilic substitution with fluorine-18 of a 2-(40-
nitrophenyl)-1,3-benzothiazole in which the benzothiazole part
acts as electron-withdrawing group. It is well known that elec-
tron-withdrawing substituents, such as a nitro or carbonyl group,
present on the ortho or para position of a nitrophenyl ring, activate
[
11C]PIB.
The in vitro affinity for amyloid of the new 18F-labelled agent
was also tested by incubating transgenic APP mouse brain slices
with the non-radioactive reference compound 2.18,19 The same
slices were immunohistochemically stained with the amyloid-
binding monoclonal mouse antibody AbN25 to compare the re-
gions with high amyloid load. Fig. 3 shows a superimposed image
of both staining methods in the mouse subiculum, a highly plaque
loaded structure located in the hippocampal region. The fluores-
cent signal from compound 2 clearly indicates the same amyloid
plaques as the immunohistochemical signal from the staining with
Scheme 2. Synthesis of 2-(40-fluorophenyl)-1,3-benzothiazole (2).
Scheme 3. Radiosynthesis of 2-(40-[18F]fluorophenyl)-1,3-benzothiazole ([18F]2).

604
K. Serdons et al. / Bioorg. Med. Chem. Lett. 19 (2009) 602–605
Figure 2. RP-HPLC chromatogram of the crude reaction mixture after labelling of 1 with 18F with A = radiometric channel and B = UV channel (254 nm). The radioactive
compound [18F]2 elutes at 13.5 min, while the precursor 1 elutes at 14.5 min.
pi: 0.60% ID/g), although the washout from normal brain (% ID
cerebrum 2 min pi/% ID cerebrum 60 min pi) seems faster for the
18F-labelled compound (14.7 vs 6.0). The tissue distribution in
other organs was quite similar to that of [11C]PIB (data not shown).
Clearance of the activity from the blood is relatively efficient and
parallels clearance from the brain. The uptake in the kidneys and
excretion in the urine is moderate. Hepatobiliary excretion to the
intestines is pronounced and rather fast. The total activity in the
hepatobiliary system is 30.3% ID at 2 min pi and 49.4% ID at
60 min pi.
2-(40-[18F]fluorophenyl)-1,3-benzothiazole [18F]2 was also in-
jected intravenously in a transgenic APP and normal WT mouse
to perform a dynamic
anaesthetic was used for the
l
PET study during 60 min.18,23 A different
lPET studies as compared to the bio-
distribution study (isoflurane vs HypnormÒ), but we previously
found that none of these anaesthetics has an influence on both
brain uptake and brain washout of phenylbenzothiazoles. How-
Figure 3. Vibratome section of a transgenic APP mouse brain subiculum stained
with AbN25 (brown) in combination with 1
benzothiazole 2 (blue).
l
M solution of 2-(40-fluorophenyl)-1,3-
ever, comparison of
lPET and biodistribution results should be
interpreted with caution. The amount of activity present in the
frontal cortex, expressed as standard uptake value (SUV), showed
a high brain uptake and fast washout. Normally we do not expect
a washout in the transgenic APP mouse but the difference in brain
washout between the APP and WT mouse was rather baseline
(Fig. 4). The same results were obtained when both mice were in-
jected with 11C-labelled PIB. The absence of difference in [11C]PIB-
retention between normal WT and transgenic APP mice is in accor-
dance with earlier published data, showing differences between
human and mouse amyloid.24,25
AbN25. Comparable images were also obtained after incubation
with the non-radioactive analogue of PIB (data not shown).
To estimate the ability of the new compound to pass the blood–
brain barrier (BBB) by passive diffusion, the lipophilicity of RP-
HPLC purified [18F]2 was determined by partitioning between 1-
octanol and 0.025 M phosphate buffer pH 7.4 (n = 6).20 The log par-
tition coefficient (P) value was 2.86 0.05, which is comparable
with that of PIB (2.48 0.06) and within the optimal range (logP
between 1 and 3) for passive diffusion of a compound through
the BBB.21
In conclusion, 2-(40-[18F]fluorophenyl)-1,3-benzothiazole [18F]2
showed excellent characteristics comparable with those of
Biodistribution of [18F]2 was studied in normal mice, which
were sacrificed at 2 or 60 min pi.18,22 The results are shown in Ta-
ble 1. The initial brain uptake was high at 2 min pi (3.20% ID/g) and
was followed by a rapid washout (at 60 min pi: 0.21% ID/g). Similar
values were observed for [11C]PIB (2 min pi: 3.60% ID/g and 60 min
[
11C]PIB, namely good affinity for amyloid plaques present in hu-
man AD brain homogenates and transgenic APP mouse brain sec-
tions, favourable logP value for BBB passage and a high initial
brain uptake in normal mice followed by a fast washout. The brain
Table 1
Tissue distribution expressed as percentage of the injected dose (% ID) and percentage of the injected dose per gram tissue (% ID/g) after iv injection of 2-(40-[18F]fluorophenyl)-
1,3-benzothiazole [18F]2 in normal mice at 2 and 60 min pi (n = 4 at each time point)
2 min pi (% ID)
2 min pi (% ID/g)
60 min pi (% ID)
60 min pi (% ID/g)
Urine
Kidneys
Liver
Lungs
Intestines
Blood
0.6 0.2
11.4 1.6
21.8 1.8
3.9 1.0
8.5 0.6
7.8 0.7
—
15.5 2.7
5.9 1.5
11.7 1.5
0.4 0.0
37.7 4.3
1.8 0.3
0.07 0.01
0.02 0.01
—
17.9 1.7
10.2 1.6
13.8 2.3
—
2.9 0.2
3.20 0.38
3.35 0.38
8.2 1.8
5.3 0.6
1.5 0.3
—
0.6 0.1
0.21 0.03
0.21 0.05
Cerebrum
Cerebellum
1.03 0.13
0.33 0.08

K. Serdons et al. / Bioorg. Med. Chem. Lett. 19 (2009) 602–605
605
room temperature and after dilution with an equal volume of 0.05 M
ammonium acetate purified with RP-HPLC using an XTerraTM MS C18 3.5
lm
column (2.1 mm ꢁ 50 mm, Waters), eluted isocratically with a mixture of
0.05 M ammonium acetate, tetrahydrofuran and ethanol (50:37:13, v/v) at a
flow rate of 1 ml/min. The fraction containing the isolated radioactive
compound was diluted with an equal volume of water and then applied on
an activated Sep-PakÒ Plus C18 cartridge (Waters, first activated by successive
washing with 5 ml ethanol and 10 ml water) that was rinsed with 10 ml water
and then eluted with 1 ml ethanol. The purity of the labeled tracer was
analysed using an XTerra RP18
5 lm 4.6 ꢁ 250 mm column (Waters) eluted
with an isocratic mixture of 50% 0.05M ammonium acetate and 50% ethanol/
tetrahydrofuran (75:25, v/v) at a flow rate of 1 ml/min (Rt [18F]2 = 28.5 min).
14. Kilbourn, M. R. Fluorine-18 Labeling of Radiopharmaceuticals. Nuclear Science
Series; National Academy Press: Washington, DC, 1990.
Figure 4. Dynamic l
PET study of [11C]PIB and 2-(40-[18F]fluorophenyl)-1,3-benzo-
thiazole [18F]2 in a normal WT and transgenic APP mouse (left coronal image at 60 s
15. Serdons, K.; Terwinghe, C.; Vermaelen, P.; Kung, H.; Bormans, G.; Verbruggen,
A. J. Nucl. Med. 2006, 47, 31P.
16. Chitneni, S. K.; Serdons, K.; Evens, N.; Fonge, H.; Celen, S.; Deroose, C. M.;
Debyzer, Z.; Mortelmans, M.; Verbruggen, A. M.; Bormans, G. M. J. Chromatogr.
A 2007, 1189, 323.
17. Kung, M. P.; Hou, C.; Zhuang, Z. P.; Skovronsky, D.; Kung, H. F. Brain Res. 2004,
1025, 89.
18. All animal experiments were approved by the local Ethical Committee.
pi was similar for both compounds in both animals).
washout of [18F]2 observed in normal mice is more than two times
faster than that observed for [11C]PIB. These promising results
make [18F]2 a potential amyloid imaging agent for in vivo visual-
isation of amyloid plaques with a similar diagnositic power as
19. Vibratome sections (40
human APP (amyloid precursor protein) were incubated for 1 h at room
temperature with the non-radioactive compound 2 at a concentration of 1 M.
lm) of the brain of transgenic mice overexpressing
11C]PIB and the potential of a widespread clinical application.
l
[
After incubation, the sections were rinsed with tap water and treated with 0.2%
NaOH in 80% ethanol to reduce background staining. The slices were rinsed
again with tap water and coverslipped using a Mowiol-DABCO solution. For
immunohistochemical staining, the same vibratome sections were treated
with a 0.1% Triton X-100 solution in PBS (PBST) and 10% foetal calf serum to
block non-specific binding. The slices were subsequently incubated overnight
with the amyloid-binding monoclonal antibody AbN25 (Oncogene Research
Products, San Diego, CA, USA) which stains both dense and fibrillar plaques.
The sections were treated again with PBST and rinsed with PBS before fixation
with Mowiol-DABCO solution. Fluorescence microscopy was performed using a
Leica DMR microscope equipped with a digital Leica DC480 camera and a UV
filter set with following specifications: excitation: 340–380 nm bandpass filter,
dichromatic mirror 400 nm; emission: 425 nm longpass filter. The images
were collected and processed with Leica IM500 image processing software.
20. Serdons, K.; Verduyckt, T.; Cleynhens, J.; Bormans, G.; Verbruggen, A. J. Label.
Compd. Radiopharm. 2008, 51, 357.
References and notes
1. Selkoe, D. J. Physiol. Rev. 2001, 81, 741.
2. Blennow, K.; de Leon, M.; Zetterberg, H. Lancet 2006, 368, 387.
3. Furumoto, S.; Okamura, N.; Iwata, R.; Yanai, K.; Arai, H.; Kudo, Y. Curr. Top. Med.
Chem. 2007, 7, 1773.
4. Klunk, W. E.; Engler, H.; Nordberg, A.; Wang, Y.; Blomqvist, G.; Holt, D.;
Bergström, M.; Savitcheva, I.; Huang, G.; Estrada, S.; Ausén, B.; Debnath, M.;
Barletta, J.; Price, J. C.; Sandell, J.; Lopresti, B.; Wall, A.; Koivisto, P.; Antoni, G.;
Mathis, C.; Langström, B. Ann. Neurol. 2004, 55, 306.
5. Mathis, C.; Lopresti, B.; Mason, N.; Price, J.; Flatt, N.; Bi, W.; Ziolko, S.; DeKosky,
S.; Klunk, W. J. Nucl. Med. 2007, 48, 56P.
6. Shi, D.-F.; Bradshaw, T. D.; Wrigley, S.; McCall, C. J.; Lelieveld, P.; Fichtner, I.;
Stevens, M. F. G. J. Med. Chem. 1996, 39, 3375.
21. Dishino, D.; Welch, M.; Kilbourn, M.; Raichle, M. J. Nucl. Med. 1983, 24, 1030.
22. A solution of [18F]2 obtained after RP-HPLC purification was diluted using 0.9%
NaCl in water for injection to a concentration of 3.7 MBq/ml. The concentration
of ethanol did not exceed 10% and the concentration of THF did not exceed
0.02%, as determined by gas chromatography. The biodistribution was studied
in male NMRI mice (body mass 30–40 g). An aliquot of 0.1 ml of the diluted
tracer solution was injected into the mice via a tail vein, after intraperitoneal
7. Mathis, C. A.; Bacskai, B. J.; Kajdasz, S. T.; McLellan, M. E.; Frosch, M. P.; Hyman,
B. T.; Holt, D. P.; Wang, Y.; Huang, G.-F.; Debnathd, M. L.; Klunk, W. E. Bioorg.
Med. Chem. Lett. 2002, 12, 295.
8. Accurate mass determination was performed on
a time-of-flight mass
spectrometer (LCT, Micromass, Manchester, UK) equipped with an orthogonal
electrospray ionisation interface, operated in positive mode (ES+). Formic acid
was added to enhance electrospray ionisation. The drift of the mass
injection of 0.1 ml HypnormÒ (fentanyl citrate 63
lg/ml and fluanisone 2 mg/
spectrometer was corrected by co-injection of
a compound with known
ml). The mice were sacrificed by decapitation at 2 or 60 min pi. Blood was
collected in a tared tube and weighed. All organs and other body parts were
mass. After acquisition of the data with Masslynx software (version 3.5), the
spectrum was corrected using this compound as lock mass.
9. Compound 1: 1H NMR (CDCl3): d 7.47 (1H, dd, 6-H); d 7.57 (1H, dd, 5-H); d 7.97
(1H, d, 4-H); d 8.14 (1H, d, 7-H); d 8.27 (2H, d, 20-H 60-H); d 8.36 (2H, d, 30-H 50-
H). Accurate MS–ES+ m/z [M+H]+ 257.0356 (calcd for C13H8N2O2S 257.0379).
Mp 226.1–227.4 °C.
dissected and weighed, and their radioactivity was counted in
a gamma
counter. Results were corrected for background radioactivity and are expressed
as percentage of the injected dose (% ID) or as percentage of the injected dose
per gram tissue (% ID/g). For calculation of total radioactivity in blood, blood
mass was assumed to be 7% of the total body mass.
10. Compound 2: 1H NMR (CDCl3): d 7.16 (2H, dd, 30-H 50-H); d 7.38 (1H, t, 5-H); d
7.50 (1H, t, 6-H); d 7.90 (1H, d, 7-H); d 8.06 (2H, d, 20-H 60-H); d 8.10 (1H, d, 4-
H). Accurate MS–ES+ m/z [M+H]+ 230.2855 (calcd for C14H10NFS 230.2856). Mp
97.2–98.5 °C.
23. Dynamic
lPET imaging was performed with a Focus 220 microPET scanner
(Siemens Medical Solutions USA, Inc), which has a transaxial resolution of
1.35 mm in full-width at half-maximum. Before being imaged, a transgenic
APP mouse (50 months old) and a normal WT mouse (2 months old) were
anaesthesised with isoflurane (1.5–2.5%) in oxygen at a flow rate of 1–2 l/min
and were injected via a tail vein with 2.11 and 6.57 MBq [18F]2, respectively.
The mice were breathing spontaneously throughout the entire experiment.
11. Kamal, A.; Ahmed, S. K.; Reddy, K. S.; Khan, M. N. A.; Shetty, R. V.; Siddhardha,
B.; Murty, U. S. N.; China, A.; Nagaraja, V. Lett. Drug Des. Discov. 2007, 4, 550.
12. Mu, X.-J.; Zou, J.-P.; Zeng, R.-S.; Wu, J.-C. Tetrahedron Lett. 2005, 46, 4345.
13.
[
18F]Fluoride was produced via a [18O(p,n)18F] reaction by irradiation of 0.5 ml
of 97% enriched H218O (Rotem HYOX18, Rotem Industries, Beer Sheva, Israel) in
a niobium target using 18-MeV protons from a Cyclone 18/9 cyclotron (Ion
Beam Applications, Louvain-la-Neuve, Belgium). The aqueous solution of
Dynamic
lPET images were acquired for 60 min (4 ꢁ 15 s, 4 ꢁ 60 s, 5 ꢁ 180 s,
8 ꢁ 300 s) and reconstruction was done using filtered back projection with a
RAMP 0.5 filter. Data were analysed using PMOD2.7, volumes of interest (VOIs)
were defined on the summed images, time–activity curves (TACs) were drawn
and values were expressed as standard uptake values (SUV). The same mice
were also injected with 2.40 and 8.47 MBq [11C]PIB, respectively (1 week
interval).
[
18F]Fꢀ was transferred to a synthesis module where [18F]Fꢀ was separated
from H218O using a Sep-PakÒ Light Waters AccellTM Plus CM cartridge (Waters).
[
18F]Fꢀ was then eluted from the cartridge into a reaction vial with a solution
containing 2.5 mg potassium carbonate and 27.9 mg 2.2.2-cryptand dissolved
in 0.75 ml of water/acetonitrile (5:95 v/v). After evaporation of the solvent
from the reaction vial under a stream of helium at 115 °C for 7 min, [18F]Fꢀ was
24. Klunk, W. E.; Lopresti, B. J.; Ikonomovic, M. D.; Lefterov, I. M.; Koldamova, R. P.;
Abrahamson, E. E.; Debnath, M. L.; Holt, D. P.; Huang, G.-F.; Shao, L.; DeKosky, S.
T.; Price, J. C.; Mathis, C. A. J. Neurosci. 2005, 25, 10598.
25. Toyama, H.; Ye, D.; Ichise, M.; Liow, J.-S.; Cai, L.; Jacobowitz, D.; Musachio, J. L.;
Hong, J.; Crescenzo, M.; Tipre, D.; Lu, J.-Q.; Zoghbi, S.; Vines, D. C.; Seidel, J.;
Katada, K.; Green, M. V.; Pike, V. W.; Cohen, R. M.; Innis, R. B. Eur. J. Nucl. Med.
Mol. Imaging 2005, 32, 593.
further dried by azeotropic distillation of traces of water using
1 ml of
anhydrous acetonitrile (115 °C, 5 min). A solution of 1.5 mg 2-(40-nitrophenyl)-
1,3-benzothiazole in 0.5 ml anhydrous DMSO was added to the radioactive
residue and the mixture was heated at 150 °C for 20 min in a closed vial to
provide the crude radiolabeled compound. The mixture was cooled down to