Journal of Medicinal Chemistry
Article
(water/acetonitrile: 2/3, v/v), the mixture was loaded to HPLC for
purification. The HPLC method is described as follows: solvent A:
0.1% trifluoroacetic acid (TFA) water; solvent B: 0.1% TFA
acetonitrile; and 0 to 2 min: isocratic elution of 40% solvent B, 2
to 22 min, 40−95% of solvent B. Flow rate: 3 mL/min. HPLC
column: Gemini 5 μm C18 110 Å, 250 mm × 10.00 mm. [18F]-2-
fluoroethyl 4-methylbenzenesulfonate (77 mCi) was collected at 15
min. The collected [18F]-2-fluoroethyl 4-methylbenzenesulfonate was
diluted with 10 mL of water and then passed through a Sep-Pak tC18
cartridge. The loaded activity was washed out with 1 mL of
acetonitrile. The elution was blow-dried in a v-vial, and then 20 μL of
piperazine solution (0.33 μmol/mL) and 60 μL of acetonitrile were
added and heated at 110 °C for a further 10 min. Then, K2CO3 (2
mg), 1-(2,3-epoxypropyl)-2-nitroimidazole (3.8 mg), and 60 μL of
acetonitrile were added and heated at 90 °C for 20 min. The resulting
tracer was purified by HPLC with the method described as follows:
solvent A: 0.1% Et3N water; solvent B: 0.1% Et3N acetonitrile, 0 to 45
min: 5−30% of solvent B. Flow rate: 1 mL/min, collected at 17.6 min.
RCY: 29.0%. [18F]-21 (0 to 35 min: 5−60% of solvent B. Flow rate: 1
mL/min, collected at 14.0 min. 22.8%) and [18F]-22 (0 to 35 min: 5−
60% of solvent B. Flow rate: 1 mL/min, collected at 15.4 min, 28.8%)
were synthesized accordingly using oxybis(ethane-2,1-diyl) bis(4-
methylbenzenesulfonate) and homopiperazine as starting materials.
Typical Radiolabeling Protocol for [18F]-23 to [18F]-25. The
precursor 2-(2-(vinylsulfonyl)ethoxy)ethyl 4-methylbenzenesulfonate
(2 mg) was added into a v-vial and then the v-vial was sealed. Then,
the [18F]-TBAF (200 mCi) in acetonitrile was added and the vial was
heated at 110 °C for 20 min. After diluting with 1 mL of water, the
mixture was loaded to HPLC for purification. The HPLC method is
described as follows: Solvent A: 0.1% TFA water; solvent B: 0.1%
TFA acetonitrile; 0 to 2 min: isocratic elution of 5% solvent B, 2 to 22
min, 5−95% of solvent B. Flow rate: 3 mL/min. HPLC column:
Gemini 5 μm C18 110 Å, 250 mm × 10.00 mm. [18F]-((2-(2-
fluoroethoxy)ethyl)sulfonyl)ethene (79 mCi) was collected at 13.6
min. Then, 2-nitroimidazole (2 mg) was mixed with the collected
[18F]-((2-(2-fluoroethoxy)ethyl)sulfonyl)ethene (5 mCi) in a sol-
ution of 50 μL of DMSO and 200 μL of 20× borate buffer (pH 8.5)
and then heated at 80 °C for 20 min. The resulting tracer [18F]-23
was purified by HPLC with the method described as follows: 0 to 2
min: isocratic elution of 10% solvent B, 2 to 22 min, 10−55% of
solvent B. Flow rate: 1 mL/min, collected at 12.4 min. RCY: 58.7%.
[18F]-24 (12.4 min, 66.8%) and [18F]-25 (13.8 min, 53.1%) were
synthesized accordingly using 4-nitroimidazole/[18F]-((2-(2-
fluoroethoxy)ethyl)sulfonyl)ethene and 2-nitroimidazole/[18F]-((2-
(2-(2-fluoroethoxy)ethoxy)ethyl)sulfonyl)ethene as starting materials.
Chemistry. Synthesis of Precursor 2-(2-(2-(Vinylsulfonyl)-
ethoxy)ethoxy)ethyl 4-Methylbenzenesulfonate (18). The 2-(2-
hydroxyethoxy)ethyl 4-methylbenzenesulfonate (384.9 mg, 1.0
equiv), which was synthesized according to the literature,40 was
stirred at room temperature with divinyl sulfone (262.0 mg, 1.5 equiv)
and triphenylphosphine (39.3 mg, 0.1 equiv) in anhydrous dichloro-
methane (200 μL) for 2 h.41 Then, the mixture was directly loaded on
silica gel column chromatography for purification (ethyl acetate/
hexane: 1/151/1). 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.3
Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.79-6.72 (m, 1H), 6.36 (d, J =
16.6 Hz, 1H), 6.08 (d, J = 9.9 Hz, 1H), 4.13−4.11 (m, 2H), 3.84 (t, J
= 5.6 Hz, 2H), 3.65 (t, J = 4.8 Hz, 2H), 3.55 (s, 4H), 3.21 (t, J = 5.7
Hz, 2H), 2.42 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 145.0, 137.9,
132.8, 129.9, 128.8, 127.9, 70.3, 69.2, 68.6, 64.6, 55.0. The precursor
2-(2-(vinylsulfonyl)ethoxy)ethyl 4-methylbenzenesulfonate (16) was
synthesized accordingly with ethane-1,2-diol as the starting material.
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.36 (d, J =
mixture was stirred at room temperature overnight and then
evaporated under a vacuum to remove excess trifluoroacetic acid.
Further purification was achieved by silica gel chromatography with
ethyl acetate/methanol (10/12/1 v/v) as the eluent. 1-(2-
fluoroethyl)piperazine: 1H NMR (400 MHz, CDCl3) δ 9.49 (s,
1H), 4.62 (t, J = 4.6 Hz, 1H), 4.50 (t, J = 4.7 Hz, 1H), 3.21 (t, J = 5.0
Hz, 4H), 2.83−2.79 (m, 5H), 2.73 (t, J = 4.7 Hz, 1H).
The mixture of 1-(2-fluoroethyl)piperazine (96.7 mg, 1.0 equiv), 2-
nitro-1-(oxiran-2-ylmethyl)-1H-imidazole (85.8 mg, 1.3 equiv), and
potassium carbonate (70.5 mg, 1.3 equiv) was mixed in 1 mL of
acetonitrile and refluxed for 30 min, and then the mixture was cooled
down to room temperature and stirred overnight. After purification
using column chromatography with elution by ethyl acetate/methanol
(10/12/1 v/v), the product was collected as an off-white solid.
1-(4-(2-Fluoroethyl)piperazin-1-yl)-3-(2-nitro-1H-imidazol-1-yl)-
propan-2-ol ([19F]-20). Off-white solid. 1H NMR (400 MHz, CDCl3)
δ 7.26 (d, J = 0.9 Hz, 1H), 7.12 (d, J = 0.9 Hz, 1H), 4.70 (dd, J =
14.0, 2.5 Hz, 1H), 4.61 (t, J = 4.8 Hz, 1H), 4.49 (t, J = 4.8 Hz, 1H),
4.25 (dd, J = 14.0, 7.4 Hz, 1H), 4.05 (m, 1H), 2.73-2.45 (m, 12H),
2.28 (dd, J = 12.3, 10.2 Hz, 1H).13 C NMR (101 MHz, CDCl3) δ
144.9, 128.0, 127.4, 82.7, 81.0, 65.7, 60.3, 58.1, 57.9, 53.4, 53.4, 53.3,
19
53.0.
F NMR (376 MHz, CDCl3) δ −218.32. HRMS calcd for
C12H21FN5O3 (M + H), 302.1628; found, 302.1630.
Typical Procedure for the Syntheses of Standards [19F]-21
and [19F]-22. 1-(4-(2-(2-fluoroethoxy)ethyl)piperazin-1-yl)-3-(2-
1
nitro-1H-imidazol-1-yl)propan-2-ol (21): Off-white solid. H NMR
(400 MHz, CDCl3) δ 7.25 (d, J = 0.9 Hz, 1H), 7.11 (d, J = 0.9 Hz,
1H), 4.68 (dd, J = 14.0 Hz, 1H), 4.58 (t, J = 4.1 Hz, 1H), 4.47 (t, J =
4.1 Hz, 1H), 4.23 (dd, J = 14.0, 7.4 Hz, 1H), 4.02 (m, 1H), 3.71 (t, J
= 4.2 Hz, 1H), 3.64-3.60 (m, 3H), 2.65-2.63 (m, 2H), 2.58 (t, J = 5.8
13
Hz, 2H), 2.51-2.42 (m, 7H), 2.25 (dd, J = 12.2, 10.2 Hz, 1H).
C
NMR (101 MHz, CDCl3) δ 144. 9, 128.0, 127.4, 83.9, 82.3, 70.3,
70.1, 69.1, 65.6, 60.3, 57.6, 53.5, 53.3. 19 F NMR (376 MHz, CDCl3)
δ −222.72. HRMS calcd for C14H25FN5O4 (M + H), 346.1891;
found, 346.1892.
1-(4-(2-Fluoroethyl)-1,4-diazepan-1-yl)-3-(2-nitro-1H-imidazol-
1-yl)propan-2-ol ([19F]-22). Off-white solid. 1H NMR (400 MHz,
CDCl3) δ 7.28 (d, J = 0.9 Hz, 1H), 7.12 (d, J = 0.9 Hz, 1H), 4.69 (dd,
J = 13.9, 2.4 Hz, 1H), 4.57 (t, J = 5.0 Hz, 1H), 4.45 (t, J = 5.2 Hz,
1H), 4.22 (dd, J = 13.9, 7.6 Hz, 1H), 3.96 (m, 1H), 2.88-2.67 (m,
13
11H), 2.29 (dd, J = 12.4, 10.4 Hz, 1H), 1.80 (m, 2H). C NMR
(101 MHz, CDCl3) δ 142.8, 128.1, 127.4, 83.2, 81.6, 66.4, 60.4, 57.9,
19
57.7, 55.6, 55.6, 55.4, 54.5, 54.3, 54.3, 53.3, 28.0. F NMR (376
MHz, CDCl3) δ −219.37. HRMS calcd for C13H23FN5O3 (M + H),
316.1785; found, 316.1791.
Typical Procedure for the Synthesis of [19F]-23. To the
solution of 2-fluoroethanol (64.1 mg, 1.0 equiv) and divinyl sulfone
(177.2 mg, 1.5 equiv) in anhydrous dichloromethane (200 μL),
triphenylphosphine (26.2 mg, 0.1 equiv) was added as portion.28 The
mixture was stirred at room temperature for 2 h and then directly
loaded on silica gel column chromatography for purification (ethyl
acetate/hexane 1/20−1/5). (2-(2-fluoroethoxy)ethylsulfonyl)ethane
(51.2 mg, 1.0 equiv) and 2-nitroimidazole (63.5 mg, 2.0 equiv) were
mixed in a solution of 200 μL of DMSO and 500 μL of 20× borate
buffer (pH 8.5) and then heated at 80 °C for 2 h; 5 mL of water and 5
mL of ethyl acetate were added to the reaction mixture. After
extracting the aqueous phase three times, the organic solutions were
combined and dried over anhydrous MgSO4. The solvent was
evaporated under reduced pressure, and the residue was purified by
elution with ethyl acetate/hexane (1/52/1) to get the product as
an off-white solid.
1-(2-((2-(2-fluoroethoxy)ethyl)sulfonyl)ethyl)-2-nitro-1H-imida-
1
zole ([19F]-23). Off-white solid. H NMR (400 MHz, acetone-d6) δ
8.1 Hz, 2H), 6.69 (m, 1H), 6.38 (d, J = 16.6 Hz, 1H), 6.07 (d, J = 9.9
Hz, 1H), 4.14 (m, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.65 (m, 2H), 3.19
(t, J = 5.6 Hz, 2H), 2.44 (s, 3H).13 C NMR (101 MHz, CDCl3) δ
145.1, 137.7, 132.8, 129.9, 129.0, 127.9, 68.7, 68.7, 64.8, 54.8, 21.6.
Typical Procedure for the Synthesis of [19F]-20. The tert-butyl
4-(2-fluoroethyl)piperazine-1-carboxylate (880 mg), which was
prepared according to the literature method,42 was dissolved in 2
mL of 50% v/v trifluoroacetic acid in dichloromethane. The reaction
7.58 (d, J = 0.9 Hz, 1H), 7.14 (d, J = 0.9 Hz, 1H), 4.98 (t, J = 6.7 Hz,
2H), 4.62 (t, J = 4.0 Hz, 1H), 4.50 (t, J = 4.0 Hz, 1H), 3.93 (t, J = 5.3
Hz, 2H), 3.82 (t, J = 6.7 Hz, 2H), 3.79 (d, J = 4.0 Hz, 1H), 3.71 (t, J =
4.0 Hz, 1H), 3.31 (t, J = 5.4 Hz, 2H). 13 C NMR (101 MHz, acetone-
19
d6) δ 128.6, 128.5, 84.4, 82.8, 71.2, 71.0, 65. 5, 54.9, 54.8, 44.1.
F
NMR (376 MHz, acetone-d6) δ −223.39. HRMS calcd for
C9H15FN3O5S (M + H), 296.0716; found, 296.0712.
5599
J. Med. Chem. 2021, 64, 5593−5602