Development of a resonant-type microwave reactor and its application to the synthesis of positron emission tomography radiopharmaceuticals

Article abstract of DOI:10.1002/jlcr.3232

Microwave technology has been successfully applied to enhance the effectiveness of radiolabeling reactions. The use of a microwave as a source of heat energy can allow chemical reactions to proceed over much shorter reaction times and in higher yields tha

Full text of DOI:10.1002/jlcr.3232

Research Article
Received 20 April 2014,
Revised 31 July 2014,
Accepted 6 August 2014
Published online 8 October 2014 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3232
Development of a resonant-type microwave
reactor and its application to the synthesis of
positron emission tomography
radiopharmaceuticals
Hiroyuki Kimura,a,b † Yusuke Yagi,a† Noriyuki Ohneda,c Hiro Odajima,c
*
a
a
*
Masahiro Ono, and Hideo Saji
Microwave technology has been successfully applied to enhance the effectiveness of radiolabeling reactions. The use of a
microwave as a source of heat energy can allow chemical reactions to proceed over much shorter reaction times and in
higher yields than they would do under conventional thermal conditions. A microwave reactor developed by Resonance
Instrument Inc. (Model 520/521) and CEM (PETWave) has been used exclusively for the synthesis of radiolabeled agents
for positron emission tomography by numerous groups throughout the world. In this study, we have developed a novel
resonant-type microwave reactor powered by a solid-state device and confirmed that this system can focus microwave power
on a small amount of reaction solution. Furthermore, we have demonstrated the rapid and facile radiosynthesis of 16α-[18F]
fluoroestradiol, 4-[18F]fluoro-N-[2-(1-methoxyphenyl)-1-piperazinyl]ethyl-N-2-pyridinylbenzamide, and N-succinimidyl 4-[18F]
fluorobenzoate using our newly developed microwave reactor.
Keywords: resonant-type microwave reactor; positron emission tomography radiochemistry; 18F-fluorination; [18F]FES; [18F]MPPF;
[18F]SFB
has been used exclusively for the synthesis of radiolabelled
Introduction
agents for PET by numerous groups throughout the world.
Since Gebye and Giguere reported microwave synthesis in a
Commercial microwave reactors use a magnetron as an
sealed tube with a domestic microwave oven in 1986, there
oscillator, which can struggle to irradiate small areas of a
has been rapid increase in research efforts directed toward the
reaction mixture (such as those found in PET radiochemistry)
study of organic reactions in a microwave.1,2
with appropriate levels of power, and it can therefore be
Based on the significance of this early work, numerous
difficult for these systems to achieve sufficient microwave
heating.14,15 In this study, we have developed
a novel
microwave reactors have been developed and optimized for
synthetic applications, where it is possible to control the
temperature and pressure of the reaction mixture inside the
reactor. Many researchers have reported that the use of a
microwave as a source of heat energy can enable reactions to
proceed over much shorter reactions times and in higher yields
than they would do under conventional thermal conditions.3–8
Compounds labeled with 18F are used as positron emission
tomography (PET) tracers. The introduction of 18F atoms into
an organic compound (i.e., 18F-fluorination reactions), however,
invariably requires high temperatures and long reaction times
because fluoride anions are only weakly nucleophilic.
Furthermore, the use of long reaction times for the introduction
of 18F atoms can be problematic because the half-life of 18F
(109.7 min) is very short. A microwave-based 18F labeling
method was recently reported and has drawn considerable
attention from researchers working in a variety of different fields
because this new microwave-assisted method improved yields,
reduced the generation of side products, and shortened reaction
times compared with conventional heating methods such as oil
baths and hotplates.9–13 A microwave reactor developed by
Resonance Instrument Inc. (Model 520/521) and CEM (PETWave)
resonant-type microwave reactor that is powered by a solid-
state device. Notably, the frequency of the solid-state oscillator
in this system can be tuned to efficiently heat a small amount
of solution in the resonant cavity and provide excellent
heating to the reaction mixture to allow for the synthesis of
PET radiopharmaceuticals.
aDepartment of Patho-Functional Bioanalysis, Graduate School of
Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Kyoto 606-8501,
Japan
bRadioisotope Research Center, Kyoto University, Yoshida Konoe-cho, Sakyo-ku,
Kyoto, Kyoto 606-8501, Japan
cTechnology Development Dept., SAIDA FDS Inc., 143-10 Isshiki, Yaizu, Shizuoka
425-0054, Japan
*Correspondence to: Hideo Saji and Hiroyuki Kimura, Department of Patho-
Functional Bioanalysis, Graduate School of Pharmaceutical Sciences. Kyoto
University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
E-mail: hsaji@pharm.kyoto-u.ac.jp; hkimura@pharm.kyoto-u.ac.jp
† These authors contributed equally to this work.
J. Label Compd. Radiopharm 2014, 57 680–686
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H. Kimura et al.
Results and discussion
Figure 1 shows a picture of the microwave reactor system
developed in this study, including the resonant cavity and
reaction vessel. The key features of this system are as follows:
(1)
a solid-state microwave device, which was originally
developed for use in cellular phone systems (instead of a
magnetron source); (2) a resonant cavity operating in a TM010
single-mode16; and (3) a high-speed feedback system for tuning
the frequency and controlling the power. The oscillation unit
consists of a voltage controlled oscillator, variable attenuator,
high power amplifier, and programmable logic controller.
Microwave power (50 W max) from the oscillation unit was
transmitted to the irradiation unit via a coax cable. This newly
developed microwave reactor can be placed in small spaces such
as a hot cell because the resonant cavity is separated from the
oscillation unit.
Figure 2. The structure of the microwave irradiation unit. The vial temperature is
monitored with an IR thermometer.
Figure 2 shows the structure of the irradiation unit. The
coupling of the microwave power to the resonant cavity was
made possible by placing an antenna in the cavity. The cavity
has two openings; one for installing a vial and another for
monitoring the temperature using an infrared (IR) thermometer.
The IR thermometer placed outside of the cavity was used to
monitor the temperature of the vial. By maintaining the resonant
conditions at a consistent level, it was possible to reduce the
leakage of any microwave power from the cavity to a negligible
level. Furthermore, this newly developed microwave reactor
operates in the industrial, scientific, and medical frequency band
of 2.4–2.5 GHz. It is difficult to calculate the electromagnetic field
of a region heated with a domestic microwave oven with a multi-
mode cavity. In contrast, the electromagnetic field of the
resonance cavity can be calculated precisely for any object
placed at the highest energy point in our newly developed
microwave reactor. This newly developed microwave reactor
can therefore provide effective heating while using minimum
electrical power. The dielectric properties of a reaction system
can change depending on the type of reagents used and the
temperature of the system. For this reason, the oscillator
frequency needs to be repeatedly tuned to the cavity resonance
during the operation. To address this issue, we equipped our
newly developed microwave reactor with a feedback control
consisting of an electric field and frequency-variable solid-state
oscillator (2.4–2.5 GHz). In this way, the operator can select either
a constant microwave power mode or a temperature control
(a)
(b)
(c)
Figure 1. (a) Resonance-type microwave reactor system (left: liquid delivering unit, center: resonant cavity, right: oscillation unit). (b) Resonant cavity (TM010 single-
mode); inner diameter: ø 82 mm, inner height: 30 mm, outer size; depth: 16 cm, width: 23 cm, height: 9 cm. (c) Screw-cap pressure vessel.
J. Label Compd. Radiopharm 2014, 57 680–686
Copyright © 2014 John Wiley & Sons, Ltd.
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H. Kimura et al.
mode, where the microwave power is automatically adjusted by (DMF), dimethyl sulfoxide (DMSO), and MeOH. Several low-
variable attenuator based on the temperature measured by the dielectric loss solvents were also investigated, including
IR thermometer. The operator can then enter the conditions for toluene and THF (Table 1). The reaction vessel was irradiated
their synthesis, including the microwave power, irradiation time, with microwave irradiation at 50 W (maximum power). The
and temperature of the reagent, through a PC interface. Our time taken to reach 60 °C, 80 °C, and the boiling point of each
newly developed microwave reactor was also equipped with a solvent was recorded. Because DMSO has a very high boiling
real-time monitoring system, which allowed for several variables point, the third temperature was taken as the maximum
to be monitored simultaneously, including (1) the resonance temperature of the microwave reactor (i.e., 180 °C) instead of
frequency, (2) electric field in the cavity, (3) input power, (4) the boiling point.
reflection power, and (5) temperature. The control unit was
The experiment revealed that the polar aprotic solvent MeOH
designed to perform various safety functions, such as instigating possessed the fastest heating rate. For DMF and DMSO, which
an automatic shutdown procedure if the temperature exceeded have high boiling points, the microwave reactor could efficiently
a preset limit to ensure safer operation.
heat these solvents at high temperatures. MeCN, which is
Figure 3 shows a simulation of the electrical field distribution frequently used as a solvent in PET radiosynthesis, could be
in the cavity together with a reagent in a borosilicate vial. It is heated efficiently without a significant decrease in the heating
can be seen from the figure that this newly developed rate, even at its boiling point. It is noteworthy that a reduction
microwave reactor can effectively irradiate a small amount of in the solvent volume (0.05–0.2 mL) had very little impact on
solvent and provide efficient heating through the direct the rate of heating. It is important to reduce the amount of
coupling of microwave energy with the molecules that are solvent used in PET chemistry, and our newly developed system
present in the reaction mixture. This reactor system could made it possible to run a reaction using a high concentration of
therefore be used to rapidly and effectively heat a small amount precursor. In contrast, toluene and THF, which are both low-
of reaction mixture such as the solutions required for the dielectric loss solvents, had low heating rates. This suggests that
synthesis of PET radiopharmaceuticals.
the choice of the rate of the temperature increase should be
To evaluate the heating efficiency of our new system, we variable to account for the solvent effects.
measured the heating rate (°C/s) of several high-dielectric loss
solvents, including acetonitrile (MeCN), dimethylformamide microwave reactor through the evaluation of the heating effect,
we carried out the radiosynthesis of several known PET tracer
compounds.
To demonstrate the effectiveness of our newly developed
16α-[18F]Fluoroestradiol ([18F]FES) was selected as a model
compound to investigate the 18F-fluorination for the sulfonate
group17,18 (Table 2). [18F]FES is an estradiol derivative with the
highest bioactivity of all of the known estrogens, and this
compound is useful for the diagnosis of estrogen-dependent
diseases and the evaluation of the effectiveness of hormone
therapy. Under conventional heating conditions, the synthesis
of [18F]FES required 10 min of fluorination with [18F]KF in the
presence of Kryptofix2.2.2 and potassium carbonate (K2CO3),
followed by a 10 min deprotection step with an aqueous
solution of hydrochloric acid (Table 2, entry 1). When the
reaction time was shortened under conventional heating
conditions, it was not possible to achieve the desired level of
18F-fluorination because the 18F-fluorination yield was low
and the deprotection reaction did not proceed (Table 2, entry
2). In contrast, microwave heating gave a better yield of [18 F]
FES, with each reaction requiring only 1 min (Table 2, entry 3).
Furthermore, the yield of [18 F]FES remained unchanged until
the concentration of the amount of the precursor was
decreased by 75% (Table 2, entries 4 and 5). This indicates
that it is possible to reduce the amount of precursor used
in the synthesis of PET tracers using our newly developed
microwave reactor.
The nucleophilic aromatic 18F-fluorination of 4-[18F]fluoro-N-
[2-(1-methoxyphenyl)-1-piperazinyl] ethyl-N-2-pyridinylbenzamide
([18F]MPPF), which is used as a PET tracer for the evaluation of the
5-HT1A serotonin receptor,19,20 was also investigated using our
newly developed microwave system (Table 3). [18F]MPPF was
synthesized via the nucleophilic aromatic substitution reaction,
which was facilitated by a neighboring nitro group. Because the
18F anion is only weakly nucleophilic, this reaction usually requires
a high temperature and a long reaction time. The conventional
heating of 4-nitro-N-[2-(1-methoxyphenyl)-1- piperazinyl]ethyl-N-
Figure 3. Simulation of the electromagnetic field in the left half of a borosilicate
vessel containing 1 mL of solvent.
2-pyridinylbenzamide in the presence of [18 F]KF, Kryptofix2.2.2
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H. Kimura et al.
of microwave power required 30 s, and the reaction was
maintained at this temperature for 1 min. This result showed that
microwave heating provides shorter reaction times and better
yields than conventional heating for 18F-fluorination reactions.
Furthermore, the use of microwave heating allowed for the
formation of the desired product in good yield using half of the
original concentration of the precursor (Table 3, entry 3).
Microwave heating gave a better yield than conventional heating
until the concentration of precursor was decreased by 75% (Table3,
entry 4). In a similar manner to the results in Table 2, the results in
Table 3 showed that the concentration of the precursor could be
decreased through efficient heating using microwave irradiation.
Finally, we carried out the multistep synthesis of N-
succinimidyl 4-[18F] fluorobenzoate ([18F]SFB), which has
been used for the 18F-labeling of bioactive peptides and
nucleic acids21–23 (Scheme 1). The synthesis of [18F]SFB
requires three steps, including (1) fluorination with [18F]KF in
the presence of Kryptofix2.2.2 and K2CO3, (2) deprotection
with tetrapropylammonium hydroxide (TPAH), and (3)
esterification using N,N,N′,N′-tetramethyl-O-(N-succinimidyl)
uranium tetrafluoroborate, and these steps require long reaction
times. We synthesized [18F]SFB under microwave heating
conditions using our newly developed reactor system. For the
18F-fluorination, the reaction had preceded by 32% after 1 min
under conventional heating conditions, whereas microwave
heating gave a conversion in excess of 95% following the
same reaction time. This result demonstrated that microwave
irradiation is effective for the 18F-fluorination of aromatic
compounds such as the SFB precursor. Subsequent sequential
deprotection and esterification reaction were conducted under
microwave heating over 1 min each to give the crude product.
Finally, purification by solid-phase extraction afforded [18F]SFB
Table 1. Evaluation of the heating effect in organic solvents
Time to reach
temperature (s)
Warming rate
(°C/s)
Solvent
MeCN
0.2 mL, 60 °C
0.2 mL, 80 °C
0.1 mL, 80 °C
0.05 mL, 80 °C
DMF
8
12
13
12
1
0
1
1
4.3 0.3
4.3 0.1
4.1 0.2
4.2 0.1
0.2 mL, 60 °C
0.2 mL, 80 °C
0.2 mL, 150 °C
DMSO
7
10
33
1
1
1
4.8 0.5
5.6 0.3
3.6 0.1
0.2 mL, 60 °C
0.2 mL, 80 °C
0.2 mL, 180 °C*
MeOH
7
11
35
1
2
2
4.7 0.5
4.9 0.6
4.3 0.1
0.2 mL, 65 °C
Toluene
6
1
5.8 0.4
0.2 mL, 60 °C
0.2 mL, 80 °C
0.2 mL, 110 °C
THF
13
18
29
1
1
0
2.7 0.2
2.9 0.2
2.8 0.1
0.2 mL, 65 °C
11
2
3.5 0.3
MeCN, acetonitrile; DMF, dimethylformamide; DMSO,
dimethyl sulfoxide; MeOH, methanol; THF, tetrahydrofuran.
*Maximum set temperature of the developed microwave
reactor. Data are the mean SD (n = 3).
and K2CO3 at 180 °C for 10 min gave [18 F]MPPF in a 26% yield in a radiochemical yield of 63 4% (decay corrected from [18F]
(Table 3, entry 1), whereas microwave heating gave the product KF) with a radiochemical purity of greater than 95% following a
in 74% yield (Table 3, entry 2). Raising the temperature of the total synthesis time of 25 5 min. This result therefore provides
microwave reaction from room temperature to 180°C using 50 W a clear demonstration of the effectiveness of our newly
Table 2. Synthesis of [18F]FES using the developed microwave reactora
Condition
Entry
Precursor
Fluorination
Deprotection
Microwave
Yield [%]b
68
1
2
3
4
5
0.5 mg
0.5 mg
0.5 mg
0.25 mg
0.125 mg
100 °C, 10 min
100 °C, 2 min
100 °C, 1 min
100 °C, 1 min
100 °C, 1 min
100 °C, 10 min
100 °C, 2 min
100 °C, 1 min
100 °C, 1 min
100 °C, 1 min
À
À
+
+
+
2
No product
89
78
70
2
7
9
[18F]FES, 16a-[18F]fluoroestradiol.
a[18F]KF: 37–74 MBq; acetonitrile (MeCN): 0.1 mL; 0.6 M HCl/90% MeCN: 0.1 mL.
bDetermined from radio-TLC. Data are the mean SD (n = 3).
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H. Kimura et al.
Table 3. Synthesis of [18F]MPPF using the developed microwave reactora
Entry
Precursor
Condition
Microwave
Yield [%]b
47 10
1
2
3
4
1.500 mg
1.500 mg
0.750 mg
0.375 mg
180 °C, 10 min
180 °C, 1 min
180 °C, 1 min
180 °C, 1 min
À
+
+
+
74
56
44
2
8
3
[18F]MPPF, 4-[18F]fluoro-N-[2-(1-methoxyphenyl)-1-piperazinyl]ethyl-N-2-pyridinylbenzamide.
a[18F]KF: 37–74 MBq; dimethyl sulfoxide: 0.1 mL.
bDetermined from radio-TLC. Data are the mean SD (n = 3).
Scheme 1. Rapid synthesis of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) using the developed microwave reactor.
developed microwave reactor for the 18F-fluorination of aromatic state oscillator, which can be used to precisely control the
substrates, with a significantly improved total synthesis of frequency for the generation of the resonant conditions and
[
18F]SFB (Figure 4).
therefore powerfully irradiate a small amount of solvent
(0.05–0.5 mL) in the resonant cavity. The effectiveness of our
newly developed microwave reactor was evaluated in terms
of the effectiveness of its heating effect by performing the
radiosynthesis of three completely different PET tracers,
including (1) [18F]FES, which was used as a model compound
to investigate the simple 18F-fluorination for a sulfonate group;
(2) [18F]MPPF, which was used as a model compound for the
nucleophilic aromatic substitution of [18F]fluoride using a nitro
Conclusions
We have performed a series of basic examinations of our
newly developed microwave reactor, which has a resonance-
type irradiation mechanism that is different from those used
in commercially available microwave reactor systems. The
microwave reactor developed in this study contains a solid-
Figure 4. Analytical radio high-performance liquid chromatography chromatogram of purified N-succinimidyl 4-[18F]fluorobenzoate.
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H. Kimura et al.
Figure 5. Analytical radio-HPLC chromatogram of crude (a) ethyl[18F]fluorobenzoate (b) [18F]fluorobenzoic acid (c) N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB).
group; and (3) [18F]SFB, which was used as a model compound
for multistep synthesis. Using our newly developed microwave
and N,N,N′,N′-tetramethyl-O-(N-succinimidyl)uranium tetrafluoroborate
were purchased from Sigma Aldrich(St. Louis, MO, USA). Kryptofix2.2.2®
and anhydrous MeCN were purchased from Merck (Darmstadt,
reactor, we successfully improved each one of these reactions
Germany). The reference standard and precursors of FES, MPPF, and
in terms of their yield and the time required for their synthesis
SFB were purchased from ABX Advanced Biochemicals (Radeburg,
compared with the same reactions under conventional
Germany). Accell Plus CM, Light QMA, Light C18, and Plus PS-2 Sep-Pak
heating conditions. These results therefore demonstrate that
cartridges were purchased from Waters Corporation (Milford, MA, USA)
our newly developed microwave reactor could be useful for
and conditioned with ethanol (10 mL) and sterile water (10 mL) prior to
PET radiosynthesis.
use. The reaction vessel was purchased from Oofuna, Ltd. (Osaka, Japan).
The material of the reaction vessel was borosilicate glass (length: 4.0 cm,
diameter: 1.0 cm, maximum volume: 3.0 mL). Radio-TLC analysis was
performed on silica gel-coated aluminum plates (60 F254, Merck),
Experimental
which were developed in EtOAc–hexane (1:2 v/v) and scanned with a
sensitive quantitative γ-detecting instrument (miniGITA Star, RAYTEST,
Straubenhardt, Germany). LC-20 AD (Shimadzu Corporation, Kyoto,
Japan) was used for HPLC with an SPD-20A (Shimadzu) and NDW-351
(Hitachi Aloka Medical, Ltd., Tokyo, Japan) as an ultraviolet detector
(ρ: 220 and 254 nm) and radioisotope detector, respectively. HPLC
solvents were of HPLC grade. (Nacalai tesque Inc., Kyoto, Japan)
General considerations
All of the reagents and solvents used in the current study were
purchased from commercial suppliers and used, as received, without
further purification. DMSO, DMF, MeOH, toluene, THF, and K2CO3 were
purchased from Wako Pure Chemical Industries (Tokyo, Japan). TPAH
J. Label Compd. Radiopharm 2014, 57 680–686
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H. Kimura et al.
phase of MeCN (A) with 0.1% trifluoroacetic acid and water (B) with
0.1% trifluoroacetic acid; 0–8 min: 30%–60% A, 8–15 min: isocratic 90%
A; and retention time of 4.98min. Specific radioactivity was
>14 GBq/μmol calculated by HPLC. Total synthesis time was 25 5 min.
Data are the mean SD (n = 3).
Evaluation of the heating effect on various solvents
The reaction vessel was charged with solvent (i.e., MeCN, DMF, DMSO,
MeOH, toluene, or THF), and the solvent was then irradiated using our
newly developed microwave reactor at 50 W (maximum power).
Example of 18F-fluorination
Acknowledgements
[
18F]Fluoride was produced by a cyclotron (CYPRIS HM-18, Sumitomo
Heavy Industries, Tokyo) via an 18O (p,n) 18F reaction and passed through
a Sep-Pak Light QMA cartridge (Waters Corporation) as an aqueous
solution in 18O-enriched water. The cartridge was dried with N2, and
the 18F activity was eluted with 1.0 mL of a Kryptofix2.2.2/K2CO3 solution
[9.5 mg of Kryptofix2.2.2 and 1.7 mg of K2CO3 in MeCN/water (96/4)]. The
solvent was removed by azeotropic dehydration with MeCN (1.0 mL) at
120 °C under a stream of argon gas at 10 min.
This work was partly supported by a Grant-in-Aid for Young
Scientists (A),
a Grant-in-Aid for Challenging Exploratory
Research from the Japan Society for the Promotion of Science,
and the New Energy and Industrial Technology Development
Organization (NEDO).
Conflict of Interest
16α-[18F]Fluoroestradiol
The authors did not report any conflict of interest.
To prepare 18F-labeled [18 F]FES, a solution of 3-O-methoxymethyl-16,17-
O-sulfuryl-16-epistriol in MeCN (0.1 mL) was added to the reaction vessel
containing the 18F activity (37–74 MBq). After microwave heating
(temperature control mode) for 1 min at 100 °C and cooling for 1 min,
0.6 M hydrochloric acid/90% MeCN (0.1 mL) was added. The mixture
was heated for 1 min at 100 °C and cooled for 1 min. Total synthesis time
was 20 2 min. TLC analysis was carried out with a γ-radioactivity TLC
scanner (miniGITA Star g-radioactivity TLC scanner, RAYTEST, decay
corrected from [18F]KF). Data are the mean SD (n = 3).
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1 min at 120 °C under microwave irradiation (temperature control mode)
and cooled for 1min, and N,N,N′,N′-tetramethyl-O-(N-succinimidyl)uranium
tetrafluoroborate in anhydrous MeCN (15 mg, 0.2mL) was then
added. After heating for 1min at 90 °C under microwave irradiation
(temperature control mode), the mixture was diluted with 5% acetic acid
and applied to a Sep-Pak Accell Plus CM Cartridge (Waters Corporation). A
Sep-Pak PS-2 Plus Cartridge (Waters Corporation) was attached to the
Sep-Pak Accell Plus CM Cartridge, and the cartridges were washed with
20mL of MeCN/water (20/80). After flowing N2 gas for 10 s, the Sep-Pak
Accell Plus CM Cartridge was removed. [18F]SFB was eluted from the
Sep-Pak Plus PS-2 Cartridge with 2.0mL of MeCN. The isolated
radiochemical yield was measured with a curiemeter (IGC-7, Hitachi Aloka
Medical, Ltd., Tokyo, Japan, decay corrected from [18 F]KF), and the
radiochemical purity of the labeled compounds was determined by
analytical radio-HPLC (Figure 5). Conditions for HPLC were a Cosmosil
5C-18 AR-II, 4.6mm× 150mm column (Nacalai tesque Inc.); a mobile
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