Synthesis of a phenolic precursor and its efficient O-[18F] fluoroethylation with purified no-carrier-added [18F]2-fluoroethyl brosylate as the labeling agent

Article abstract of DOI:10.1002/jlcr.3046

[¹⁸F]2-Fluoroethyl-p-toluenesulfonate also called [ ¹⁸F]2-fluoroethyl tosylate has been widely used for labeling radioligands for positron emission tomography (PET). [¹⁸F]2- Fluoroethyl-4-bromobenzenesulfonate, also called [¹⁸F]2-fluoroethyl brosylate ([¹⁸F]F(CH₂)₂OBs), was used as an alternative radiolabeling agent to prepare [¹⁸F]FEOHOMADAM, a fluoroethoxy derivative of HOMADAM, by O-fluoroethylating the phenolic precursor. Purified by reverse-phase HPLC, the no-carrier-added [ ¹⁸F]F(CH₂)₂OBs was obtained in an average radiochemical yield (RCY) of 35%. The reaction of the purified and dried [ ¹⁸F]F(CH₂)₂OBs with the phenolic precursor was performed by heating in DMF and successfully produced [¹⁸F] FEOHOMADAM, after HPLC purification, in RCY of 21%. Copyright

Full text of DOI:10.1002/jlcr.3046

Research Article
Received 1 February 2013,
Revised 7 March 2013,
Accepted 12 March 2013
Published online 3 May 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3046
Synthesis of a phenolic precursor and its
efficient O-[18F]fluoroethylation with purified
no-carrier-added [18F]2-fluoroethyl brosylate
as the labeling agent
*
Nashwa Jarkas, Ronald J. Voll, and Mark M. Goodman
[
18F]2-Fluoroethyl-p-toluenesulfonate also called [18F]2-fluoroethyl tosylate has been widely used for labeling radioligands
for positron emission tomography (PET). [18F]2-Fluoroethyl-4-bromobenzenesulfonate, also called [18F]2-fluoroethyl
brosylate ([18F]F(CH2)2OBs), was used as an alternative radiolabeling agent to prepare [18F]FEOHOMADAM, a fluoroethoxy
derivative of HOMADAM, by O-fluoroethylating the phenolic precursor. Purified by reverse-phase HPLC, the no-carrier-
added [18F]F(CH2)2OBs was obtained in an average radiochemical yield (RCY) of 35%. The reaction of the purified and dried
[
18F]F(CH2)2OBs with the phenolic precursor was performed by heating in DMF and successfully produced [18F]
FEOHOMADAM, after HPLC purification, in RCY of 21%.
Keywords: fluoroethylation; FEOHOMADAM; fluorine-18; [18F]fluoroethyl brosylate
fluorination of phenols, [18F]F(CH2)2OBs and [18F]2-fluoroethyl
Introduction
nosylate were more reactive than F(CH2)2OTs.7 Furthermore,
the same authors showed that when heated in an open vessel,
[18F]F(CH2)2OBs was less volatile than the widely used F(CH2)
2OTs7 making the brosylate better-suited for open vessel
radiolabeling procedures.7 Because of those findings and because
the F-18 radiolabelings in our laboratory are in general performed in
an open vessel, [18F]F(CH2)2OBs was chosen as the fluoroethylating
agent to produce [18F]FEOHOMADAM. As for the synthesis of the
standard (11) (Figure 1), F(CH2)2OTs8 was the reagent of choice
to prepare 10 from 8 as the fluorination reaction was performed
in a sealed vessel to minimize the volatility effect of the
fluoroethylating agent on the yield of formation of FEOHOMADAM
(Scheme 1).
The serotonin transporter (SERT) controls the synaptic levels of
serotonin by its reuptake into the presynaptic neurons.1 Because
of its implication in numerous psychiatric and neurological
disorders such as major depression2 and Alzheimer’s disease,3
respectively, SERT has been of great interest for study in humans.
Among the carbon-11 (C-11) and fluorine-18 (F-18) ligands
developed to image the SERT, C-11 N,N-dimethyl-2-(20-amino-40-
hydroxymethylphenylthio)benzylamine ([11C]HOMADAM) (Figure 1)
is one of the most promising candidates.4 Despite the successful
imaging of the SERT with positron emission tomography (PET)
tracers,5 there is still a need to find a potent F-18 SERT radiotracer.
Reported herein is the synthesis of FEOHOMADAM (11), a
fluorinated derivative of HOMADAM with a fluoroethoxy chain
on phenyl ring B (Figure 1). [18F]FEOHOMADAM was prepared by
reacting the appropriate phenolic precursor with [18F]F(CH2)2OBs
as the fluoroethylating agent.
In the field of labeling radiotracers with F-18 for PET studies,
no-carrier-added (NCA) [18F]2-fluoroethyl-p-toluenesulfonate,
also called [18F]2-fluoroethyl tosylate (F(CH2)2OTs), has been
widely used as the labeling agent to perform O-, N-, and S-
fluoroalkylations.6 This reagent is attractive owing to its relatively
simple radiosynthesis, good stability in purification, and
reasonable applicability in reacting with a variety of nucleophiles.6
However, F(CH2)2OTs suffers some restrictions including a lower
reactivity6 and higher volatility7 than alternative labeling agents
such as [18F]2-fluoroethyl-4-bromobenzenesulfonate also called
[18F]F(CH2)2OBs.7 Musachio et al.7 reported that the radiochemical
yields were appreciably higher for brosylate and nosylate than for
tosylate for the reaction of p-nitrophenol with the corresponding
[18F]2-fluoroethyl arylsulfonates demonstrating that for F-18
Results and discussions
Chemistry and in vitro data
Commercially available 2-amino-5-methoxybenzoic acid (1)
was converted, via Sandmeyer reaction, to 2,20-dithiobis-(5-
methoxybenzoic) acid (2) in 50% yield. 2 was reduced to 5-
Department of Radiology and Imaging Sciences, Emory University School of
Medicine, Center for Systems Imaging, Wesley Woods Health Center, Atlanta,
GA, USA
*Correspondence to: Nashwa Jarkas, Ph.D., Department of Radiology and
Imaging Sciences, Emory University School of Medicine, Center for Systems
Imaging, Wesley Woods Health Center, 1841 Clifton Road, NE, Room # 212,
Atlanta, GA 30329, USA.
E-mail: njarkas@emory.edu
J. Label Compd. Radiopharm 2013, 56 539–543
Copyright © 2013 John Wiley & Sons, Ltd.

N. Jarkas et al.
NH2
CH2NCH3(11CH3)
NH2
CH2N(CH3)2
The affinities (Kis) of FEOHOMADAM for the human SERT,
human dopamine transporter (DAT), and human norepinephrine
transporter (NET) were determined through in vitro competitive
binding assays following a previously published procedure.5d
The Ki values of FEOHOMADAM (Ki (SERT) = 0.69 nM,
Ki (DAT) = 845 nM, and Ki (NET) = 175 nM) showed that the
fluoroethoxy derivative displayed a high affinity for the
SERT and selectivity over the DAT and NET. Comparison with
2'
1
6
2'
1
6
S
2
1'
S
2
1'
3'
4'
3'
4'
A
B
A
B
5
5
6'
3
6'
3
HOH2C
HOH2C
O(CH2)218F
5'
4
5'
4
18F]FEOHOMADAM ([18F]11)
[
11C]HOMADAM ([11C]12)
[
Figure 1. HOMADAM (12) and its fluoroethoxy derivative FEOHOMADAM (11).
methoxy-2-mercaptobenzoic acid (3) in 84% yield with the parent HOMADAM (Ki (SERT) = 0.57 nM)4a showed that the
sodium borohydride in anhydrous THF (Scheme 1). Thiol (3) affinity for the SERT was influenced by introduction of the
was coupled with bromo-nitrotoluene derivative (4) (prepared fluoroethoxy chain.
following published procedure)4a to provide benzoic acid (5)
in 61% yield (Scheme 1). Amide (6) was synthesized, in 86% yield,
by first treating the carboxylic acid function of 5 with thionyl
Radiochemistry
chloride and then subsequently reacting the freshly prepared acid The preparation of [18F]11 was performed by a nucleophilic
chloride (used without further purification) with a solution of 2.0M substitution of the phenolic precursor (9) with the prepared
N,N-dimethylamine in THF. Demethylation of 6 using a 1.0 M labeling agent [18F]F(CH2)2OBs (Scheme 2). [18F]F(CH2)2OBs was
boron tribromide solution in dichloromethane (BBr3-DCM) yielded synthesized, as the fluoroethylating agent, by a nucleophilic
7 in 86% yield. The simultaneous reduction of the amide and substitution of ethylene-1,2-4-bromobenzenesulfonate (BsO(CH2)
bromomethyl groups of 7 with the complex BH3-THF produced 2OBs) (prepared as previously reported)9 with the dried and
8 in 39% yield (Scheme 1). The latter compound served as the activated fluoride complex, 18Fꢀ/Kryptofix 222 (K222)/potassium
starting point for the preparation of the precursor for labeling (9) carbonate (K2CO3) in acetonitrile (CH3CN) (Scheme 2).
and the fluoroethoxy derivative (11). Reduction of the nitro group
[18F]F(CH2)2OBs was purified by reverse-phase HPLC, isolated
of 8 with tin chloride produced 9 in 27% yield (Scheme 1). The free by solid phase extraction (SPE), and recovered in a 2-mL
OH group of 8 was alkylated by F(CH2)2OTs in the presence of volume of acetonitrile. Solvent was evaporated to dryness with
cesium carbonate (Cs2CO3) in N,N-dimethylformamide (DMF) to argon and the [18F]fluoroethylating agent was obtained with
provide compound (10) in 44% yield. Reduction of the nitro group radiochemical and chemical purities higher than 99% in an
with tin chloride transformed 10 to the nonradioactive compound average radiochemical yield of 35% (decay-corrected from the
(11) in 56% yield (Scheme 1).
transfer of the cyclotron produced [18F]HF(aq)). The identity of
CO2H
H2N
CO2H
CO2H
HS
50%
i
84%
ii
S
OCH3
OCH3
OCH3
2
1
3
2
Conditions: (i) H2O, HCl, NaNO2, Na2S2; (ii) NaBH4, THF, 0°C to rt
NO2
CO2H
61%
i
86%
ii
CO2H
NO2
S
NO2
CON(CH3)2
OCH3
HS
Br
S
H3COCOH2C
OCH3
+
OCH3
H3COCOH2C
H3COCOH2C
5
6
4
3
86%
iii
NO2
CON(CH3)2
OH
NH2
CH2N(CH3)2
OH
27%
NO2
CH2N(CH3)2
OH
39%
S
S
S
v
iv
HOH2C
BrH2C
HOH2C
9
8
7
44%
NO2
vi
56%
v
NH2
CH2N(CH3)2
O(CH2)2F
CH2N(CH3)2
O(CH2)2F
S
S
HOH2C
HOH2C
11
10
Conditions: (i) K2CO3, DMF, 130°C; (ii) 1- SOCl2, DCM, reflux; 2- (CH3)2NH/THF, -70°C; (iii) BBr3-DCM,
DCM, -78°C to rt; (iv) BH3-THF, THF, reflux; (v) SnCl2.H2O, MeOH, HCl, 0°C; (vi) F(CH2)2OTs, Cs2CO3,
DMF, 130°C
Scheme 1. Synthesis of FEOHOMADAM (11) and its phenolic precursor (9).
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Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 539–543

N. Jarkas et al.
18F-
OBs
OBs
18F
BsO
K222/K2CO3
CH3CN, 110°C, 10 min
[18F[F(CH2)2OBs
BsO(CH2)2OBs
NH2 CH2N(CH3)2
(Bs = BrC6H4O2S)
NH2
S
CH2N(CH3)2
[18F]F(CH2)2OBs
S
O(CH2)218F
HOH2C
OH
HOH2C
0.1 M Bu4NOH, DMF, 100°C
[18F]11
9
Scheme 2. Synthesis of [18F]FEOHOMADAM ([18F]11) from its phenolic precursor (9).
[18F]F(CH2)2OBs was confirmed because the corresponding HPLC
profiles were consistent with the authentic compound F(CH2)
2OBs (prepared as previously reported).9 To prepare [18F]11,
the purified and dried [18F]F(CH2)2OBs was heated with 9 at
100 ꢁC in the presence of tetrabutylammonium hydroxide
(0.1M Bu4NOH) as a base in DMF. Figure 2 presents the analytical
HPLC (column B) chromatogram of the crude reaction mixture of
[18F]FEOHOMADAM (before the semi-preparative HPLC purification)
where are shown radioactive impurities (retention time (tR =
2.3 min)), unreacted [18F]F(CH2)2OBs (tR = 4.0 min), and the
desired [18F]FEOHOMADAM (tR = 6.5min). No other radioactive
by-products were detected as shown in Figure 2. The HPLC solvent
used for analytical HPLC was MEOH):H2O:triethylamine (Et3N)
(50:50:0.1) and flow rate= 1 mL/min. [18F]11 was separated from
unreacted [18F]F(CH2)2OBs and radioactive impurities by semi-
preparative reverse-phase HPLC using column A, MEOH:H2O:Et3N
(50:50:0.1) as the HPLC solvent, and flow rate= 6 mL/min. [18F]
FEOHOMADAM (tR = 17 min on column A) was isolated by solid
phase extraction (SPE) and formulated in a (pH = 5–6) 0.9% saline
solution containing ethanol (10%) to be evaluated in nonhuman
primate imaging studies that will be reported later. The
radiochemical yield was 21% (decay-corrected form transfer of
[18F]F(CH2)2OBs) and the specific activity was ≥ 2 Ci/mmol at end
of synthesis (EOS). The radiochemical and chemical purities of
the final formulated product were higher than 99%. The total
synthesis time was 150 min from end of bombardment (EOB).
The authenticity of [18F]11 was confirmed as the HPLC profiles
were consistent with the standard FEOHOMADAM.
and m (multiplet). High resolution mass spectrometry (HRMS) was carried
out at the Chemistry Department of Emory University. Radioactive
compounds were purified by reverse phase HPLC using HPLC grade
solvents. The HPLC columns used were a Waters XTerraW 18 reverse phase
C
column A (19ꢂ 100 mm) for purification and a Waters NOVA-PAK C18
reverse phase column B (3.9ꢂ 150mm) for quality control. The cartridge
used for the solid phase extraction (SPE) method was a Waters reversed-
phase (silica-based) tC18 cartridge (tC18: tri-functional bonded phase with
increased hydrolytic stability). Radioactivity measurements were performed
using a Dose Calibrator, Capintec (Ramsey, NJ, USA) CRC-5R.
Chemistry
2,20-Dithiobis(5-methoxybenzoic) acid (2)
A solution of 2-amino-5-methoxybenzoic acid (1) (3.00 g, 18.0 mmol) in a
mixture of water (36 mL) and concentrated hydrochloric acid (conc. HCl)
(6 mL) was diazotized at 0 ꢁC with a solution of sodium nitrite (NaNO2)
(2.14 g, 31.0 mmol) in water (12 mL), added dropwise. The solution was
stirred 1 h at 0 ꢁC and then added to a solution of Na2S2 [prepared by
heating sodium sulfide∙nonahydrate (Na2S∙9H2O) (7.91 g, 33.0 mmol)
and sulfur (S) (1.04 g, 32.4 mmol) in water (100 mL), treating the yellow
clear solution with NaOH (1.20 g, 30.0 mmol) in water (10 mL) and
cooling] containing ice. The mixture was allowed to stand for 3 h at room
temperature (rt), acidified with conc. HCl, and the precipitated crude
product was filtered. It was dissolved in a warm solution of Na2CO3,
filtered with charcoal through celite, and the filtrate acidified again with
conc. HCl. The precipitated product was filtered, washed with water, and
dried to give a light orange solid (3.27 g, 50%). It was used in the next
step without further purification.
5-Methoxy-2-mercaptobenzoic acid (3)
To a 50-mL, round-bottom flask capped with a rubber septum was added
anhydrous THF (12 mL) under argon. To this was added 2 (1.00 g,
2.73 mmol) to give an orange solution of the disulfide in the solvent.
The flask was immersed in an ice water bath. To the reaction mixture
Experimental
General
Compound (4)4a was prepared as previously reported and (1) was was slowly and portion-wise added sodium borohydride (NaBH4)
commercially available. All laboratory chemicals used for synthesis were (0.41 g, 11.0 mmol). The orange mixture was stirred 20 h at room
reagent grade used without further purification, unless otherwise noted. temperature after which it turned yellow. The reaction was slowly
Anhydrous solvents (100 mL septum-capped bottles) were purchased from quenched with cold water and acidified with conc. HCl. The precipitated
Sigma-Aldrich (Milwaukee, WI, USA). Proton nuclear magnetic resonance product was filtered, washed with water, and dried to give the desired
(1H NMR) spectra were obtained at 300 MHz (Mercury Unit 300) with thiol (3) as a yellow solid (0.42 g, 84%). 1H NMR (CDCl3, d): 3.83 (s, 3H,
tetramethylsilane (TMS) as internal standard. The multiplicity of the peaks OCH3), 4.44 (s, 1H, SH), 7.01 (dd, 1H, J = 2.4, 11.1 Hz, ArH), 7.23 (m, 1H,
was defined as s (singlet), d (doublet), dd (doublet of doublet), t (triplet), ArH), 7.64 (d, 1H, J = 2.1 Hz, ArH).
Figure 2. HPLC chromatogram (column B) of the crude mixture of [18F]FEOHOMADAM.
J. Label Compd. Radiopharm 2013, 56 539–543
Copyright © 2013 John Wiley & Sons, Ltd.
www.jlcr.org

N. Jarkas et al.
2-(40-Acetoxymethyl-20-nitrophenylthio)-5-methoxybenzoic acid (5)
NaHCO3 was added to neutralize the solution to pH 6 ~ 7. Resulting
aqueous solution was extracted with EtOAc. Combined organic layers
were dried over Na2SO4 and the solvent was removed under reduced
pressure. Silica gel flash column chromatography (DCM/MEOH, 70:30)
gave 8 as a light yellow oil (51 mg, 39%). 1H (CD3OD, d): 2.52 (s, 6H,
NCH3), 3.87 (s, 2H, CH2N), 4.61 (s, 2H, CH2OH), 6.95 (dd, 1H, J = 2.7,
8.7 Hz, ArH), 7.13 (d, 1H, J = 2.4 Hz, ArH), 7.41 (dd, 1H, J = 1.8, 8.1 Hz,
ArH), 7.51 (d, 1H, J = 8.4 Hz, ArH), 8.26 (d, 1H, J = 0.9 Hz, ArH). Calculated
HRMS m/z 334.10. Found HRMS m/z 335.1058 (M + H)+.
To a solution of 44a (0.81 g, 3.0 mmol) in anhydrous DMF (8 mL) was
added methoxy-thiosalicylic acid (3) (0.54 g, 3.0 mmol) followed by
K2CO3 (1.22 g, 8.85 mmol). The reaction mixture was stirred 23 h at
130 ꢁC. After cooling down to room temperature, the reaction mixture
was poured into cold water and extracted with EtOAc. Aqueous layers
were acidified with conc. HCl and extracted with EtOAc. Organic layers
were washed with water, dried over Na2SO4, and concentrated under
reduced pressure to give the crude product as a brown oil. Purification
by silica gel flash column chromatography (DCM/MEOH, 90:10) afforded
5 as an orange oil (0.68 g, 61%). 1H NMR (CDCl3, d): 2.11 (s, 3H, COCH3),
3.91 (s, 3H, OCH3), 5.08 (s, 2H, CH2O), 6.81 (d, 1H, J = 8.4 Hz, ArH),
7.12 (dd, 1H, J = 3.0, 9.0 Hz, ArH), 7.32 (dd, 1H, J = 1.8, 8.1 Hz, ArH), 7.53
(d, 1H, J = 8.4 Hz, ArH), 7.58 (d, 1H, J = 2.7 Hz, ArH), 8.21 (d, 1H, J = 1.8 Hz,
ArH). Calculated HRMS m/z 377.06. Found HRMS m/z 400.0466 (M + Na)+.
N,N-Dimethyl-2-(20-amino-40-hydroxymethylphenylthio)-5-hydroxy-
benzylamine (9)
To a solution of 8 (63.0 mg, 0.19 mmol) dissolved in MEOH (10 mL) and
conc. HCl (1.5 mL), tin chloride∙dihydrate (SnCl2∙2H2O) (0.34 g, 1.5 mmol)
was added at 0ꢁC. The resulting yellow reaction mixture was stirred
10 min at 0ꢁC, thereafter, it was allowed to come up to room temperature
and stirred for 21 h. The solvent was evaporated to dryness and the light
yellow residue taken into water. A saturated solution of Na2CO3 was
added to adjust the pH to 6 ~ 7 and the aqueous solution was extracted
with EtOAc. The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. Purification by silica gel flash
column chromatography (DCM/MEOH, 70:30) afforded 9 as a colorless
oil (15.7 mg, 27%). 1H NMR (CD3OD, d): 2.31 (s, 6H, NCH3), 3.59 (s, 2H,
CH2N), 4.50 (s, 2H, CH2OH), 6.59 (dd, 1H, J = 2.7, 8.4 Hz, ArH), 6.63 (dd,
1H, J = 1.8, 7.8 Hz, ArH), 6.79 (m, 2H, ArH), 6.89 (d, 1H, J = 8.4 Hz, ArH),
7.15 (d, 1H, J = 7.8 Hz, ArH). Calculated HRMS m/z 304.12. Found HRMS
m/z 305.1317 (M + H)+.
N,N-Dimethyl-2-(50-acetoxymethyl-20-nitrophenylthio)-5-methoxy-
benzamide (6)
To a suspension of 5 (0.41 g, 1.1 mmol) in anhydrous dichloromethane
(DCM) (8 mL) were added thionyl chloride (SOCl2) (0.32 g, 2.7 mmol)
and a few drops of DMF. The reaction mixture was refluxed for 1 h under
argon. The solvent was evaporated, and the solid was used without
further purification.
A solution of dimethylamine in THF ((CH3)2NH-THF) (2.0 M solution in
THF) (2.72 mL, 5.45 mmol) was added dropwise to a stirred solution of
the freshly prepared acid chloride (0.43 g, 1.1 mmol) in anhydrous THF
(7 mL) at ꢀ70ꢁC. The reaction mixture was allowed to stand overnight
at room temperature, then the solvent was removed under reduced
pressure. The orange residue was extracted with EtOAc. The organic
phase was washed with saturated Na2CO3 solution followed by water
and the resulting organic layers were combined, dried over Na2SO4,
and concentrated under reduced pressure. The product was purified by
silica gel flash column chromatography (DCM/EtOAc: 80/20) to yield
the desired compound (6) as an orange oil (0.38 g, 86%). 1H NMR (CDCl3,
d): 2.09 (s, 3H, COCH3), 2.87 (s, 3H, NCH3), 3.03 (s, 3H, NCH3), 3.88 (s, 3H,
OCH3), 5.05 (s, 2H, CH2O), 6.93 (m, 2H, ArH), 7.00 (dd, 1H, J = 3.0, 8.7 Hz,
ArH), 7.34 (dd, 1H, J = 2.1, 8.7 Hz, ArH), 7.48 (d, 1H, J = 8.4 Hz, ArH),
8.20 (d, 1H, J = 1.5 Hz, ArH). Calculated HRMS m/z 404.10. Found HRMS
m/z 405.1112 (M + H)+.
N,N-Dimethyl-2-(50-hydroxymethyl-20-nitrophenylthio)-5-(2-
fluoroethoxy)-benzylamine (10)
Compound (8) (70 mg, 0.21 mmol) was dissolved in anhydrous DMF
(3 mL), and the solution was purged with argon. Cs2CO3 (89 mg,
0.27 mmol) was then added, and the reaction mixture was stirred
20 min at room temperature. A DMF (1.5 mL) solution of 2-fluoroethyl-
p-toluenesulfonate (F(CH2)2OTs)8 (60 mg, 0.27 mmol) was added. The
resulting yellow reaction mixture was heated, in a sealed vessel, at
130ꢁC for 22 h during which it turned dark brown, and then was
quenched with cold water. The aqueous phase was neutralized to pH
to 6~7 with conc. HCl and extracted with EtOAc. The organic extracts
were combined, dried over Na2SO4, filtered, and concentrated under
reduced pressure. Silica gel flash column chromatography (DCM/MEOH,
90:10) gave 10 as a light yellow oil (35 mg, 44%). 1H (CDCl3, d): 2.22
(s, 6H, NCH3), 3.54 (s, 2H, CH2N), 4.26 (m, 1H, CH2), 4.36 (m, 1H, CH2),
4.71 (s, 2H, CH2OH), 4.72 (m, 1H, CH2), 4.88 (m, 1H, CH2), 6.62 (d, 1H,
J = 8.4 Hz, ArH), 6.93 (dd, 1H, J = 3.0, 8.4 Hz, ArH), 7.31 (m, 2H, ArH), 7.50
(d, 1H, J = 8.4 Hz, ArH), 8.27 (d, 1H, J = 1.0 Hz, ArH). Calculated HRMS m/z
380.12. Found HRMS m/z 381.1403 (M + H)+.
N,N-Dimethyl-2-(50-bromomethyl-20-nitrophenylthio)-5-hydroxy-
benzamide (7)
A solution of 6 (0.21 g, 0.52 mmol) in anhydrous DCM (2 mL) was purged
with argon and cooled to ꢀ78ꢁC. A solution of boron tribromide in
dichloromethane (BBr3-DCM) (1.0 M soln. in DCM) (2.60 mL, 2.60 mmol)
was added slowly and dropwise via syringe and the resulting reaction
mixture was stirred 15 min at ꢀ78ꢁC. Thereafter, the reaction mixture
was allowed to stand overnight at room temperature. The reaction
mixture was poured into ice water and extracted with DCM. Organic
layers were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The product was purified by silica gel flash column
chromatography (DCM/MEOH, 90:10) to yield the desired compound
(7) as a yellow oil (0.18 g, 86%). 1H NMR (CDCl3, d): 2.92 (s, 3H, NCH3),
3.08 (s, 3H, NCH3), 4.46 (s, 2H, CH2Br), 6.90 (m, 2H, ArH), 6.96 (d, 1H,
J = 2.4 Hz, ArH), 7.39 (d, 1H, J = 8.4 Hz, ArH), 7.44 (dd, 1H, J = 2.0, 8.4 Hz,
ArH), 8.23 (d, 1H, J = 1.5 Hz, ArH). Calculated HRMS m/z 409.99. Found
HRMS m/z 411.0001 (M + H)+.
N,N-Dimethyl-2-(20-amino-40-hydroxymethylphenylthio)-5-(2-
fluoroethoxy)-benzylamine (11)
Compound (10) (35 mg, 0.092 mmol) was treated with SnCl2.2H2O
(0.10 g, 0.46 mmol) as described for 9. The desired compound (11)
was obtained following purification by silica gel flash column
chromatography (DCM/MEOH, 70:30) as a colorless oil (18 mg, 56%).
1H NMR (CDCl3, d): 2.33 (s, 6H, NCH3), 3.60 (s, 2H, CH2N), 4.13 (m, 1H,
CH2), 4.22 (m, 1H, CH2), 4.62 (s, 2H, CH2OH), 4.65 (m, 1H, CH2), 4.80
(m, 1H, CH2), 6.70 (m, 2H, ArH), 6.73 (m, 1H, ArH), 6.93 (d, 2H, J = 8.7 Hz,
ArH), 7.37 (d, 1H, J = 7.8 Hz, ArH). Calculated HRMS m/z 350.15. Found
HRMS m/z 351.1536 (M + H)+.
N,N-Dimethyl-2-(50-hydroxymethyl-20-nitrophenylthio)-5-hydroxy-
benzylamine (8)
Radiochemistry
To a solution of 7 (0.16 g, 0.39 mmol) in anhydrous THF (3 mL), BH3-THF
complex (1.0 M soln. in THF) (2.0 mL, 2.0 mmol) was added dropwise at
0ꢁC. The mixture was refluxed 3 h and left 16 h at room temperature.
Radiosynthesis of [18F]F(CH2)2OBs
The reaction was quenched by addition of conc. HCl at 0ꢁC and the An aqueous [18F]HF solution (~ 2 Ci), produced by a Siemens 11 MeV RDS
solvent was removed under reduced pressure. To the residue, water
111 cyclotron using the 18O(p,n)18F reaction in H128O, was collected on a
(3 mL) was added and the mixture was refluxed for 30 min with vigorous trap/release cartridge. It was released with a solution of (1.5 mg/mL)
stirring. After cooling down to room temperature, a saturated solution of K2CO3/H2O (0.6 mL), transferred to a chemical processing control unit
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Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 539–543

N. Jarkas et al.
(CPCU), and added to the open CPCU vessel containing a solution of
Conclusions
(5.0 mg/mL) K222/CH3CN (1.0 mL). The [18F]fluoride mixture was partially
dried by heating at 110ꢁC with argon and finally adding 3.5 mL of CH3CN. FEOHOMADAM, a derivative of HOMADAM with a fluoroethoxy
To the dried and activated K222/[18F]fluoride complex, BsO(CH2)2OBs
chain on phenyl ring B, was prepared. It was radiolabeled with
fluorine-18 by reacting the phenolic precursor with the
(~6.00 mg) in CH3CN (0.5 mL) was added, and the reaction mixture was
heated at 110ꢁC for 10 min before addition of the solvent mixture abs.
synthesized labeling agent, [18F]F(CH2)2OBs. [18F]FEOHOMADAM
EtOH:H2O:Et3N (50:50:0.1) (5 mL). The quenched reaction mixture was
was obtained in an average radiochemical yield of 21%. In vivo
purified by HPLC using column A. The appropriate fractions were
pharmacological and imaging properties of [18F]FEOHOMADAM
collected and concentrated via a solid phase extraction (SPE) method
have been evaluated in nonhuman primates and data will be
published later.
using a tC18 cartridge. The 18F fractions collected from the semi-
preparative HPLC were diluted with two volumes of sterile water and
combined in one flask. After mixing, the homogenous solution was
transferred with vacuum through a tC18 Sep Pak (previously activated
with abs. EtOH (10 mL) and water (10 mL)), the eluate being directed to
the waste. After washing with water (20 mL) directed into the waste,
Acknowledgement
This research was sponsored by an NIMH K01 Career Development
Award Grant (K01MH090278).
[
18F]F(CH2)2OBs (220–570 mCi) was eluted off the cartridge with CH3CN
(2 mL) and directed into a conical vessel to give [18F]F(CH2)2OBs in an
18
average RCY of 35% (decay-corrected from transfer of H
F
(aq)
to the
Conflict of Interest
CPCU). An aliquot (0.1 mL) of the 18F solution was used to establish the
chemical and radiochemical purities of the 18F synthon by analytical
HPLC using column B. Further evidence for the identity of the
radiolabeled product was achieved by co-injection with the authentic
standard material. The conical vessel was placed in a 100ꢁC oil bath,
and the solvent was removed to dryness with argon. [18F]F(CH2)2OBs:
Column A, solvent: abs. EtOH:H2O:Et3N (50:50:0.1), flow rate = 3 mL/min,
tR = 14 min. Column B, solvent: MEOH:H2O:Et3N (50:50:0.1), flow rate =
1 mL/min, tR = 3.9 min.
The authors did not report any conflict of interest.
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J. Label Compd. Radiopharm 2013, 56 539–543
Copyright © 2013 John Wiley & Sons, Ltd.
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