Radiosynthesis of [3H]-ABP688 using [3H]-methyl nosylate: A non-volatile alternative methylating agent

Article abstract of DOI:10.1002/jlcr.1665

Tritiated ABP688 was synthesized from desmethyl ABP688 with [ ³H]-methyl nosylate in high radiochemical yield. The results demonstrate that [³H]-methyl nosylate is a good alternative methylating agent for radiosynthesis. Copyright

Full text of DOI:10.1002/jlcr.1665

Note
Received 1 June 2009,
Revised 12 June 2009,
Accepted 22 June 2009
Published online 11 August 2009 in Wiley Interscience
(
www.interscience.wiley.com) DOI: 10.1002/jlcr.1665
3
Radiosynthesis of [ H]-ABP688 using
3
[
alternative methylating agent
H]-methyl nosylate: a non-volatile
Ã
Pixu Li and John D. Olszewski
3
Tritiated ABP688 was synthesized from desmethyl ABP688 with [ H]-methyl nosylate in high radiochemical yield. The
3
results demonstrate that [ H]-methyl nosylate is a good alternative methylating agent for radiosynthesis.
Keywords: tritiation; radiosynthesis; methylation; mGlu5 receptor antagonist
Introduction
observed that excess KHMDS did not adversely affect the
reaction or the product, but changed the excess starting
ABP688 (1,3-((6-methylpyridin-2-yl)ethynyl)cyclohex-2-enone material E/Z ratio to about 1:1 (by LC/MS mass chromatogram
O-methyl oxime, Figure 1) was reported as a selective and high area integration). The obtained ABP688 E/Z mixture was tested
affinity ligand for the mGlu5 receptor and was proposed to act
1
as a negative allosteric modulator. Tritiated ABP688 was
in the binding assay and performed very well. With the success
3
of the cold run, [ H]-ABP688 (4) was prepared using tritiated
proposed to be useful for receptor occupancy and other studies methyl nosylate (3) in a similar manner (Figure 2). Excellent
in drug discovery programs at Wyeth. The radiosyntheses of radiochemical yield (90%) and purity (498%) were obtained,
ABP688, in both tritiated and carbon-11 forms, have been
reported using radiolabeled iodomethane with desmethyl [ H]-ABP688 synthesis. This study clearly demonstrated that
ABP688 (2,3-((6-methylpyridin-2-yl)ethynyl)cyclohex-2-enone methyl nosylate is a good, non-volatile methylating agent. It is
However, better radiosynthesis strategy was
whereas the yield was not provided in the previously reported
3
1
,2
oxime).
a
especially beneficial in the field of radiosynthesis for avoiding
warranted because the existing reactions were carried out at personnel exposure and reducing emissions of radioactive
3
high temperature and iodomethane is a volatile reagent. Methyl material. Moreover, the obtained [ H]-ABP688 E/Z isomer ratio
nosylate (Methyl 4-nitrobenzenesulfonate) was investigated
was about 22:1 (by radio HPLC area percent, major isomer
because it is a non-volatile methylating reagent and tritiated undetermined). The highest reported E/Z isomer ratio for
3
1
methyl nosylate is commercially available. Herein, we report our preparation of radiolabeled ABP688 was 10:1.
results on the preparation of [ H]-ABP688 using tritiated methyl
nosylate.
3
Experimental
Results and discussion
General: Radioactivity was measured with a Wallac 1450
Microbeta Trilux. UV, radiochemical purity and Mass spectra
In our study, desmethyl ABP688 (2) was deprotonated with were obtained by LC/MS (Shimadzu LCMS 2010EV with an IN/US
potassium bis(trimethylsilyl)amide (KHMDS), and then treated b-Ram model 4 radioflow detector). Aldrich 200–400 mesh 60 A˚
with methyl nosylate at room temperature. ABP688 was
silica gel was used for column chromatography. All reactions
obtained with excellent yield after silica gel flash chromato- were done under a nitrogen atmosphere with anhydrous
graphy. Interestingly, very high E/Z isomer ratio (12:1) was solvents. Tritiated methyl nosylate was obtained from Perkin
obtained under the new reaction conditions, while the E/Z
Elmer (100 mCi in 5 mL toluene solution, 75 Ci/mmol). Desmethyl
isomer ratio of the starting material was about 8:1. The E/Z ratios ABP688 and ABP688 reference material were prepared by a
of the ABP688 and desmethyl ABP688 were measured by HPLC Wyeth authorized vendor. All other reagents and solvents were
UV area percent at 220 nm (major isomer undetermined). It was
obtained from standard commercial sources and used without
additional purification.
Wyeth Research, Chemical Development–Radiosynthesis, 401 North Middletown
Road, Pearl River, NY 10965, USA
N
N
OCH3
*
Correspondence to: Pixu Li, Wyeth Research, Chemical Development–Radio-
synthesis, 401 North Middletown Road, Pearl River, NY 10965, USA.
E-mail: lip6@wyeth.com
Figure 1. Structure of ABP688 (1).
J. Label Compd. Radiopharm 2009, 52 512–513
Copyright r 2009 John Wiley & Sons, Ltd.

P. Li and J. D. Olszewski
O
KHMDS
N
N
+
T3CO S
NO2
N
OCT3
N
Toluene / DMF
O
OH
90 %
[3H]-ABP688 (4)
2
3
3
Figure 2. Synthesis of [ H]-ABP688 (4) using [ H]-Methyl Nosylate (3).
3
3
oxime (ABP688, 1)
-((6-Methylpyridin-2-yl)ethynyl)cyclohex-2-enone O-methyl (0.5 M in toluene, 10.68 mL, 5.34 mmol) was added to ensure
complete consumption of tritiated methyl nosylate. The reaction
mixture was stirred at room temperature for 4 h and then
concentrated in vacuo. The residue was purified by flash
In a 10 mL pear flask, desmethyl ABP688 (12.5 mg, 0.055 mmol)
was dissolved in DMF (1 mL) to give a colorless solution. KHMDS
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chromatography with 10% EtOAc/toluene to give [ H]-ABP688
(
(
0.5 M in toluene, 0.11 mL, 0.055 mmol) was added. After 15 min,
90.2 mCi, 90%). Specific activity (84.9 Ci/mmol) was determined
methyl nosylate (3 mg, 0.014 mmol) was added and the reaction
mixture was stirred at room temperature overnight. The reaction
mixture was concentrated in vacuo, and the residue purified by
flash chromatography with 10% EtOAc/toluene to give ABP688
by MS. Chemical purity and radiochemical purity were
determined to be greater than 98% by HPLC (same method as
the cold run with radioflow detector).
(
3.4 mg, quantitative). The material was confirmed by compar-
ison to the reference material with LCMS (Nucleosil 100-3 C18
HD column, 150 Â 4.6 mm; mobile phase A: 5% ACN/H O,
2
mobile phase B: 100% ACN; 50% B to 95% B over 15 min, References
1
mL/min, 401C; t = 6.5 and 7.2 min).
R
[
[
[
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[ H]-3-((6-Methylpyridin-2-yl)ethynyl)cyclohex-2-enone
O-methyl oxime ([ H]-ABP688, 4)
3
3
In a 50 mL pear flask, methyl nosylate [methyl- H] (100 mCi/5 mL
in toluene) and desmethyl ABP688 (25 mg/100 mL solution in
DMF, 4.85 mL, 5.34 mmol) were combined to give a colorless
solution. KHMDS (0.5 M in toluene, 10.68 mL, 5.34 mmol) was
added. After 1 h, additional potassium bis(trimethylsilyl)amide
J. Label Compd. Radiopharm 2009, 52 512–513
Copyright r 2009 John Wiley & Sons, Ltd.
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