Synthesis of [11C]FEDAA1106 as a new PET imaging probe of peripheral benzodiazepine receptor expression

Article abstract of DOI:10.1016/j.ejmech.2008.08.001

Peripheral benzodiazepine receptor (PBR) is associated with neuroinflammation and tumor progression. [¹¹C]DAA1106 and [¹⁸F]FEDAA1106 are two promising radioligands for positron emission tomography (PET) imaging of PBR. This study was

Full text of DOI:10.1016/j.ejmech.2008.08.001

European Journal of Medicinal Chemistry 44 (2009) 2748–2753
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Laboratory note
Synthesis of [11C]FEDAA1106 as a new PET imaging probe of peripheral
benzodiazepine receptor expression
*
Min Wang, Mingzhang Gao, Gary D. Hutchins, Qi-Huang Zheng
Department of Radiology, Indiana University School of Medicine, 1345 West 16th Street, L3-208, Indianapolis, IN 46202-2111, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 June 2008
Received in revised form 1 August 2008
Accepted 4 August 2008
Available online 13 August 2008
Peripheral benzodiazepine receptor (PBR) is associated with neuroinflammation and tumor progression.
[
11C]DAA1106 and [18F]FEDAA1106 are two promising radioligands for positron emission tomography
(PET) imaging of PBR. This study was designed to develop a new radiolabeled analog of [11C]DAA1106
and [18F]FEDAA1106, [11C]FEDAA1106, for PET imaging of PBR expression in brain and cancer. Precursor
N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-hydroxybenzyl)acetamide (9) was synthesized
in multiple steps with moderate to high chemical yields. Precursor 9 was labeled by [11C]CH3OTf and
isolated by high pressure liquid chromatography (HPLC) purification to provide target radioligand
N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-[11C]methoxybenzyl)acetamide ([11C]FEDAA1106,
Keywords:
Positron emission tomography
Peripheral benzodiazepine receptor
11C]FEDAA1106
[
[
11C]10) in 60–70% radiochemical yields, decay corrected to end of bombardment (EOB), based on
[
11C]CO2. The specific activity of the target radiotracer [11C]10 was in a range of 111–185 GBq/
m
mol at the
Brain and tumor imaging
end of synthesis (EOS).
Ó 2008 Elsevier Masson SAS. All rights reserved.
1. Introduction
nzyl)acetamide) were reported as potent and selective ligands for
PBR and displayed high PBR binding affinities (Ki ¼ 0.16 nM and
0.078 nM in rat brain sections, respectively) [19–22]. Both ligands
had more potent in vitro binding affinities for PBR than PK11195
(1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-isoquinoline-3-
carboxamide), a standard ligand for PBR [23,24]. Consequently,
The peripheral benzodiazepine receptor (PBR) is a protein found
in lung, liver, heart, spleen, kidney, adrenals, brain, glial cells, masts
cell and macrophages and implicated in numerous nervous system
disorders such as epilepsy, cerebral ischemia, nerve injury and
neurodegenerative diseases, and immune system diseases such as
cancer [1]. PBR is an attractive target for molecular imaging
of neuroinflammation and tumor progression. There is great interest
in imaging of PBR expression in human diseases such as Alzheimer’s
disease and neurofibromas [2–18]. The high-affinity PBR ligands
include new compounds with structural classes of isoquinoline
carboxamides, quinoline carboxamides, benzothiazepines, benzox-
azepines, indoleacetamides, pyrazolopyrimidines, vinca alkaloids,
and aryloxyanilides [1]. These small molecule ligands may have
high binding affinity but still lack specificity for the receptor
due to non-specific interactions. Recently two acetamide parent
compounds DAA1106 (N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-
phenoxyphenyl)acetamide) and its derivative FEDAA1106 (N-
(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-methoxybe
carbon-11 labeled analog of DAA1106,
11C]methoxy-5-methoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)
acetamide) and fluorine-18 labeled analog of FEDAA1106,
18F]FEDAA1106 (N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-[18F]fluo-
[
11C]DAA1106 (N-(2-
[
[
roethoxy)-5-methoxybenzyl)acetamide), have been developed as
two promising radioligands for positron emission tomography (PET)
[22,25–27], and the in vivo biological evaluation displayed high
specific binding of both radioligands to PBR, which suggested both
compounds have high specificity [25]. Previous results indicated
[
[
18F]FEDAA1106 has higher PBR affinity and specificity than
11C]DAA1106, but requires more complex radiosynthesis.
Compared to fluorine-18 tracers (half-life 110 min), carbon-11
tracers (half-life 20 min) have some advantages in back-to-back
same-day PET studies, such as avoiding movement of the subject
from the PET scanner and performing another study within 2–3 h to
explore drug effects at the first study. These advantages become very
valuable in studying pharmacological or behavioral changes [28].
We are interested in the development of new PET PBR radioligands.
This study was designed to develop a new analog radioligand of
Abbreviations: PBR, peripheral benzodiazepine receptor; PET, positron emission
tomography; HPLC, high pressure liquid chromatography; EOB, end of bombard-
ment; EOS, end of synthesis; TMS, tetramethylsilane; HRMS, high resolution mass
spectra; TLC, thin-layer chromatography; rt, room temperature; RDS, radionuclide
delivery system; INGEN, Indiana Genomics Initiative.
[
11C]DAA1106 and [18F]FEDAA1106, [11C]FEDAA1106 (N-(5-fluoro-
2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-[11C]methoxybenzyl)
acetamide, [11C]10), a carbon-11 labeled form of FEDAA1106, which
* Corresponding author. Tel.: þ1 317 278 4671; fax: þ1 317 278 9711.
E-mail address: qzheng@iupui.edu (Q.-H. Zheng).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.08.001

M. Wang et al. / European Journal of Medicinal Chemistry 44 (2009) 2748–2753
2749
will combine the advantages of both
[
11C]DAA1106 and
In our approach as shown in Scheme 3, acetanilide 7 was alky-
lated with benzyl bromide 4 using NaH as a base in DMF to give
compound 8 in 71% yield. The benzyl groups of compound 8 were
removed by catalytic hydrogenation with 10% Pd–C in THF and
MeOH to provide precursor 9 in 66% yield. O-Methylation of the
phenol precursor 9 with CH3I in the presence of NaH in DMSO
afforded standard FEDAA1106 (10) in 70% yield.
[
18F]FEDAA1106, for PET imaging of PBR expression in brain and
tumor (Fig. 1). Here, we report the synthesis of [11C]FEDAA1106.
2. Results and discussion
2.1. Chemistry
2.2. Radiochemistry
The chemistry is straightforward. Synthetic approach for
phenolic precursor and standard compound FEDAA1106 is shown
in Schemes 1–3.
Synthesis of target radioligand [11C]FEDAA1106 ([11C]10) is
indicated in Scheme 4. Precursor 9 was labeled by a reactive [11C]
As depicted in Scheme 1, the key intermediate 4 was prepared
from commercially available 2,5-dihydroxybenzaldehyde. 2,5-
Dihydroxybenzaldehyde was benzylated selectively using benzyl
bromide in the presence of NaHCO3 and KI in CH3CN to obtain 5-
monobenzylated compound 1 in 32% yield [29,30], the slight
selectivity is normally attributed to the intramolecular H-bonding
that exists between the 2-hydroxyl and the carbonyl group pre-
venting the 2-position from being alkylated, which resulted in low
chemical yield. The mixture of both 2- and 5-hydroxyl benzylation
products was purified by flash column chromatography. Alkylation
of the hydroxyl group of 1 with BrCH2CH2F in the presence of NaH
in DMF gave 2-fluoroethyl ether 2 in 21% yield. Reduction of alde-
hyde 2 with NaBH4 in MeOH provided the alcohol 3 in 97% yield,
which was treated with PBr3 in Et2O to afford benzyl bromide 4 in
83% yield.
As indicated in Scheme 2, another key intermediate acetanilide
7 was obtained efficiently from commercial materials based on the
literature procedures [21,23,27]. 1,4-Difluoro-2-nitrobenzene was
treated with phenol under basic condition to afford compound 5 in
99% yield. The reaction is highly selective and 1-fluoro position is
preferred over 4-fluoro position of the ring system due to the effect
of the electron-withdrawal group 2-nitro, which resulted in very
high chemical yield. Reduction of 5 with powdered Fe and NH4Cl in
EtOH and H2O formed anilide 6 in 97% yield, which was acetylated
with acetyl chloride in the presence of Et3N in CH2Cl2 to afford
acetanilide 7 in 93% yield.
methylating agent, [
11C]methyl triflate ([11C]CH3OTf) [31,32]
prepared from [11C]CO2, in the presence of NaH in acetonitrile
through the O-[11C]methylation and isolated by semi-preparative
high pressure liquid chromatography (HPLC) method to provide
target tracer [11C]10 in 60–70% radiochemical yields, decay cor-
rected to end of bombardment (EOB), based on [11C]CO2. The
synthesis was performed in an automated multi-purpose 11C-
radiosynthesis module, allowing measurement of specific activity
during synthesis [33,34]. The specific activity of [11C]FEDAA1106
was in a range of 222–370 GBq/
the-fly technique using semi-preparative HPLC method during
synthesis [34] and 111–185 GBq/ mol at the end of synthesis (EOS)
mmol at EOB measured by the on-
m
determined by analytical HPLC method [35], respectively. Chemical
purity and radiochemical purity were determined by analytical
HPLC method [35]. The chemical purity of the precursor 9 and
reference standard 10 was >97%. The radiochemical purity of the
target tracer [11C]10 was >99% determined by radio-HPLC through
g
-ray (NaI) flow detector, and the chemical purity of the target
tracer [11C]10 was >96% determined by reversed-phase HPLC
through UV flow detector.
Both [11C]DAA1106 and [18F]FEDAA1106 have been used as PET
PBR imaging probes to study neuroinflammation such as Alz-
heimer’s disease and tumor progression such as neurofibromas in
animals [2–18] and humans [36]. New PET PBR imaging probe
[
11C]FEDAA1106 has higher PBR binding affinity and specificity than
its parent compound
[
11C]DAA1106, easier radiosynthesis
OCH3
CH3
O
O
O
N
F
N
N
O11CH3
11CH3
11CH3
O
Cl
Cl
(S)-[11C]PK 11195
(R)-[11C]PK 11195
[
11C]DAA1106
OCH3
O
O
11CH3
O
CH3
O
CH3
N
F
N
F
O
18F
O
F
O
11C]FEDAA1106, [11C]10
[
18F]FEDAA1106
[
Fig. 1. The structures of (R)-[11C]PK11195, (S)-[11C]PK11195, [11C]DAA1106, [18F]FEDAA1106 and [11C]FEDAA1106.

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M. Wang et al. / European Journal of Medicinal Chemistry 44 (2009) 2748–2753
OBn
OBn
OBn
O
OH
OH
BrCH2CH2F
NaH, DMF
BnBr, K2CO3, KI
CH3CN
NaBH4, MeOH
HOH2C
OHC
OHC
OHC
O
OH
1
32%
F
F
2
21%
3
97%
PBr3, Et2 O
OBn
BrH2C
O
4
83%
F
Scheme 1. Synthesis of key intermediate 4.
procedures than its fluorine-18 labeled form [18F]FEDAA1106. These
advantages encourage further biological evaluation of [11C]FEDAA1106.
The in vivo biodistribution and PET imaging of PBR transgenic mice
(brain Alzheimer’s disease) and neurofibromatosis type 1 (NF1)
gene knockout tumor mice with [11C]FEDAA1106 are currently
underway, and the results will be reported in due course.
in parts per million (ppm, d scale) relative to internal standard TMS
(d 0.0), and coupling constants (J) were reported in hertz (Hz). The
high resolution mass spectra (HRMS) were obtained using
a Thermo MAT 95XP-Trap spectrometer. Thin-layer chromatog-
raphy (TLC) was run using Analtech silica gel GF uniplates
(5 ꢀ10 cm2). Plates were visualized under UV light. Preparative TLC
was run using Analtech silica gel UV 254 plates (20 ꢀ 20 cm2). Flash
column chromatography was run using EM Science, silica gel 60
(230–400 mesh). Chromatographic solvent proportions are indi-
3. Materials and methods
cated in a volume:volume ratio. Sterile Millex-GS 0.22 mm vented
3.1. General
filter unit was obtained from Millipore Corporation, Bedford, MA.
All moisture- and/or air-sensitive reactions were performed under
a positive pressure of nitrogen maintained by a direct line from
a nitrogen source.
All commercial reagents and solvents from Aldrich and Sigma
were used without further purification. [11C]CH3OTf was prepared
according to a literature procedure [31]. Melting points were
determined on a MEL-TEMP II capillary tube apparatus and were
uncorrected. 1H NMR spectra were recorded on a Varian Gemini
2000 200 MHz FT-NMR and Bruker Avance II 500 MHz NMR
spectrometer using tetramethylsilane (TMS) as an internal stan-
dard. Chemical shift data for the proton resonances were reported
3.2. 5-Benzyloxy-2-hydroxybenzaldehyde (1)
A mixture of 2,5-dihydroxybenzaldehyde (4.0 g, 29.0 mmol),
NaHCO3 (2.77 g, 33.0 mmol) and KI (0.48 g, 2.90 mmol) in CH3CN
NO2
O
F
NH2
O
F
NO2
PhOH, K2CO3, DMF
F
Fe/NH4Cl, EtOH/H2O
F
5
99%
6
97%
CH3COCl
Et3N, CH2Cl2
O
NH
F
O
7
93%
Scheme 2. Synthesis of key intermediate 7.

M. Wang et al. / European Journal of Medicinal Chemistry 44 (2009) 2748–2753
2751
OBn
O
O
CH3
NH
O
OBn
F
N
F
NaH, DMF
O
O
BrH2C
F
O
F
4
7
8
71%
H2 /Pd-C
THF, MeOH
OH
O
OCH3
O
CH3
O
CH3
N
N
F
F
NaH, CH3I
DMSO
O
O
O
F
F
9
66%
10
70%
Scheme 3. Synthesis of phenolic precursor 9 and standard FEDAA1106, 10.
(50 mL) was heated to 60 ꢁC, followed by addition of benzyl
bromide (4.47 mL, 37.6 mmol). The reaction mixture was stirred
and refluxed under nitrogen overnight. The solvent was evapo-
rated, and the residue was dissolved in EtOAc and washed with 1 N
HCl, water, brine and dried over anhydrous Na2SO4. The crude
product was purified by column chromatography with EtOAc–
hexanes (1:4) as eluent to afford 1 (2.13 g, 32%) as a pale yellow
solid, mp 88–89 ꢁC (lit. [29] 91–92 ꢁC). 1H NMR (500 MHz, CDCl3):
mixture was poured into water and extracted with CH2Cl2. The
organic layer was washed with water and brine, and dried over
anhydrous Na2SO4. The solvent was evaporated and the crude
product was purified by column chromatography with EtOAc–
hexanes (1:4) as eluent to afford 2 (354 mg, 21%) as a yellow solid,
mp 39–40 ꢁC. 1H NMR (500 MHz, CDCl3):
d 10.51(1H, s, CHO), 7.46–
7.33 (6H, m, Ar-H), 7.21 (1H, dd, J ¼ 9.0, 3.0 Hz, Ar-H), 6.91 (1H, d,
J ¼ 9.0 Hz, Ar-H), 5.07 (2H, s, PhCH2), 4.86–4.84 (1H, m, OCHHCH2F),
4.77–4.75 (1H, m, OCHHCH2F), 4.36–4.34 (1H, m, OCH2CHHF),
4.30–4.28 (1H, m, OCH2CHHF). HRMS (CI) m/z calculated for
C16H15FO3 ([M]þ), 274.1000; found, 274.1005.
d
10.69 (1H, s, CHO), 9.85 (1H, s, OH), 7.46–7.35 (5H, m, Ar-H), 7.24
(1H, dd, J ¼ 9.0, 3.0 Hz, Ar-H), 7.09 (1H, d, J ¼ 3.0 Hz, Ar-H), 6.96 (1H,
d, J ¼ 9.0 Hz, Ar-H), 5.08 (2H, s, PhCH2).
3.3. 5-Benzyloxy-2-(2-fluoroethoxy)benzaldehyde (2)
3.4. (5-Benzyloxy-2-(2-fluoroethoxy)phenyl)methanol (3)
To a solution of compound 1 (1.39 g, 6.09 mmol) in DMF (5 mL)
at 0 ꢁC was added NaH (60% dispersion in mineral oil, 487 mg,
12.2 mmol) portionwise at 0 ꢁC. The mixture was stirred at 0 ꢁC for
20 min, followed by addition of BrCH2CH2F (1.55 g, 12.2 mmol).
After stirring at room temperature (rt) for 48 h, the reaction
To a solution of compound 2 (280 mg, 1.02 mmol) in MeOH
(10 mL) was added NaBH4 (77 mg, 2.04 mmol) portionwise at 0 ꢁC.
After stirring at rt for 4 h, the solvent was evaporated, and to the
residue was added ice water and extracted with EtOAc. The organic
layer was washed with water and brine, dried over anhydrous
O11CH3
OH
O
CH3
O
CH3
[
11C]CH3OTf, NaH
CH3CN
N
N
F
F
O
O
O
O
F
F
[
11C]10
60-70%
9
Scheme 4. Synthesis of [11C]FEDAA1106 ([11C]10).

2752
M. Wang et al. / European Journal of Medicinal Chemistry 44 (2009) 2748–2753
Na2SO4. Evaporation of the solvent afforded 3 (273 mg, 97%) as
a white solid, mp 64–65 ꢁC. 1H NMR (500 MHz, CDCl3):
7.43–7.30
7.17–7.10 (1H, m, Ar-H), 7.00–6.96 (2H, m, Ar-H), 6.85–6.65 (2H, m,
Ar-H), 2.16 (3H, s, CH3).
d
(5H, m, Ar-H), 6.99 (1H, d, J ¼ 3.0 Hz, Ar-H), 6.84 (1H, dd, J ¼ 9.0,
3.0 Hz, Ar-H), 6.79 (1H, d, J ¼ 9.0 Hz, Ar-H), 5.11 (2H, s, PhCH2), 4.80–
4.78 (1H, m, OCH2CHHF), 4.70–4.69 (3H, m þ s, OCH2CHHF þ Ph-
CH2OH), 4.26–4.24 (1H, m, OCHHCH2F), 4.20–4.18 (1H, m,
OCHHCH2F). HRMS (CI) m/z calculated for C16H17FO3 ([M]þ),
276.1156; found, 276.1155.
3.9. N-(5-Fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-
benzyloxybenzyl)acetamide (8)
To a suspension of NaH (60% dispersion in mineral oil, 24 mg,
0.60 mmol) in DMF (1 mL) was added compound 7 (128 mg,
0.52 mmol) at 0 ꢁC, and the mixture was stirred at 0 ꢁC for 20 min,
followed by addition of compound 4 (200 mg, 0.59 mmol). After
stirring at 0 ꢁC for 4 h, the reaction mixture was poured into water
and extracted with EtOAc. The organic layer was washed with
water and brine, and dried over anhydrous Na2SO4. The solvent was
evaporated and the crude product was purified by column chro-
matography with EtOAc–hexanes (1:4) as eluent to afford 8
(214 mg, 71%) as a white solid, mp 89–90 ꢁC. 1H NMR (500 MHz,
3.5. 4-(Benzyloxy)-2-(bromomethyl)-1-(2-fluoroethoxy)
benzene (4)
To a solution of compound 3 (250 mg, 0.91 mmol) in anhydrous
Et2O (7 mL) was added a solution of PBr3 (90 mL, 0.95 mmol) in Et2O
(2 mL) dropwise. After stirring at rt for 3.5 h, the reaction mixture
was poured into water and extracted with CH2Cl2. The organic layer
was washed with water and brine, and dried over anhydrous
Na2SO4. The solvent was evaporated and the crude product was
purified by column chromatography with EtOAc–hexanes (1:4) as
eluent to afford 4 (254 mg, 83%) as a white solid, mp 65–66 ꢁC. 1H
CDCl3):
d
7.43–7.30 (7H, m, Ar-H), 7.12 (1H, t, J ¼ 2.5 Hz, Ar-H), 7.01
(1H, d, J ¼ 3.0 Hz, Ar-H), 6.95–6.91 (1H, m, Ar-H), 6.88–6.81 (3H, m,
Ar-H), 6.79 (1H, dd, J ¼ 9.0, 6.0 Hz, Ar-H), 6.70–6.68 (2H, m, Ar-H),
5.18 (1H, d, J ¼ 15 Hz, CHHN), 4.94 (2H, q, J ¼ 11.5 Hz, PhCH2), 4.66–
4.51 (2H, d þ m, J ¼ 15 Hz, CHHN þ OCH2CHHF), 4.56–4.49 (1H, m,
OCH2CHHF), 4.07–3.90 (2H, m, OCH2CH2F), 1.95 (3H, s, CH3). HRMS
(CI) m/z calculated for C30H27F2NO4 ([M]þ), 503.1903; found,
503.1920.
NMR (500 MHz, CDCl3):
d 7.43–7.31 (5H, m, Ar-H), 7.00 (1H, d,
J ¼ 3.0 Hz, Ar-H), 6.88 (1H, dd, J ¼ 9.0, 3.0 Hz, Ar-H), 6.82 (1H, d,
J ¼ 9.0 Hz, Ar-H), 5.02 (2H, s, PhCH2), 4.83–4.81 (1H, m, OCH2CHHF),
4.74–4.72 (1H, m, OCH2CHHF), 4.55 (2H, s, PhCH2Br), 4.28–4.27 (1H,
m, OCHHCH2F), 4.23–4.21 (1H, m, OCHHCH2F). HRMS (CI) m/z
calculated for C16H16BrFO2 ([M]þ), 338.0312; found, 338.0324.
3.10. N-(5-Fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-
hydroxybenzyl)acetamide (9)
3.6. 5-Fluoro-2-phenoxynitrobenzene (5)
A solution of compound 8 (180 mg, 0.36 mmol) in THF (1.5 mL)
and MeOH (3 mL) was hydrogenated at atmospheric pressure over
10% Pd–C (36 mg) overnight. The catalyst was removed by filtration
and the solution was evaporated. The product was purified by
preparative TLC plate using EtOAc–hexanes (1:2) as eluent to afford
9 (98 mg, 66%) as a white solid, mp 124–125 ꢁC. 1H NMR (500 MHz,
A mixture of 1,4-difluoro-2-nitrobenzene (20 g, 125.7 mmol),
phenol (12.4 g, 131.7 mmol) and K2CO3 (19.1 g, 138.2 mmol) in DMF
(70 mL) was stirred at 96 ꢁC for 4 h. After cooling to rt, water was
added and the mixture was extracted with EtOAc. The combined
organic layer was washed with water and brine, and dried over
anhydrous MgSO4. The solvent was removed in vacuo to obtain 5
(29.1 g, 99%) as a yellow solid, mp 35–36 ꢁC. 1H NMR (200 MHz,
CDCl3): d 7.35–7.32 (2H, m, Ar-H), 7.16–7.12 (2H, m, Ar-H), 6.99–6.95
(1H, m, Ar-H), 6.93–6.87 (3H, m, Ar-H), 6.79 (1H, dd, J ¼ 8.5, 3.0 Hz,
Ar-H), 6.73 (1H, dd, J ¼ 8.5, 3.0 Hz, Ar-H), 6.66 (1H, d, J ¼ 9.0 Hz, Ar-
H), 5.16 (1H, d, J ¼ 14.5 Hz, CHHN), 4.63 (1H, d, J ¼ 14.5 Hz, CHHN),
4.57–4.37 (2H, m, OCH2CH2F), 4.00–3.84 (2H, m, OCH2CH2F), 1.95
(3H, s, CH3). HRMS (CI) m/z calculated for C23H21F2NO4 ([M]þ),
413.1433; found, 413.1422.
CDCl3):
d
7.70 (1H, dd, J ¼ 3.0, 7.8 Hz, Ar-H), 7.38 (2H, t, J ¼ 7.8 Hz,
Ar-H), 7.27–7.14 (2H, m, Ar-H), 7.08–6.99 (3H, m, Ar-H).
3.7. 5-Fluoro-2-phenoxyaniline (6)
A mixture of compound 5 (29 g, 124.4 mmol), iron (21.7 g,
388.9 mmol), and ammonium chloride (13.8 g, 257.9 mmol) in EtOH
(300 mL) and water (100 mL) was stirred under nitrogen overnight
at 110 ꢁC. After cooling, the reaction mixture was filtered and
extracted with EtOAc. The combined organic layer was washed with
water and brine, dried over anhydrous Na2SO4, and evaporated. The
crude product was purified bycolumn chromatography with EtOAc–
hexanes (1:10) as eluent to afford 6 (24.4 g, 97%) as an orange oil. 1H
3.11. N-(5-Fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-
methoxybenzyl)acetamide (FEDAA1106, 10)
To a stirred solution of compound 9 (10 mg, 0.024 mmol) in
DMSO (0.3 mL) was added NaH (60% dispersion in mineral oil,
1.9 mg, 0.048 mmol), and the mixture was stirred at rt for 30 min,
followed by addition of CH3I (5 mL, 0.08 mmol). After stirring at rt
NMR (200 MHz, CDCl3):
d
7.34 (2H, t, J ¼ 8.0 Hz, Ar-H), 7.26 (1H, t,
for 15 h, the reaction mixture was poured into water and extracted
with CH2Cl2. The organic layer was washed with water and brine,
and dried over anhydrous Na2SO4. The solvent was evaporated and
the crude product was purified by preparative TLC plate using
EtOAc–hexanes (1:3) as eluent to afford 10 (7.2 mg, 70%) as a pale
J ¼ 3.0 Hz, Ar-H), 6.97–6.80 (3H, m, Ar-H), 6.53 (1H, dd, J ¼ 3.0,
9.8 Hz, Ar-H), 6.43 (1H, dt, J ¼ 2.9, 8.1 Hz, Ar-H), 3.82 (2H, br s, NH2).
3.8. N-(5-Fluoro-2-phenoxyphenyl)acetamide (7)
yellow oil. 1H NMR (200 MHz, CDCl3):
d 7.35–7.26 (2H, m, Ar-H),
To a stirred solution of compound 6 (0.6 g, 3.0 mmol) and Et3N
(0.5 mL, 3.6 mmol) in CH2Cl2 (6 mL) was added acetyl chloride
(0.5 mL, 3.3 mmol) dropwise at 0 ꢁC. After stirring at rt for 2.5 h, the
reaction mixture was concentrated in vacuo. The residue was
poured into water and extracted with EtOAc. The organic layer was
washed with saturated aqueous NaHCO3, water and brine, and
dried over anhydrous Na2SO4. The solvent was evaporated and the
crude product was purified by column chromatography using
EtOAc–hexanes (1:4) as eluent to obtain 6 (0.67 g, 93%) as a white
7.13–7.06 (1H, m, Ar-H), 6.92–6.77 (6H, m, Ar-H), 6.78–6.76 (2H, m,
Ar-H), 6.68–6.54 (2H, m, Ar-H), 5.16 (1H, d, J ¼ 15 Hz, CHHN), 4.68–
4.59 (2H, d þ m, J ¼ 15 Hz, CHHN þ OCH2CHHF), 4.42 (1H, m,
OCH2CHHF), 4.12–4.01 (1H, m, OCHHCH2F), 3.99–3.84 (1H, m,
OCHHCH2F), 3.65 (3H, s, OCH3), 1.95 (3H, s, CH3).
3.12. N-(5-Fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-
[
11C]methoxybenzyl)acetamide ([11C]FEDAA1106, [11C]10)
solid, mp 81–82 ꢁC. 1H NMR (200 MHz, CDCl3):
J ¼ 2.9, 9.6 Hz, Ar-H), 7.72 (1H, br s, NH), 7.72–7.32 (2H, m, Ar-H),
d
8.31 (1H, dd,
[
11C]CO2 was produced by the 14N(p,
a)
11C nuclear reaction in
small volume (9.5 cm3) aluminum gas target (CTI) from 11 MeV

M. Wang et al. / European Journal of Medicinal Chemistry 44 (2009) 2748–2753
2753
proton cyclotron on research purity nitrogen (þ1% O2) in a Siemens
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4. Conclusions
An efficient and convenient synthesis of new PET PBR radio-
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This work was partially supported by the Indiana Genomics
Initiative (INGEN) of Indiana University, which is supported in part
by Lilly Endowment Inc. The authors would like to thank Dr. Bruce H.
Mock and Barbara E. Glick-Wilson for their assistance in production
of [11C]CH3OTf. The referees’ criticisms and editor’s comments for
the revision of the manuscript are greatly appreciated.