Synthesis of no-carrier-added [11C]methanesulfonyl chloride as a new labeling agent for PET radiopharmaceutical development

Article abstract of DOI:10.1002/jlcr.745

Three methods are described for labeling methanesulfonyl (mesyl) chloride with no-carrier-added (NCA) carbon-11 (t_1/2 = 20.4min; β ⁺ = 99.8%) to provide a new labeling agent of potential value in radiopharmaceutical development for p

Full text of DOI:10.1002/jlcr.745

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 1127–1140.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.745
Research Article
Synthesis of no-carrier-added
[11C]methanesulfonyl chloride as a new labeling
agent for PET radiopharmaceutical development
Julie A. McCarron* and Victor W. Pike
MRC Cyclotron Unit, Imperial College School of Medicine,
Hammersmith Hospital, Ducane Road, London W12 0NN, UK
Summary
Three methods are described for labeling methanesulfonyl (mesyl) chloride
with no-carrier-added (NCA) carbon-11 (t1/2=20.4 min; b+=99.8%) to
provide a new labeling agent of potential value in radiopharmaceutical
development for positron emission tomography (PET). Each method uses
NCA [11C]iodomethane, which is readily prepared from cyclotron-produced
[11C]carbon dioxide or [11C]methane by known procedures. The first method
(route 1) consisted of converting [11C]iodomethane into [11C]methyllithium and
then treatment with sulfuryl chloride. NCA [11C]mesyl chloride was obtained
in 78% decay-corrected radiochemical yield (RCY) from [11C]iodomethane at
30 min from the end of radionuclide production (ERP). However, co-
production of n-butanesulfonyl chloride limited the extent of reaction of this
labeling agent with 1,2,3,4-tetrahydroisoquinoline (THIQ). Two new syntheses
were devised, based on converting [11C]iodomethane into [11C]methanethiol by
passage over heated sodium hydrogen sulfide for subsequent treatment with
either chlorinated water (route 2) or over heated manganese(IV) oxide and then
calcium hypochlorite (route 3). These procedures gave NCA [11C]mesyl
*Correspondence to: J. A. McCarron, PET Radiopharmaceutical Sciences Section, Molecular
Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10,
Rm. B3 C346A, 10 Center Drive, Bethesda, MD 20892-1003, USA. E-mail: mccarroj@intra.nimh.
nih.gov
Contract/Grant sponsor: Human Frontier Science Programme Organisation; contract/grant
number: RG 0235/1998-B
Copyright # 2003 John Wiley & Sons, Ltd.
Received 3 June 2003
Accepted 24 June 2003

1128
J. A. McCARRON AND V. W. PIKE
chloride in 77% (route 2) and 28% (route 3) RCYs from [11C]iodomethane at
about 20 min from ERP. Crude [11C]mesyl chloride, produced by route 2 or 3,
reacted rapidly with THIQ to give the corresponding NCA [11C]methanesul-
fonamide in 49 or 74% RCY, respectively. Phenol was also converted rapidly
with [11C]mesyl chloride into the corresponding [11C]mesylate (>90%
RCY). Copyright # 2003 John Wiley & Sons, Ltd.
Key Words: Carbon-11; labeling agent; PET; [11C]mesyl chloride; [11C]metha-
nesulfonamide; [11C]mesylate
Introduction
The development of new labeling agents is fundamentally important to
the search for new radiopharmaceuticals in the field of positron
emission tomography (PET),1–3 an important biomedical imaging
modality that finds increasingly widespread application in clinical
research,1–3 clinical diagnosis,4 drug development5–7 and biological
investigations in small animals.8,9 Methanesulfonyl (mesyl) groups are
present in several drugs and potential PET radiopharmaceuticals.10
Mesyl chloride is well known to be reactive towards amines,
alcohols and phenols,11 and hence, no-carrier-added (NCA) [11C]mesyl
chloride could have widespread use for labeling with the short-lived
positron-emitter, carbon-11 (t1/2=20.4 min; bþ ¼ 99:8%), if a rapid
and effective radiosynthesis could be developed. Following our
earlier brief reports,12,13 we describe three methods for the
radiosynthesis of [11C]mesyl chloride in full detail, one based on
treatment of [11C]methyllithium with sulfuryl chloride and two
others that each use [11C]methanethiol as an intermediate for oxidation
and chlorination. One of these is a complete ‘on-line’ gas phase
process from [11C]iodomethane and especially suited to future easy
automation.
Results and discussion
NCA [11C]iodomethane can be readily prepared from cyclotron-
produced [11C]carbon dioxide14–16 or [11C]methane17–19 in high radio-
activity and high specific radioactivity, and has the potential to serve as
a useful substrate for the preparation of [11C]mesyl chloride. Initially,
we explored the preparation of NCA [11C]mesyl chloride by treating
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140

NEW LABELING AGENT FOR PET
1129
[11C]iodomethane with n-butyllithium and the resultant [11C]methyl-
lithium20,21 with sulfuryl chloride (Figure 1; route 1). This procedure
gave [11C]mesyl chloride in 78% RCY (decay-corrected radiochemical
yield) within 12 min from the production of [11C]iodomethane. Reaction
of NCA [11C]mesyl chloride with 1,2,3,4-tetrahydroisoquinoline (THIQ;
51 mg) gave [11C]N-mesyl-THIQ in 61% RCY.
However, when reactions were performed with the amount of THIQ
reduced to 26 and 13 mg, the RCYs of the [11C]N-mesyl-THIQ were
reduced to 50 and 26%, respectively. This effect is probably due to
competition for reaction with THIQ by the substantial quantity of n-
butanesulfonyl chloride that is expected to be co-produced with the
labeling agent. This route was therefore considered impractical for
application in cases where it might be necessary to use a small amount
of precursor in the labeling reaction. Examples would be cases where
there is a need to conserve precious precursor material or to enable
effective single pass HPLC separation of the radiopharmaceutical.
Use of the more sterically hindered t-butyllithium22 in place of
n-butyllithium was not effective in eliminating competing reaction
with THIQ.
We examined a second approach, whereby NCA [11C]iodomethane
might be converted into [11C]methanethiol, which might then be
oxidized and chlorinated to [11C]mesyl chloride. It has been reported
that [11C]methanethiol may be prepared almost instantaneously and
quantitatively by dispensing NCA [11C]iodomethane into a solution of
sodium hydrogen sulfide in anhydrous N,N-dimethylformamide.23 We
prepared [11C]methanethiol satisfactorily by this procedure. Since
[11C]methanethiol is gaseous (b.pt.: 68C), simple nitrogen purge of the
reaction mixture enabled transfer of this product to a collection vessel
Figure 1. Routes to NCA [11C]mesyl chloride from NCA [11C]iodomethane and
its use for labeling a methanesulfonamide and mesylate
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140

1130
J. A. McCARRON AND V. W. PIKE
that contained reagent for further transformation. Chlorine-saturated
water at 08C has been used to prepare fluoromesyl chloride from 4-
chlorobenzyl fluoromethyl sulfide.24 We found that this reagent would
also convert [11C]methanethiol into [11C]mesyl chloride. Thus, after
such a reaction, analysis of the aqueous medium revealed that greater
than 90% of the trapped radioactivity was [11C]mesyl chloride.
However, only about 60% of the initial radioactivity, presumed to be
[11C]methanethiol, was successfully transferred over a period of 10 min;
a significant proportion of radioactivity, of undetermined chemical
form, remained in the reaction vessel that was used to produce the
[11C]methanethiol.
This experience prompted us to explore the development of an ‘on-
line’ process for the preparation of [11C]methanethiol. Such a procedure
would also be attractive for ease of future radiosynthesis automation
and operation with high radioactivity levels. We investigated passage of
[11C]iodomethane over anhydrous solid sodium hydrogen sulfidey
contained in a silica tube placed within a furnace, with any generated
[11C]methanethiol collected in chlorine-saturated water (Figure 1, route
2). The formation of [11C]methanethiol by this method was found to be
temperature-dependent. At room temperature (RT), no [11C]mesyl
chloride was detected in the chlorinated water. By increasing the fur-
nace temperature to 1508C and then 2108C there was 3 and 15%
radiochemical conversion, respectively. At 2858C, 60–80% of the
collected radioactivity was found to be [11C]mesyl chloride by HPLC
(Figure 2). Byproducts accounted for the remaining radioactivity.
Although [11C]mesyl chloride, generated by this method, is obtained
in chlorine-saturated water, it was found possible to prepare [11C]N-
mesyl-THIQ rapidly in 40% overall RCY from [11C]iodomethane by the
addition of THIQ in dichloromethane, containing triethylamine (TEA),
to the aqueous mixture. It was also found that [11C]mesyl chloride could
be isolated from the reaction mixture in which it was generated with a
silica Sep-pak1 cartridge that had been pre-activated with chloroform.
The reaction mixture was injected onto the cartridge and the [11C]mesyl
chloride eluted with chloroform. About 30% of the radioactivity eluted
from the cartridge under these conditions. It was further found that an
equal mixture of chloroform and dioxane gave improved elution of the
labeling agent, equivalent to about 50% of the radioactivity loaded onto
the cartridge.
yPotassium hydrogen sulfide was also used satisfactorily until its commercial availability ceased.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140

NEW LABELING AGENT FOR PET
1131
Figure 2. HPLC analysis (system A) of crude NCA [11C]mesyl chloride produced
by route 2
We directed further effort towards developing a complete ‘on-line’
method for producing [11C]mesyl chloride from [11C]iodomethane.
The first attempt produced [11C]methanethiol as before and passed
that over solid calcium hypochlorite at RT. However, only unreacted
[11C]methanethiol was present in the effluent. Passage of [11C]metha-
nethiol over a combination of pyridinium dichromate and calcium
hypochlorite at RT produced [11C]mesyl chloride in 10% RCY from
[11C]iodomethane. Pyridinium dichromate was replaced with potassium
permanganate with no resulting increase in RCY. A variety of other
oxidizing agents were tried in the furnace at 2558C with
the effluent passed over calcium hypochlorite at RT. These oxidants
included potassium dichromate, chromium(III) oxide and mangane-
se(IV) oxide. The last oxidant was the most successful; about 35% of
the radioactivity passed into the furnace tubes as [11C]iodomethane
was recovered in acetonitrile and 87% of this radioactivity was found to
be [11C]mesyl chloride by HPLC (Figure 3). Hence, gas phase
[11C]iodomethane was successfully and rapidly converted into [11C]me-
syl chloride by a succession of solid reagents (Figure 4). We expect that
a similar approach might be adopted for the radiosynthesis of
potentially useful higher [11C]alkanesulfonyl chlorides from the known
corresponding [11C]iodoalkanes,25,26 though we have not yet explored
this possibility.
In other experiments, [11C]mesyl chloride from route 3 was trapped
in a vial containing THIQ (4–8 mg) and TEA in THF. The reaction
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140

1132
J. A. McCARRON AND V. W. PIKE
Figure 3. HPLC analysis (system B) of crude NCA [11C]mesyl chloride produced
by route 3
Figure 4. Diagram of apparatus for the ‘on-line’ conversion (route 3) of NCA
[11C]iodomethane into [11C]mesyl chloride
mixture was stirred at RT for 5 min and then analyzed by HPLC. The
major radioactive fraction (74%) eluted with the same reten-
tion time as authentic N-mesyl-THIQ. This demonstrates the potential
of [11C]mesyl chloride for the preparation of 11C-labeled methane-
sulfonamides from small amounts of precursor. [11C]Mesyl chloride
is also potentially applicable to the introduction of [11C]mesyl groups
at other nucleophilic sites (e.g., hydroxyl, carboxyl and phenolic
oxygens). We were able to demonstrate that [11C]mesyl chloride reacts
rapidly with phenol to give the corresponding [11C]mesylate in
90% RCY.
The radiochemical yields of [11C]mesyl chloride from repeated use of
this ‘on-line’ production method were found to be quite variable,
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140

NEW LABELING AGENT FOR PET
1133
indicating that the procedure will require some further optimization
before possible inclusion in a system for PET radiopharmaceutical
production. It is expected that this process will be particularly sensitive
to trace oxygen (with risk of oxidation of the heated sodium hydrogen
sulfide). Our limited experience with this new process indicates that
results are optimal when great care is taken to purge the apparatus with
dry nitrogen before use. Each charge of sodium hydrogen sulfide could
be used for three productions.
Conclusion
Three methods produced NCA [11C]mesyl chloride, which was shown
to react with a secondary amine precursor and phenol so demonstrating
its potential application in PET radiopharmaceutical development.
Two of the methods (2 and 3), which use [11C]methanethiol as
an intermediate, are especially useful. Route 2 gives moderate and
reliable radiochemical yields and would be easily automated for use
in routine PET radiopharmaceutical productions. Route 3 is an ‘on-line’
method that produces [11C]mesyl chloride in the gas phase within
2 min from the production of [11C]iodomethane (ꢀ15 min from ERP),
ready for collection in a solvent of choice for further reaction.
This method is very promising and needs further optimization for
consistent radiochemical yield and utility in PET radiopharmaceutical
production.
Experimental
Materials
Anhydrous sodium hydrogen sulfide (m.p.: 3508C) was purchased from
Alfa Chemicals. Hydrated sodium hydrogen sulfide (NaSH ꢁ H2O;
m.p.: 52–548C), mesyl chloride, anhydrous sulfuryl chloride (2.0 M in
diethyl ether), 1,2,3,4-tetrahydroisoquinoline (THIQ), n-butyllithium
(1.6 M in hexanes), n-butyllithium (1.6 M in hexanes), triethylamine
(TEA), chlorine and other commonly used reagents and solvents were
purchased from Aldrich Chemical Co. Ltd. m-Bondapak1 HPLC
columns (300 ꢁ 7.8 mm i.d.) and silica Sep-pak1 cartridges were
purchased from Waters Associates Inc.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140

1134
J. A. McCARRON AND V. W. PIKE
Analytical HPLC
Analytical HPLC was performed on a m-Bondapak C18 column
(300 ꢁ 7.8 mm i.d.) with eluate monitored with detectors for
UV absorbance (Model SA 6506; Severn Analytical) and radioacti-
vity (NaI, 20 mm diameter; Bioscan) linked to a computerized
data acquisition program (Labview1). The column was eluted
with acetonitrile – 0.05 M – potassium dihydrogen orthophosphate
(40: 60 v/v) at 2.5 ml/min (system A) (Rt: mesyl chloride, 8.1 min;
N-mesyl-THIQ, 11.7 min) or acetonitrile – 0.05 M – potassium dihydro-
gen orthophosphate (20: 80 v/v) at 3.0 ml/min (system B) (Rt: mesyl
chloride, 10.4 min). Mesyl chloride was adequately stable to the HPLC
conditions at RT (ꢀ208C; rates of hydrolysis in water and aqueous-
organic solvents at 25 and 34.58C are 52%/min27). Radioactive
compounds were identified by (i) comparison of Rt with that of
authentic non-radioactive standards and (ii) observation of coelution of
reference compound by UV absorbance (at 210 nm for aliphatic
compounds or 254 nm for aromatic compounds) and radioactivity after
spiking the radioactive product with reference compound.
Mass spectrometry
Mass spectrometry (MS) was performed on an analytical quadrupole
instrument (R10/10C; Nermag) with a probe interface (Nermag). The
spectrometer was calibrated for mass number with residual air and
perfluorotributylamine and run in chemical ionization mode (CI +ve),
using ammonia or methane as reactant gas.
Gas chromatography–mass spectrometry
Gas chromatography–mass spectrometry (GC–MS) was performed on a
Polaris Q instrument (ThermoFinnigan). GC was run on an Rtx
capillary column (0.25 mm i.d. ꢁ 30 m; Restek) with a split-less injector
at 2208C, transfer-line at 2008C, helium flow at 1 ml/min and
temperature program of 608C for 1 min increased to 1808C at 208C/
min. The MS was run in electron ionization (EI) mode with an ion
source temperature of 2508C.
NMR spectroscopy
1H-NMR and proton-decoupled 13C-NMR spectra were recorded with
a 400 MHz instrument (Avance 4000; Bruker). Chemical shifts (d) are
reported in ppm from tetramethylsilane as internal standard.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140

NEW LABELING AGENT FOR PET
1135
Synthesis of N-mesyl-THIQ28,29
A solution of THIQ (940 ml; 7.5 mmol) in anhydrous THF (6.0 ml) was
added under nitrogen to a two-necked round-bottom flask. TEA
(1.26 ml; 9 mmol) was added and the contents stirred for 5 min at RT.
Mesyl chloride (1.036 g; 9 mmol) was then added portionwise. The
reaction mixture was stirred overnight at RT, dissolved in dichlor-
omethane (20 ml) and washed with saturated sodium hydrogen
carbonate solution (2 ꢁ 20 ml) and brine (2 ꢁ 20 ml). The organic layer
was separated, dried over magnesium sulfate, filtered and concentrated
under reduced pressure to give a yellow solid (1.14 g; 78%). M.p.: 126–
1
1288C. H-NMR (CDCl3; 298 K) d (ppm): 2.74 (s, 3 H), 2.87 (t, 2 H,
J=5.9 Hz), 3.47 (t, 2 H, J=5.9 Hz), 4.36 (s, 2 H), 6.99–7.12 (m, 4 H); cf.
Ishibashi et al.30 13C-NMR (CDCl3; 298 K) d (ppm): 28.66, 35.76, 43.41,
47.26, 126.34, 126.53, 126.98, 129.03, 131.67, 133.12. MS (CI +ve,
NH3) m/z: 212 {[M+H]+, 6.3%}, 229 {[M+NH4]+, 100%}. HPLC
(system A) gave a single peak. TLC (silica gel: CH2Cl2-MeOH;
4: 1 v/v), Rf=0.69.
Synthesis of phenylmethanesulfonate
A solution of phenol (1.00 g; 10.6 mmol) and TEA (1.2 g; 12.7 mmol) in
THF was cooled to 08C and mesyl chloride (1.45 g; 12.7 mmol) was
added dropwise. The reaction mixture was stirred at 08C for 1 h and
then warmed to RT and stirred overnight. The reaction mixture was
then poured into water (100 ml) and ethyl acetate (100 ml) added. The
organic layer was separated and washed with saturated sodium
bicarbonate solution (100 ml) and water (100 ml). The organic layer
was dried over anhydrous magnesium sulfate and concentrated in vacuo
to give phenylmethanesulfonate as a white solid (1.64 g; 88%). M.p.:
1
59–608C. (Lit. m.p.: 61.58C;31 62–638C32). H-NMR (CDCl3; 298 K) d
(ppm): 3.14 (s, 3 H) 7.25–7.6 (m, 5 H); cf. Percec et al.32 13C-NMR
(CDCl3; 298 K) d (ppm): 37.35, 122.01, 122.33, 127.09, 127.42, 127.65.
129.76, 130.05, 149.33. GC-MS (EI) m/z: 172 {[M]+, 11%}, 94
{[M-PhH]+, 100%}.
Production of [11C]carbon dioxide
l4
No-carrier-added [11C]carbon dioxide was prepared by the N(p, a)11C
nuclear reaction by bombarding nitrogen gas containing 0.1% oxygen
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140

1136
J. A. McCARRON AND V. W. PIKE
at 1.5 MPa (15 bar) with a beam (30 mA) of 19 MeV protons from a
Scanditronix MC40 (Mark II) cyclotron. The [11C]carbon dioxide was
transferred in nitrogen from the target to the lead-shielded hot-cell
through stainless steel tubing (81 in o.d.) and passed through a column of
magnesium perchlorate before being trapped in a spiral of stainless steel
tubing (116 in o.d.) immersed in liquid argon.
Production of NCA [11C]iodomethane
[11C]Iodomethane was produced in a lead-shielded hot-cell using
automated apparatus driven by a programmable logic controller
(Toshiba Ltd).33 Cryogenically trapped [11C]carbon dioxide was
warmed to RT and dispensed into a solution of lithium aluminum
hydride in THF (0.2 ml; 0.2 M) in a stream of nitrogen (8 ml/min) for
2 min. The solvent was evaporated off at 1208C for 3 min and the
reaction pot then cooled to RT by compressed air for 2.5 min.
Hydroiodic acid (0.2 ml) was added and the reaction pot heated
at 1608C for 2 min. NCA [11C]iodomethane was obtained within
10 min from the end of radionuclide production (ERP) in >90%
RCY from [11C]carbon dioxide. Generally, this procedure gave
[11C]iodomethane with a specific radioactivity far exceeding 185 GBq/
mmol (5 Ci/mmol).
Synthesis of [11C]mesyl chloride from [11C]methyllithium (route 1)
n-Butyllithium (1.6 M in hexanes; 0.1 ml) and anhydrous diethyl ether
(0.4 ml) were added to a septum-sealed vial (volume 1 ml; Pierce) under
nitrogen and cooled to ꢂ788C (acetone-cardice bath). [11C]Iodomethane
(ꢀ370 MBq; ꢀ10 mCi) was transferred into the vial in a stream of
nitrogen and the sealed contents then stirred vigorously for 5 min.
Anhydrous sulfuryl chloride (1.0 M solution in dichloromethane; 0.1 ml)
was then added and stirring continued at ꢂ788C for 2 min before
the reaction mixture was allowed to warm to RT. The reaction mixture
was stirred for a further 8 min. On opening the vial about 20% of
the radioactivity was lost as an unknown volatile product. A sample
of the reaction mixture (0.1 ml) was diluted with acetonitrile
(0.5 ml) and analyzed by HPLC (system A). One major radioactive
peak was identified as [11C]mesyl chloride (78% RCY from
[11C]iodomethane).
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140

NEW LABELING AGENT FOR PET
1137
Synthesis of NCA [methyl-11C]N-mesyl-THIQ from [11C]mesyl chloride
prepared by route 1
[11C]Mesyl chloride was produced by route 1 as described above and
transferred to a Teflon1-sealed reaction vial (volume, 2 ml) containing
THIQ (51 mg; 0.38 mmol) and TEA (40 ml; 0.29 mmol) in THF (0.4 ml).
The reaction mixture was stirred at 708C for 10 min. Analysis of the
mixture by HPLC (system A) gave one major radioactive peak identified
as [methyl-11C]N-Mesyl-THIQ (61% RCY from trapped [11C]mesyl
chloride). Reactions were repeated using 26 and 13 mg of THIQ giving
[methyl-11C]N-mesyl-THIQ in 50 and 26% RCY, respectively.
Synthesis of [11C]mesyl chloride from [11C]iodomethane (route 2)
[11C]Iodomethane (370 MBq; 10 mCi) in nitrogen was slowly (ꢀ50 ml/
min) passed over heated (2858C) anhydrous sodium hydrogen sulfide
(100 mg) in a silica tube (30 cm ꢁ 2 mm i.d.) that had been pre-flushed
with nitrogen for at least 2 h. The [11C]methanethiol emerging from the
furnace was then trapped in cold (08C) chlorine-saturated water (1 ml).
Analysis of the reaction mixture by HPLC (system A) gave one major
radioactive peak identified as [11C]mesyl chloride (77% RCY from
trapped [11C]iodomethane). Mesyl chloride was stable in this solution
for up to 45 min at RT.
Synthesis of NCA [methyl-11C]N-mesyl-THIQ from [11C]mesyl chloride
prepared via route 2
[11C]Mesyl chloride was obtained via route 2 in cold (08C) chlorinated
water (1.5 ml), as described above. A solution of THIQ (5 mg; 37 mmol)
and TEA (30 ml, 0.22 mmol) in dichloromethane (2 ml) was added and
stirred at RT for 3 min. A sample of the organic layer (ꢀ60% of the
total radioactivity) was analyzed by HPLC (System A). The major
radioactive fraction was identified as [methyl-11C]N-mesyl-THIQ (57%
RCY from trapped [11C]mesyl chloride).
Synthesis of [11C]mesyl chloride from [11C]iodomethane (route 3)
The apparatus (Figure 4) was flushed with dry nitrogen for at least 2 h
before the start of radiochemistry. [11C]Iodomethane (ꢀ1.85 GBq;
ꢀ50 mCi) in nitrogen was passed sequentially at 60 ml/min through
(i) a silica tube (30 cm ꢁ 2 mm i.d.) containing sodium hydrogen sulfide
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140

1138
J. A. McCARRON AND V. W. PIKE
(100 mg) heated in a furnace to 2858C, (ii) a silica tube (30 cm ꢁ
2 mm i.d.) containing manganese(IV) oxide (40 mg) in a furnace heated
at 2558C and (iii) a calcium hypochlorite (20 mg) reactor at RT. The
radioactivity emerging from the reactor was trapped in acetonitrile
(1 ml) and analyzed by HPLC (system B). One major fraction was
identified as [11C]mesyl chloride (27% RCY from [11C]iodomethane).
Synthesis of [11C]N-mesyl-THIQ from [11C]mesyl chloride prepared
via route 3
Crude [11C]mesyl chloride (ꢀ370 MBq; ꢀ10 mCi), prepared via route 3,
was dispensed into THF (1.0 ml) containing THIQ (4–8 mg; 30–
60 mmol) and TEA (30 ml; 0.22 mmol) in a septum-sealed vial. The
contents of the vial were stirred at RT for 5 min and then analyzed by
HPLC (system A). One major fraction was identified as [11C]N-mesyl-
THIQ (74% RCY from crude [11C]mesyl chloride).
Synthesis of [methyl-11C]phenylmesylate from [11C]mesyl chloride
prepared via route 2
Crude [11C]mesyl chloride (ꢀ370 MBq; ꢀ10 mCi) in diethyl ether
(2.0 ml) was added to a vial containing phenol (10 mg; 0.1 mmol) and
TEA (40 ml; 0.29 mmol). The reaction mixture was heated to reflux for
8 min and then analyzed by HPLC (system A). One major fraction was
identified as [methyl-11C]phenyl mesylate (90% RCY from crude
[11C]mesyl chloride).
Acknowledgements
The authors are grateful to Imaging Research Solutions Ltd., and the
Human Frontier Science Programme Organisation (Grant Number RG
0235/1998-B) for their support. The authors are also grateful to
Dr U. Shetty (NIMH) for GC–MS analysis.
References
1. Phelps ME, Mazziotta JC. Science 1985; 228: 799–809.
2. Phelps ME. Neurochem Res 1991; 16: 929–940.
3. Phelps ME. Proc Natl Acad Sci USA 2000; 97: 9226–9233.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140

NEW LABELING AGENT FOR PET
1139
4. Wagner HN. J Nucl Med 1991; 32: 561–564.
5. Gardner SF, Green JA, Bednarczyk EM, Farnett L, Miraldi F. Am J Hosp
Pharm 1992; 49: 1499–1506.
6. Comar D (ed.). PET for Drug Development and Evaluation. Kluwer
Academic Publishers, Dordrecht, 1995.
7. Luciagni G. Eur J Nucl Med 1995; 22: 489–490.
8. Budinger TF. Sem Nucl Med 1998; 28: 247–267.
9. Chatziioannou AF. Eur J Nucl Med 2002; 29: 98–114.
10. Labat Y. Phosphorus, Sulfur, Silicon Related Elements 1993; 74: 173–194.
11. Pearson AJ, Rousch WR (eds). Handbook of Reagents for Organic
Synthesis. Activating Agents and Protecting Groups. Wiley: New York,
1999; 257–299.
12. McCarron JA, Pike VW, Clark RD. J Nucl Med 1998; 39 (Suppl.): 119P
(Abstract 466).
.
13. McCarron JA, Wikstrom H, Pike VW. J Label Compd Radiopharm 1999;
42 (Suppl. 1): S132–S134.
.
14. Langstrom B, Lundqvist H. Int J Appl Radiat Isot 1976; 27: 357–363.
15. Marazano M, Maziere M, Berger G, Comar D. Int J Appl Radiat Isot
1977; 28: 49–52.
.
16. Crouzel C, Langstrom B, Pike VW, Coenen HH. Appl Radiat Isot 1987; 38:
601–603.
.
17. Larsen P, Ulin J, Dahlstrom K, Jensen M. Appl Radiat Isot 1992; 48:
153–157.
18. Link JM, Krohn KA, Clark JC. Nucl Med Biol 1997; 24: 93–97.
19. Steel CJ, Prenant C, Shah F, Brown G, Henderson D, Brady F, Luthra
SK, Pike VW. J Nucl Med 1998; 39 (Suppl.): 237.
20. Reiffers S, Vaalburg W, Wiegman T, Wynberg H, Woldring MG. Appl
Radiat Isot 1980; 31: 535–539.
21. Berger G, Maziere M, Prenant C, Sastre J, Comar D. Int J Appl Radiat Isot
1981; 32: 811–815.
.
22. Langstrom B. Ph.D. Thesis, University of Uppsala, Sweden, 1980.
23. Suehiro M, Shiue C-Y, Gonzalez C, Dembowski B. J Label Compd
Radiopharm 1993; 35: 109–110.
24. Lange U, Senning A. Chem Ber 1991; 124: 1879–1880.
25. Slegers G, Sambre J, Goethals P, Vandecasteele C, Van Haver D. Appl
Radiat Isot 1986; 37: 279–282.
.
26. Langstrom B, Antoni G, Gullberg P, Halldin C, Nagren K, Rimland A,
(
.
Svard H. Appl Radiat Isot 1986; 37: 1141–1145.
27. Nair MR, Jayaraman PO. Ind J Chem 1983; 22A: 63–64.
28. Proctor GR, Thomson RH. J Chem Soc 1957; 2302–2314.
29. Ito K, Tanaka H. Chem Pharm Bull 1977; 25: 1732–1739.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140

1140
J. A. McCARRON AND V. W. PIKE
30. Ishibashi H, Nakamura N, Ito K, Kitayama S, Ikeda M. Heterocycles
1990; 31: 1781–1784.
31. Becker HJ, Stedehouder PL. Rec Trav Chim 1931; 50: 931.
32. Percec V, Bae J-Y, Zhao M, Hill DH. J Org Chem 1995; 60: 176–185.
33. Turton DR, Brady F, Pike VW, Selwyn AP, Shea MJ, Wilson RA, De
Landsheere CM. Int J Appl Radiat Isot 1984; 41: 337–344.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 1127–1140