Preparation of [11C]methyl nona-fluorobutyl-1-sulfonate ([ 11C]MeONf) and its use in the synthesis of [11C]-6-OH-BTA- 1

Article abstract of DOI:10.1002/jlcr.1432

The rapid, simple and high-yield synthesis of the extraordinarily reactive ¹¹C-methylating agent, [¹¹C]methyl nona-fluorobutyl-1- sulfonate ([¹¹C]MeONf), and its use in the synthesis of the promising β-amyloid imaging agent, [¹¹C]-6-OH-BTA-1, is reported. In terms of radioactive methylation yields, [¹¹C]MeONf seems to surpass [¹¹C]methyl trifluoromethansulfonate ([¹¹C]MeOTf) as a methylating agent in this particular case giving the ¹¹C-labelled compound in high-preparative radiochemical yields between 27 and 29% EOS with a minimum formation of radioactive by-products. Copyright

Full text of DOI:10.1002/jlcr.1432

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 1230–1233.
Published online 2 August 2007 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1432
JLCR
Note
Preparation of [11C]methyl nona-fluorobutyl-1-sulfonate
([11C]MeONf) and its use in the synthesis of [11C]-6-OH-BTA-1
DEAN JOLLY1, YOUNES LAKHRISSI1, MIRIAM M. KOVACEVIC1, HOWARD CHERTKOW2 and RALF SCHIRRMACHER1,3,
1 McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal Que., Canada H3A2B4
*
2 Department of Clinical Neuroscience, Sir Mortimer B. Davis, Jewish General Hospital, 3755 Chemin de la Cote St. Catherine, Montreal Que., Canada
H3T1E2
3 Lady Davis Institute, Jewish General Hospital, Neurology and Neurosurgery, McGill University, 3755 Chemin de la Cote St. Catherine, Montreal Que.,
Canada H3T1E2
Received 30 April 2007; Revised 11 June 2007; Accepted 12 June 2007
Abstract: The rapid, simple and high-yield synthesis of the extraordinarily reactive 11C-methylating agent,
[
11C]methyl nona-fluorobutyl-1-sulfonate ([11C]MeONf), and its use in the synthesis of the promising b-amyloid
imaging agent, [11C]-6-OH-BTA-1, is reported. In terms of radioactive methylation yields, [11C]MeONf seems to
surpass [11C]methyl trifluoromethansulfonate ([11C]MeOTf) as a methylating agent in this particular case giving the
11C-labelled compound in high-preparative radiochemical yields between 27 and 29% EOS with a minimum
formation of radioactive by-products. Copyright # 2007 John Wiley & Sons, Ltd.
Keywords: 11C-methylation; nonaflate; Pittsburgh compound
Introduction
necessary to label 1 with [11C]CH3I. Furthermore, the
phenolic hydroxy group present in the molecule has to
be protected in advance to avoid unwanted O-methyla-
tion. Despite the inconvenient and time-consuming
deprotection step and the insufficient reactivity of
The synthesis of 11C-labelled compounds is based
predominantly on the use of
[
11C]methyliodide
([11C]CH3I),1 a labelling precursor routinely produced
by commercially available synthesis modules for simple
methylation reactions of desmethyl precursors. Despite
its straightforward synthesis, in some cases the
reactivity of [11C]CH3I is not high enough to guarantee
high radiochemical yields (RCYs) of the labelled com-
pound and more reactive methylating agents are
therefore needed. Especially, the 11C-methylation of
an aniline structure element, which is e.g. present in
2-(40-aminophenyl)-6-hydroxybenzothiazole (1) used as
a precursor for the synthesis of the b-amyloid imaging
compound [11C]-6-OH-BTA-1 (2),2 has been proven to
be difficult as a result of its low reactivity towards
alkylation. Harsh reaction conditions such as high
temperatures and the use of potassium hydroxide are
[
11C]CH3I, compound 2 was obtained in RCYs of 12%.
To circumvent these difficulties, Wilson et al. as well as
Solbach et al. independently reported the rapid one-
step radiosynthesis of [11C]-6-OH-BTA-1 using the far
more reactive labelling agent
[
11C]MeOTf and the
unprotected phenolic benzothiazole labelling precursor
6-HO-BTA-0.3,4 RCYs of 11–16% (Wilson et al., pre-
parative RCY at EOS, uncorrected for radioactive
decay) and 58% (Solbach et al., RCYs based on
integration of the radio-high-performance liquid chro-
matography (HPLC) chromatogram) of [11C]-6-OH-BTA-
1 have been reported after a synthesis time of 22 and
33 min, respectively, which is a great improvement
when compared with the original labelling procedure
using [11C]CH3I. A significant difference between these
two procedures is the used reaction temperature
(Wilson et al. used 208C, Solbach et al. used 808C) as
well as the applied amount of precursor (Wilson et al.
applied 0.4 mg, Solbach et al. applied between 4 and
8 mg). The corresponding HPLC chromatogram (Wilson
et al.) of the crude reaction mixture showed still large
*Correspondence to: Ralf Schirrmacher, Lady Davis Institute, Jewish
General Hospital, Neurology and Neurosurgery, McGill University,
3755 Chemin de la Cote st. Catherine, Montreal, Quebec, Canada H3T IE2.
E-mail: ralf.schirrmacher@mcgill.ca
Contract/grant sponsor: CIHR
Contract/grant sponsor: Fonds de la Recherche en Sante´ du Que´bec
(FRSQ)
Copyright # 2007 John Wiley & Sons, Ltd.

PREPARATION OF [11C]METHYL NONA-FLUOROBUTYL-1-SULFONATE ([11C]MEONF) 1231
Figure 1 Top: Synthesis of [11C]MeONf via online conversion of [11C]CH3I using a AgONf/C filled glass column at 1708C and a flow
rate of 10 mL/min. Bottom: Reaction of 1 with [11C]MeONf at 5–78C within 2 min in acetone.
Synthesis of [11C]MeONf and [11C]-6-OH-BTA-1
amounts of radioactive by-products. Between 2 and
4 min large amounts of unspecified by-products were
observed and the formation of the unwanted
A short glass column (4 mm ID ꢀ 95 mm) was partially
O-methylated compound was low but still observable
(55%). We here report the synthesis of the homologous
11C-labelling agent [11C]MeONf starting from [11C]CH3I.
We successfully applied [11C]MeONf to the synthesis of
filled (approximately one-third its volume) with
a
mixture of AgONf (200 mg, 0.49 mmol) and graphitized
carbon (200 mg), prepared by simply mixing the
compounds in a mortar with a spatula according to
Figure 1. The prepared column was placed in a
commercially available synthesis unit (MEI plus by
[
11C]-6-OH-BTA-1 (Figure 1). RCYs of [11C]-6-OH-BTA-
could be enhanced by further minimizing the
1
Bioscan,
[
11C]CH3I is produced by conversion of
formation of uncharacterized by-products as well as
completely avoiding the formation of O-[11C]methylated
compound (Figure 2).
[
[
11C]CO2 with LiAlH4 and HI) for the preparation of
11C]CH3I and [11C]MeOTf and heated up to 1708C in a
stream of nitrogen for 5 min.
[
11C]CH3I from the
module, which was previously passed over a short
drying column (5.0 g NaOH), was streamed through the
AgONf/C column and was bubbled (N2 sweep flow of
Experimental
Authentic 6-HO-BTA-0, 6-OH-BTA-1 and 6-OCH3-
BTA-1 were purchased from ABX (Germany). Graphi-
tized carbon (Carbograph1 60/80) was purchased from
Alltech. Silvercarbonate, 4-(40-nitrobenzyl)pyridine
(NBP) and nona-fluorobutane-1-sulfonic acid were
available from Sigma Aldrich.
10 mL/min) into
a solution of 1 (0.8–2 mg, 3.3–
8.2 mmol) dissolved in acetone (0.5 mL) at 5–78C for
2 min. Purification was performed according to Wilson
et al.3 using slightly different HPLC conditions (HPLC
column: Phenomenex Prodigy 10 m (250 ꢀ 10 mm),
eluent: acetonitrile/0.1 N NH4HCO3 50/50, flow:
3 mL/min). Before the reaction mixture was subjected
to the HPLC, 1.5 mL of HPLC solvent (acetonitrile/0.1 N
NH4HCO3 50/50) was added. After collection of the
peak corresponding to 2, the HPLC solvent was
removed by using a vacuum evaporator at 808C. To
the dried compound, ethanol (0.5 mL) and sterile
phosphate buffer (10 mL, pH 7, SABEX1) were added
and the mixture was passed through a sterile filter
(MILLEX1GV) to obtain the final injectable solution.
The overall synthesis time was between 25 and 27 min.
For quality control of the final sterile product, we used
a Prodigy 5 m 250 ꢀ 4.6 mm HPLC column and an
Synthesis of nona-fluorobutane-1-sulfonic acid silver
salt (AgONf)
The synthesis based on a procedure published by
Frasch et al. was simplified as a result of available
starting material of higher quality.5 In brief, to a stirred
solution of nona-fluorobutane-1-sulfonic acid (2.5 g,
8.3 mmol) in water (5 mL), Ag2CO3 (1.14 g, 4.15 mmol)
was carefully added in small portions until a clear
solution was obtained. The solution was filtered and
freeze dried under light exclusion to obtain AgONf as a
white solid (3 g, 7.4 mmol, 90%).
Agilent 1200 HPLC system equipped with
a UV-
detector (Agilent 1200 series) and radioactivity
a
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 1230–1233
DOI: 10.1002.jlcr

1232 D. JOLLY ET AL.
Figure 2 Radio-HPLC chromatogram of the crude reaction mixture of the reaction between 1 and [11C]MeONf showing high RCYs
of 2 and decreased formation of radioactive by-products. No formation of O-[11C]methylated product (retention time: 12 min) was
observed.
detector (Raytest, Germany). The following conditions
for quality control were applied: HPLC-solvent: acet-
onitrile/0.1 NH4HCO3 50/50; flow: 0.7 mL/min; Rt 2:
9.5 min. The purity of the final sterile compound was
determined to be >95%.
an important advancement because the demand for 1
is steadily increasing. When the reaction was per-
formed at 08C (n ¼ 2), according to the HPLC chroma-
tograms, the first peak (Rf: 4.5 min) in the radio-HPLC
chromatogram, which we assume corresponds to
hydrolyzed un-reacted
[
11C]MeONf gets more pro-
nounced and accounts for 40% of the detected radio-
activity. When performed at room temperature (n ¼ 2),
a new radioactive by-product (Rf: 9 min) occurred,
accounting for 25% of the observed radioactivity. As
these experiments served the purpose of optimizing the
reaction, no isolated uncorrected RCYs were deter-
mined. In comparison to Wilson et al., we did not apply
the HPLC loop technique for performing the reaction
between 1 and [11C]MeONf. In order to trap most of the
Results and discussion
The higher homolog of [11C]MeOTf, [11C]MeONf could
be synthesized in high RCYs (90% based on [11C]CH3I)
from
11C]methyl-sulfonate using a AgONf–graphitized car-
[
11C]CH3I, which was converted to the
[
bon column. Non-radioactive MeONf has been reported
to be a more reactive methylation agent than MeOTf.6,7
For the synthesis of
[ a commercially
11C]MeONf,
available synthesis unit for [11C]CH3I was used, which
already contains a compartment for the synthesis of
[
11C]MeONf, we used a larger amount of solvent (0.5 mL
acetone instead of 0.25 mL methylethylketone) and
between 0.8 and 2 mg of 1. This is a shortcoming in
terms of needed precursor material compared with
Wilson et al., who used only 0.4 mg of precursor
material. In contrast to Solbach et al. who used 5–10
times more precursor, the other methods are preferable
from an economical point of view. To directly compare
[
11C]MeOTf and could therefore be used for the
production of [11C]MeONf without modification. The
11C]CH3I was streamed over the pre-heated column
[
(1708C) using a flow rate of 10 mL/min according to
Jewett’s procedure for the synthesis of [11C]MeOTf.8
Higher flow rates resulted in a dramatically decreased
RCY of [11C]MeONf. When a flow rate of 15 mL/min was
used, the conversion rate dropped to 3% only. The
conversion of [11C]CH3I could be easily monitored by
the reaction of [11C]MeONf with NBP which does not
react with unconverted [11C]CH3I.8 In order to max-
imize the RCY of the reaction with 1 and [11C]MeONf in
acetone, the temperature dependency of the reaction
was investigated. Best results were obtained between 5
and 78C giving compound 2 in preparative RCYs
between 27 and 29% at EOS (obtaining the final
injectable solution is defined as EOS) as a sterile
injectable solution (based on production of 5 GBq of
[
11C]MeONf and [11C]MeOTf at our individual labora-
tory conditions, the methylation of 1 was performed
with [11C]MeOTf either at room temperature or between
5 and 78C. At room temperature (n ¼ 3), we obtained
nearly the same results as published by Wilson et al.
Our isolated yields were between 13 and 17% at EOS
(after 22–27 min) and the radio-HPLC chromatogram
showed still a large radioactivity peak (ca. 30%) at
4.5 min. This peak was even more pronounced when
the reaction was performed at 5–78C (n ¼ 2) and
accounted for more than 40% of the detected radio-
activity. Furthermore, the increased formation of radio-
active by-products was observed. In this case no
isolated yields were determined. Interestingly, the
formation of the O-[11C]methylated product could not
be observed in any case using [11C]MeONf, giving rise to
[
11C]CO2) which almost doubles the previously pub-
lished amount using [11C]MeOTf. The specific activity
of 2 was determined using a UV-calibration curve and
was found to be between 40 and 50 GBq/mmol. This is
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 1230–1233
DOI: 10.1002.jlcr

PREPARATION OF [11C]METHYL NONA-FLUOROBUTYL-1-SULFONATE ([11C]MEONF) 1233
speculations whether it is true that [11C]methyl-sulfo-
Mirko Diksic for discussions. This study was supported
in part by operating grants from the CIHR and the
Fonds de la Recherche en Sante´ du Que´bec (FRSQ)
awarded to H. C. H. C. is a chercheur national of the
FRSQ (Fonds de la Recherche en Sante´ du Que´bec).
nates such as [11C]MeOTf and [11C]MeONf are less
discriminative methylating agents in comparison to
[
11C]CH3I. According to our observations, [11C]MeONf
obviously seems to distinguish between the aromatic
amino moiety and the phenolic hydroxy function to
100% at the temperatures we investigated. Wilson et al.
reported the formation of small amounts of O-methy-
lated product using [11C]MeOTf3 at 208C, but Solbach
et al. who performed the synthesis at 808C for 1 min did
not confirm this observation. We are currently investi-
gating whether [11C]MeONf is applicable to the selective
11C-methylation of bi- or multifunctional compounds
in general. Furthermore, it would be worthwhile to
introduce 11C-methylating agents covering a wider
spectrum of reactivity to thoroughly investigate the
dependency of discrimination of methylation and
leaving group in complex multifunctional molecules.
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Acknowledgements
The authors would like to thank Dr Esther Schirrma-
cher for the determination of specific activity and Dr
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Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 1230–1233
DOI: 10.1002.jlcr