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M. Suehiro et al. / Bioorg. Med. Chem. 19 (2011) 2287–2297
brine (0.1 mL) followed by water (0.1 ml), and dried over sodium
sulfate. After evaporation of ether, 2,2,2-[18F]trifluoroethyl tosylate
was dissolved in anhydrous DMF.
0.19 mmole) and the non-radioactive tosylate (24 mg, 0.09 mmole)
(Route 2) were carried out in DMF-d7 in the presence of NaH (60%,
washed with pentane and dried under a stream of Ar) in a similar
fashion as described above (Approach C).
Step 2: O-[18F]Trifluoroethylation of 3-chloro-1,2-propanediol: To
a Reacti-vial containing 2–8 mg of NaH (60% in mineral oil) sus-
pended in 100
diol in anhydrous DMF was added at 0 °C followed by the
18F]trifluoroethyl tosylate solution obtained from Step 1, and stir-
l
L of dry DMF, 4–15 mg of 3-chloro-1,2-propane-
6.9. 18F-labeling of TFMISO using 3-(2-nitroimidazolyl)-1,2-
propanediol (10) as the precursor (Approach D, Scheme 5)
[
red at room temperature for 45–60 min. An aliquot of the reaction
mixture was analyzed by analytical HPLC running with a mobile
phase of acetonitrile–water (15/85).
Step 3: Reaction of the intermediate products from Step 2 with 2-
nitroimidazole: To a Reacti-vial containing 10–13 mg of 2-nitroim-
idazole in 100 lL of DMF, an equivalent amount of sodium meth-
oxide in methanol was added and heated at 150 °C for 3 min, the
reaction mixture let cool to 120 °C, and then the Step 2 reaction
[
18F]Trifluoroethyl tosylate produced as described above was
added to a DMF solution containing 8 mg of the diol precursor
(10) and 3 mg of 60% NaH and the reaction mixture stirred at room
temperature for 45 min. The progress of the reaction was exam-
ined by analytical HPLC with a mobile phase of acetonitrile–water
(15/85). The deprotonation reaction of the diol precursor (10) with
NaH was further examined by NMR as follows. To a Reacti-vial con-
taining NaH (60%, 3.2 mg) washed with pentane and dried, the
mixture added through a 0.45
lm membrane filter (Supelco, PA).
same precursor 10 (10 mg) dissolved in 200 lL of DMF-d7 was
The vial was heated at 120 °C for 30 min. This procedure was
adopted from Beaman et al.6 and used with modifications. Alterna-
tively, the reaction mixture of Step 2 was added to a vial containing
2-nitroimidazole and K2CO3 in 0.3 mL of ethanol and the vial
heated at 100 °C for 30 min. The progress of the reaction was mon-
itored by analytical HPLC running with a mobile phase of acetoni-
trile–water (15/85). The 18F-labeled product which eluted at the
retention time corresponding to that of authentic TFMISO was iso-
lated by semi-preparative HPLC, concentrated by solid phase
extraction using a tC18 SepPak Plus cartridge (Waters) and eluted
with 2 mL of methanol and the solvent evaporated. The final prod-
uct was confirmed as [18F]TFMISO by HPLC and mass spectrometry.
MS (ESI): 292 ([M+Na]+), 304 ([M+Cl]ꢀ. The radiochemical and
chemical purity of the purified final product were determined by
analytical HPLC and found to be 100% and greater than 98%, respec-
tively. The specific activity of [18F]TFMISO was determined by
dividing the radioactivity of the radiotracer by its mass, which
was calculated by comparing the area under its HPLC UV peak at
320 nm with that of a standard TFMISO solution of known
concentration.
added at 0 °C and the reaction stirred at room temperature for
5 min. The reaction mixture was analyzed by 1H NMR and mass
spectrometry. In addition, the solvent was evaporated under vac-
uum and the residue dissolved in CD3OD for 1H NMR.
Acknowledgments
We thank Dr. Jacek Koziorowski of Herlev University Hospital in
Denmark for fruitful discussions. We thank Ms. Chuyan (Alice) Cao
of Organic Synthesis Core Facility for her assistance in LC–MS puri-
fication of Compounds 7 and 8. We also thank Dr. Jason Lewis, Mr.
Howard Sheh, and Mr. Calvin Lom of the MSKCC Cyclotron Core
Facility for 18F production essential for this work. The authors also
thank Dr. Cynthia Jung for valuable assistance with the preparation
of the manuscript. This work was supported by NIH grant P01
CA115675 (P.I. John Humm/Clifton Ling), and in part P30 CA
008748-43 (Cancer Center Support Grant).
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