Novel Radiotracers for Imaging SERT via PET
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3105
addition of ethyl acetate (10 mL) and 10% aqueous sulfuric
acid (10 mL). The organic layer was filtered through a plug of
Na2SO4 under nitrogen and evaporated to dryness to leave a
yellow oil (3.43 g). This was treated with K2CO3 (5.5 g, 40
mmol), 4-chloro-2-nitrobenzonitrile (3.9 g, 21.3 mmol), copper
powder (0.38 g, 6 mmol) and DMF (30 mL). The mixture was
stirred under nitrogen for 1 h, diluted with water (100 mL),
and extracted with ethyl acetate (3 × 60 mL). The combined
extracts were washed with water (100 mL), dried (K2CO3), and
filtered, and volatiles removed to leave a yellow foam (6.67 g,
89%). A portion (0.5 g) was purified by flash chromatography
on silica gel with ethyl acetate followed by recrystallization
from 80% aqueous ethanol to give an analytical sample of 5
filtered, and evaporated to dryness to give crude 10. Purifica-
tion by column chromatography on silica gel (ethyl acetate/
petroleum ether/Et3
N 55/45/5) gave a light brown oil (0.09 g,
37%), which partially crystallized upon drying under high
vacuum: 1H NMR 7.34 (d, 1H, J ) 8.3), 7.28 (dd, 1H, J ) 1.7
and 7.3), 7.06-7.13 (m, 2H), 6.84 (dd, 1H, J ) 1.7 and 7.3),
6.73 (d, 1H, J ) 2.2), 6.69 (dd, 1H, J ) 2.2 and 8.3), 4.51 (br
s, 2H), 3.90 (s, 2H), 2.50 (s, 3H), 1.49 (br s, 1H); 13C NMR 149.7,
138.2, 137.7, 136.6, 135.3, 129.4, 127.9, 127.2, 125.8, 118.5,
114.8, 113.0, 54.1, 36.1; malonate salt mp 128-130 °C. Anal.
(C14H15ClN2S‚C3H4O4) C, H, N.
In a similar fashion with similar yields, using either 40%
aqueous methylamine or 40% aqueous dimethylamine were
prepared the following, either as free base, hydrochloride salt,
or malonate salt:
1
as a yellow powder (0.35 g): mp 120-126 °C; H NMR 8.54
(d, 1H, J ) 1.8), 7.74 (dd, 1H, J ) 1.3 and 7.7), 7.63 (dt, 1H,
J ) 1.3 and 7.6), 7.58 (dd, 1H, J ) 1.2 and 7.7), 7.51 (dd, 1H,
J ) 1.8 and 8.5), 7.47 (dt, 1H, J ) 1.5 and 7.7), 6.81 (d, 1H,
J ) 8.5), 4.77 (s, 2H), 1.94 (br s, 1H). Anal. (C14H10N2O3S) C,
H, N.
5-Met h oxy-2-(2-m et h yla m in om et h ylp h en ylsu lfa n yl)-
1
p h en yla m in e (11): H NMR 7.34 (d, 1H, J ) 8.3), 7.27 (dd,
1H, J ) 2.6 and 6.7), 7.04-7.09 (m, 2H), 6.78 (dd, 1H, J ) 2.2
and 6.5), 6.35 (dd, 1H, J ) 2.7 and 8.5), 6.32 (d, 1H, J ) 2.7),
3.91 (s, 2H), 3.78 (s, 3H), 2.50 (s, 3H); 13C NMR 162.4, 150.4,
138.9, 136.9, 136.8, 129.2, 127.7, 126.1, 125.1, 105.5, 105.2,
100.4, 55.2, 53.9, 36.0; hydrochloride salt mp 162-166 °C dec.
Anal. (C15H18N2OS) C, H, N.
[2-(2-Am in o-4-ch lor op h en ylsu lfa n yl)p h en yl]m et h a n -
ol (6). A solution of 3 (1.67 g, 6 mmol) in THF (15 mL) was
added dropwise to a solution of LiAlH4 (0.5 g, 13.2 mmol) in
THF (15 mL) and stirred for 1 h. The mixture was quenched
with aqueous NaOH (2.1 mL, 4%) at 0 °C and filtered through
diatomaceous earth, washing solids well with ether. Evapora-
tion left a brown solid which was recrystallized from cyclo-
hexane/toluene to give a light brown solid (1.24 g, 77%): mp
109-111 °C; hydrochloride salt mp 153-156 °C; 1H NMR 7.40
(dd, 1H, J ) 1.5 and 7.3), 7.31 (d, 1H, J ) 8.3), 7.11-7.19 (m,
2H), 6.86 (dd, 1H, J ) 1.3 and 7.7), 6.77 (d, 1H, J ) 2.2), 6.71
(dd, 1H, J ) 2.2 and 8.3), 4.83 (s, 2H), 4.35 (s, 2H), 2.06 (s,
1H). Anal. (C13H12ClNOS‚HCl) C, H, N.
[2-(2-Am in o-4-m et h oxyp h en ylsu lfa n yl)p h en yl]m et h -
a n ol (7). Prepared in 61% yield from the carboxylic acid 4 by
reduction with LiAlH4 as described for 6 above. Column
chromatography (silica, EtOAc/petroleum ether/Et3N 45/50/
5) gave a pale yellow oil which yielded a waxy solid upon
drying under high vacuum: mp 92-93 °C; 1H NMR 7.37 (dd,
1H, J ) 2.7 and 6.3), 7.32 (d, 1H, J ) 8.5), 7.07-7.13 (m, 2H),
6.80 (dd, 1H, J ) 1.7 and 6.6), 6.35 (dd, 1H, J ) 2.7 and 8.5),
6.31 (d, 1H, J ) 2.7) 4.81 (s, 2H), 4.30 (br s, 2H), 3.77 (s, 3H),
2.7 (br s, 1H). Anal. (C14H15NO2S) C, H, N.
3-Am in o-4-(2-m eth yla m in om eth ylp h en ylsu lfa n yl)ben -
1
zon itr ile (12): H NMR 7.36 (d, 1H, J ) 8.3), 7.33 (dd, 1H,
J ) 1.6 and 7.4), 7.21 (dt, 1H, J ) 1.3 and 7.4), 7.15 (dt, 1H,
J ) 1.6 and 7.6), 7.00 (dd, 1H, J ) 1.3 and 7.8), 6.91-6.94 (m,
2H), 4.73 (br s, 2H), 3.89 (s, 2H), 2.47 (s, 3H), 1.75 (br s, 1H);
13C NMR 148.3, 139.6, 136.0, 133.6, 130.2, 130.1, 128.5, 127.4,
122.5, 121.3, 119.1, 117.8, 113.2, 54.4, 36.3. Anal. (C14H11NO5S)
C, H, N.
5-Ch lor o-2-(2-d im et h yla m in om et h ylp h en ylsu lfa n yl)-
p h en yla m in e (14): 1H NMR 7.38 (d, 1H, J ) 7.8), 7.19-7.23
(m, 1H), 7.07-7.71 (m, 2H), 6.89-6.92 (m, 1H), 6.67-6.70 (m,
2H), 4.54 (br s, 2H), 3.55 (s, 2H), 2.29 (s, 6H); 13C NMR 149.9,
138.4, 137.2, 136.7, 136.5, 130.3, 128.2, 128.0, 125.6, 118.1,
114.7, 114.2, 62.5, 45.2; hydrochloride salt mp of 237-238 °C
dec. Anal. (C15H17ClN2S‚HCl) C, H, N.
2-(2-Dim et h yla m in om et h ylp h en ylsu lfa n yl)-5-m et h -
oxyp h en yla m in e (15): 1H NMR 7.39 (d, 1H, J ) 8.3), 7.22-
7.25 (m, 1H), 7.05-7.09 (m, 2H), 6.84-6.87 (m, 1H), 6.33 (dd,
1H, J ) 2.7 and 8.5), 6.29 (d, 1H, J ) 2.7), 4.51 (br s, 2H),
3.78 (s, 3H), 3.57 (s, 2H), 2.31 (s, 6H); 13C NMR 162.4, 150.7,
139.2, 138.2, 136.5, 130.3, 128.0, 127.0, 125.1, 106.9, 105.0,
100.5, 62.5, 55.4, 45.5; malonate salt mp 102-105 °C dec. Anal.
(C15H15N2S‚C3H4O4) C, H, N.
3-Am in o-4-(2-d im et h yla m in om et h ylp h en ylsu lfa n yl)-
ben zon itr ile (16): 1H NMR 7.47 (d, 1H, J ) 7.8), 7.23 (d, 1H,
J ) 7.3), 7.11-7.18 (m, 2H), 6.99 (d, 1H, J ) 8.5), 6.93 (dd,
1H, J ) 1.5 and 7.8), 6.88 (d, 1H, J ) 1.7), 4.97 (br s, 2H),
3.55 (s, 2H), 2.28 (s, 6H); 13C NMR 148.6, 138.3, 136.7, 135.0,
130.7, 130.1, 128.3, 126.6, 121.2, 120.6, 118.8, 117.5, 113.2,
62.6, 45.1; hydrochloride salt mp 212-218 °C dec. Anal.
(C15H17N3S‚HCl‚0.25H2O) C, H, N.
Ra d ioch em istr y. 1. Ra d iosyn th esis of [11C]-16. [11C]-
Iodomethane, produced from 11CO2 as described previously,18
was swept by a flow of N2 gas (10 mL/min) into a solution of
12 (1.0 mg) in DMF (200 µL) at -20 °C. When radioactivity
had peaked the solution was heated to 90 °C for 4 min and
quenched with HPLC buffer (0.5 mL). The mixture was
purified by semipreparative HPLC; Phenomenex Prodigy C18
(250 × 10 mm, 35% CH3CN:65% H2O + 0.1 N NH4HCO2, 10
mL/min (tR of 16 ) 8 min, tR of 12 ) 3 min). The desired
fraction was collected and evaporated to dryness at 50 °C and
the residue taken up in 10 mL of sterile saline. The saline
solution of [11C]-16 was passed through a sterile 0.22-µm filter
into a sterile, pyrogen-free bottle containing aqueous sodium
bicarbonate (1 mL, 8.4%). An aliquot (100 µL) of the formulated
solution was used to establish the chemical and radiochemical
purity and specific activity of the final solution by analytical
HPLC; Phenomenex Prodigy C18 (250 × 4.5 mm, 40% CH3-
CN:60% H2O + 0.1 N NH4HCO2, 3 mL/min (tR of 16 ) 4 min).
[11C]-14 and [11C]-15 were prepared in a similar manner with
3-Am in o-4-(2-h yd r oxym eth ylp h en ylsu lfa n yl)ben zon i-
tr ile (8). A mixture of crude 5 (90% pure by HPLC, 12.1 g, 38
mmol), ferric chloride (0.19 g, 1.2 mmol), and charcoal (0.95
g) in ethanol (100 mL) was stirred at reflux and treated with
a solution of hydrazine hydrate (2 mL) in ethanol (5 mL). After
3 days of heating, the hot mixture was filtered through
diatomaceous earth and evaporated to dryness. The residue
was partitioned between ethyl acetate (200 mL) and saturated
aqueous NaHCO3 (150 mL); the organic layer was washed with
brine (100 mL), dried (K2CO3), filtered, and evaporated to give
a red sticky solid (12.3 g). Purification by column chromatog-
raphy on silica gel (ethyl acetate/petroleum ether/Et3N 40/55/
5) followed by recrystallization from 80% aqueous ethanol gave
off-white needles (4.7 g 49%): mp 121-124 °C; 1H NMR 7.47
(d of m, 1H, J ) 7.5), 7.29 (dt, 1H, J ) 1.3 and 7.5), 7.27 (d,
1H, J ) 7.9), 7.21 (dt, 1H, J ) 1.5 and 8.9), 7.04 (dd, 1H, J )
1.1 and 8.9), 6.96 (d, 1H, J ) 1.7), 6.94 (dd, 1H, J ) 1.7 and
7.9), 4.82 (s, 2H), 4.44 (br s, 2H), 2.17 (br s, 1H). Anal.
(C14H12N2OS) C, H, N.
5-Ch lor o-2-(2-m eth ylam in om eth ylph en ylsu lfan yl)ph en -
yla m in e (10). A solution of 6 (0.23 g, 0.87 mmol) in diethyl
ether (1.5 mL) was treated with a solution of HCl in diethyl
ether (5 mL, 1 N). The ether was evaporated; the solid stirred
at ambient temperature with toluene (4 mL) and was treated
with thionyl chloride (0.5 mL). After 2 h volatiles were
removed, toluene (5 mL) was added, and the mixture evapo-
rated to dryness. The crude benzyl chloride was stirred with
toluene (5 mL) and treated with 40% aqueous methylamine
(1 mL). After 24 h water (5 mL) was added, the organic layer
separated, and the aqueous fraction extracted with toluene (5
mL). The combined organic extracts were dried (K2CO3),