Effective synthesis of 99mTc tricarbonyl complexes by microwave heating

Article abstract of DOI:10.1016/j.jorganchem.2011.08.033

Technetium-99m (^99mTc) is one of the most frequently used nuclides for single-photon emission computed tomography (SPECT) imaging because of its radiochemical characteristics, such as gamma emission of suitable energy (141 keV) and adequate half-life (6.01 h). Although triaquatricarbonyl ^99mTc cation ([^99mTc(CO)₃(H₂O) ₃]⁺) has several advantages as a ^99mTc-labeling agent, e.g., compact chelate size, chelate stability, and simplicity of preparation, its synthetic protocols should be improved. Because microwave heating is a convenient method for synthetic reactions, we studied the effect of microwave irradiation on the synthesis of ^99mTc tricarbonyl complexes. We found several factors beneficial for the preparation of nuclear medicines. In particular, microwave heating promoted one-pot syntheses of ^99mTc tricarbonyl chelates in a short time. In addition, the ^99mTc tricarbonyl complex could be obtained using low concentrations of ligands.

Full text of DOI:10.1016/j.jorganchem.2011.08.033

Journal of Organometallic Chemistry 696 (2011) 3745e3749
Contents lists available at SciVerse ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Effective synthesis of 99mTc tricarbonyl complexes by microwave heating
,
a
a
b
Naoya Haradaa, Hiroyuki Kimuraa , Masahiro Ono , Daisuke Mori , Yoshiro Ohmomo ,
*
Tetsuya Kajimotob, Hidekazu Kawashimac, Hideo Sajia
,
*
a Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
b Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
c Kyoto University Hospital, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan
a r t i c l e i n f o
a b s t r a c t
Technetium-99m (99mTc) is one of the most frequently used nuclides for single-photon emission
computed tomography (SPECT) imaging because of its radiochemical characteristics, such as gamma
emission of suitable energy (141 keV) and adequate half-life (6.01 h). Although triaquatricarbonyl 99mTc
cation ([99mTc(CO)3(H2O)3]þ) has several advantages as a 99mTc-labeling agent, e.g., compact chelate size,
chelate stability, and simplicity of preparation, its synthetic protocols should be improved. Because
microwave heating is a convenient method for synthetic reactions, we studied the effect of microwave
irradiation on the synthesis of 99mTc tricarbonyl complexes. We found several factors beneficial for the
preparation of nuclear medicines. In particular, microwave heating promoted one-pot syntheses of 99mTc
tricarbonyl chelates in a short time. In addition, the 99mTc tricarbonyl complex could be obtained using
low concentrations of ligands.
Article history:
Received 16 April 2011
Received in revised form
19 August 2011
Accepted 23 August 2011
Keywords:
99mTc tricarbonyl complex
Microwave heating
SPECT
Radiopharmaceutical
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
[3e6]. Therefore, we studied improvements in the synthesis of
99mTc tricarbonyl chelates.
Single-photon emission computed tomography (SPECT) is
a potential tool for applications in nuclear medicine diagnosis,
which can permit noninvasive diagnosis of diseases in early
stages.
Microwave irradiation provides instantaneous reactions with
effective heat conduction and dielectric heating. This method can
be clinically used because it is easy and safe to attain reactions at
high temperatures [7e9]. One-pot synthesis of 99mTc-labeled
compounds has been previously reported in Ref. [4]. Such meth-
odology is desirable for the synthesis of 99mTc-labeled compounds
because the deprotection step can be avoided under acidic or basic
conditions, which may be unsuitable for preparing peptidic probes
and antibodies. For these reasons, we designed a novel synthetic
protocol of 99mTc tricarbonyl chelates using microwave reactions. In
this paper, we report the development of fast and effective
syntheses of 99mTc tricarbonyl chelates by using microwave
heating.
Technetium-99m (99mTc) is a frequently used nuclide for SPECT
imaging because of its radiochemical characteristics such as gamma
emission of suitable energy (141 keV) and adequate half-life
(6.01 h). We can easily prepare 99mTc by using a 99Moe99mTc
generator, which yields Na 99mTcO4 as a 99mTc-containing molecule.
Among several species of 99mTc, [99mTc(CO)3(H2O)3]þ, which can
be prepared using a commercially available kit (IsoLinkÒ) [1], has
potential for use as a 99mTc-labeling agent because it forms compact
[2] and stable [3] chelates with tridentate ligands, such as imino-
diacetic acid (IDA), picolylamine monoacetic acid (PAMA), and N,N-
dipicolylamine (DPA). However, for effective synthesis, the reaction
of [99mTc(CO)3(H2O)3]þ with ligands generally requires heating
Nitrogen
atoms
coordinate
preferentially
to
[Re/99mTc(CO)3(H2O)3]þ compared to oxygen atoms [2]. Although
carboxyl groups are not present in DPA, they are contained in IDA
and PAMA. Therefore, we hypothesized that IDA, PAMA, and DPA
could react differently with [99mTc(CO)3(H2O)3]þ under microwave
irradiation. In addition, these ligands form 99mTc complexes with
various electric charges: IDA forms anionic complexes, PAMA forms
neutral complexes, and DPA forms cationic complexes. On the basis
of this characteristic, we can synthesize several 99mTc-labeled
probes with various electric charges. For these reasons, we evalu-
ated the effects of microwave irradiation for the synthesis of 99mTc
tricarbonyl complexes by using IDA, PAMA, and DPA.
Abbreviations: DPA, N,N-dipicolylamine; IDA, iminodiacetic acid; IDAME,
dimethylester of iminodiacetic acid; PAMA, picolylamine monoacetic acid;
PAMAEE, ethylester of picolylamine monoacetic acid; RI, radioisotope; SPECT,
single-photon emission computed tomography; UV, ultraviolet; HPLC, high-
performance liquid chromatography; TLC, thin-layer chromatography.
* Corresponding authors. Tel.: þ81 75 753 4566; fax: þ81 75 753 4568.
E-mail addresses: hkimura@pharm.kyoto-u.ac.jp (H. Kimura), hsaji@pharm.
kyoto-u.ac.jp (H. Saji).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2011.08.033

3746
N. Harada et al. / Journal of Organometallic Chemistry 696 (2011) 3745e3749
Table 2
2. Results and discussion
HPLC retention time (min) of Re and 99mTc complexes.
Bn-IDAaeMd
PAMAbeMd
DPAceMd
2.1. Analysis by radio-high performance liquid chromatography
Metal
Re
10.9
11.8
18.9
19.5
32.4
33.3
Using an IsoLink kit, [99mTc(CO)3(H2O)3]þ was obtained in
a good radiochemical yield (>95%) (data not shown).
99mTc
a
IDA ¼ Iminodiacetic acid.
b
c
Tc (Z ¼ 43) appears in the middle of the second-row transition
series in the periodic table of elements and has no stable isotopes.
The development of Tc complexes as potential radiopharmaceuti-
cals is facilitated by the use of Re, a group 7 congener of Tc in the
periodic table. For this reason, Tc complexes are generally identified
by comparison with high-performance liquid chromatography
(HPLC) retention time of corresponding Re complexes.
We detected the complexes of Re with various ligands by UV
spectra. The benzyl group of 2 was introduced as a chromophore for
UV absorption. The HPLC retention times of the Re complexes were
10.9 (3), 18.9 (4), and 32.4 min (5) (Table 1). The HPLC retention
times of the 99mTc complexes were 11.8 (6), 19.5 (7), and 33.3 min
PAMA ¼ Picolylamine monoacetic acid.
DPA ¼ N,N-Dipicolylamine.
M ¼ Metal.
d
(8) (Table 1). Because these RI peaks approximately corresponded
to the UV peaks of Re complexes, they can be attributed to the peaks
of the 99mTc complexes.
2.2. Determination of reaction temperature
In reactions of 300 mM of Bn-IDAME (dimethylester of imino-
diacetic acid) with [99mTc(CO)3(H2O)3]þ at 75 ꢀC, we could obtain 6
in significantly higher radiochemical yields by using microwave
heating than by the conventional method, despite the same reac-
tion temperature (Table 2; Entries 1 and 2). On the basis of these
results, it suggested that microwave heating is superior for heat
conduction than oil-bath heating.
Table 1
Structures of 99mTc/Re complexes.
No.
Abbreviation
Structure
In reactions at higher temperatures, radiochemical yields
increased (Table 2; Entries 2, 3, and 4). This result suggests that
3
Bn-IDAeRe
[
99mTc(CO)3(H2O)3]þ should be treated with ligands at 110 ꢀC by
microwave heating to effectively obtain 99mTc tricarbonyl
complexes.
2.3. Microwave-promoted one-pot synthesis
4
PAMAeRe
The effects of microwave heating were observed more clearly in
the reactions of [99mTc(CO)3(H2O)3]þ with Bn-IDAME or PAMAEE
(ethylester of picolylamine monoacetic acid) compared to those
with N,N-dipicolylamine (DPA). The yields of 6 increased more than
50-fold by using microwave heating (Table 3; Entries 1 and 2), and
the yields of 7 increased by the same method (Table 3; Entries 3 and
4). Although the yields of 8 increased using microwave heating, the
ratio (microwave/oil bath) was only 1.7 (Table 4; Entries 5 and 6).
These results suggest that microwave heating promoted the
hydrolysis step, which makes this method particularly effective for
one-pot syntheses of 99mTc tricarbonyl complexes.
5
DPAeRe
2.4. Microwave-accelerated synthesis of Bn-IDAMEe99mTc
By the conventional method, the radiochemical yield of the
reaction of [99mTc(CO)3(H2O)3]þ with Bn-IDAME was only 6.4% at
1 min (Table 4).15e30 min was required to produce 6 in good yields
6
Bn-IDAe99mTc
(Table 4). Meanwhile, the radiochemical yield of
6 reached
a plateau in just 1 min by microwave heating. These results show
that microwave heating enabled rapid production of 99mTc tri-
carbonyl complexes. Rapid synthesis is essential in nuclear medi-
cine because it can suppress the decrease of radioactivity and
7
8
PAMAe99mTc
Table 3
Effect of temperature on the synthesis of Bn-IDAe99mTc.
Entry
Ligand
[Ligand]
M)
Method
Temp.
(ꢀC)
Time
(min)
Yield
(%)
(
m
DPAe99mTc
1
2
3
4
Bn-IDAME
Bn-IDAME
Bn-IDAME
Bn-IDAME
300
300
300
300
Oil bath
75
75
90
30
30
30
30
29.7
51.5
86.9
98.5
Microwavea
Microwavea
Microwavea
110
a
Heated with microwave radiation (300 W, 17 bar maximum pressure).

N. Harada et al. / Journal of Organometallic Chemistry 696 (2011) 3745e3749
3747
Table 4
Ratios of radiochemical yields of 99mTc complexes by microwave heating to that by oil-bath heating.
Entry
Ligand
Product
[Ligand]
M)
Method
Temp.
(ꢀC)
Time
(min]
Yield
(%)
Yield ratio
(Microwave/oil bath)
(
m
1
2
3
4
5
6
Bn-IDAME
Bn-IDAME
PAMAEE
PAMAEE
DPA
3
3
4
4
5
5
300
300
30
30
30
Microwavea
Oil bath
110
75
110
75
110
75
30
30
5
5
5
78.6
1.5
93.4
8.0
84.9
49.0
52.4
Microwavea
Oil bath
11.7
1.7
Microwavea
Oil bath
DPA
30
5
a
Heated by microwave radiation (300 W, maximum pressure was 17 bar).
avoiding long-time heating of precursors, particularly those of
peptides and antibodies.
column 40 mm 60 Å (Yamazen) was used as the column. LC-20AD
(Shimadzu, Japan) was used for HPLC. SPD-20A (Shimadzu) and
NDW-351D (Aloka, Japan) were employed as ultraviolet (UV;
l
¼ 254 nm) and radioisotope (RI) detectors, respectively. Cosmosil
2.5. Decrease in concentrations of ligands by microwave heating
5C18-AR-II 10 mm ꢁ 250 mm (Nacalai Tesque, Japan) was used as
the HPLC column. Methanol (0.1% trifluoroacetic acid) and nano-
pure water (0.1% trifluoroacetic acid) were used as the mobile
phase (flow rate ¼ 2 mL/min). Nanopure water was prepared by MQ
Integra15 (Nihon Millipore, Japan). 1H and 13C NMR spectra were
recorded on LNM-AL500 (JEOL, Japan) with CDCl3, DMSO-d6, or
CD3OD as a solvent and with tetramethylsilane as an internal
standard (Euriso-Top, France). Mass spectra were recorded on
LCMS-2010 EV (Shimadzu) or JMS-SX 102A QQ (JEOL). Discover
(CEM Japan, Japan) was used as the microwave reactor. The
maximum energy of microwave irradiation was set at 300 W, and
the maximum pressure was set at 17 bar. All chemicals used were of
reagent grade.
Although 6 could be obtained in more than 90% radiochemical
yield by the conventional method, a high concentration of Bn-
IDAME (30 mM) must be employed (Table 5). Moreover, the
radiochemical yield of 6 was high (>90%) only when the concen-
tration of Bn-IDAME was higher than 30 mM.
In contrast, by microwave heating, the radiochemical yield of 6
was high (>90%), although the concentration of Bn-IDAME was
30 mM. Moreover, we could obtain 6 by microwave heating with
only 30 nM of Bn-IDAME (Table 6).
These results imply that concentrations of precursors can be
decreased using microwave heating. Therefore, this method is
considered to be beneficial for the preparation of probes. It is
usually impossible to separate labeling precursors and 99mTc-
labeled compounds. Free precursors may not only inhibit the
binding of 99mTc-labeled compounds to target molecules but also
cause adverse effects [11]. Such issues can be avoided by microwave
heating.
4.2. Selection of tridentate ligands
We selected three tridentate ligands that have amino groups,
carboxyl groups, or pyridyl groups as the coordinating groups. To
avoid hindrance in the synthesis of precursors, we protected free
carboxyl groups as esters in this study.
3. Conclusion
4.3. Chemistry
We were able to more effectively synthesize 99mTc tricarbonyl
complexes by microwave heating than by the conventional
method. We rapidly obtained 99mTc tricarbonyl complexes by
microwave heating using lower concentrations of ligands than that
required by the conventional method. In addition, we demon-
strated that microwave heating can be employed for 99mTc tri-
carbonyl complex synthesis. Hence, microwave heating can be
efficiently used in nuclear medicine.
4.3.1. Triaquatricarbonylrhenium bromide (1)
1 was prepared as previously reported in Ref. [10]. Briefly, 5 g of
Re(CO)5Br (Strem Chemicals, USA) was suspended in excess water
and refluxed for 1 day. The reaction mixture was lyophilized to
yield 1 as a chamois solid (4.4 g; 89% yield).
4.3.2. Dimethyl 2,20-(benzylanedily)diacetate (Bn-IDAME) (2)
To a solution of dimethyl iminodiacetate (2.4 g; Fluka, USA) in
5 mL of anhydrous dimethylformamide, benzyl bromide (2.1 g;
Aldrich, USA) and K2CO3 (2.1 g; Nacalai Tesque) were added. The
mixture was stirred at 60 ꢀC for 14 h and extracted with diethyl
ether. The organic phase was washed with brine and dried with
Na2SO4 (Nacalai Tesque). Purification by silica gel chromatography
(hexane/AcOEt ¼ 2/1) yielded 2 as a pale yellow oil (2.8 g; 87%
yield). TLC Rf ¼ 0.42 (hexane/AcOEt ¼ 2/1). 1H NMR (500 MHz,
4. Material and methods
4.1. General procedure
Kieselgel 60 F-254 plates (Merck, Germany) were used for thin-
layer chromatography (TLC). W-Prep 2XY (Yamazen, Japan) was
used for silica gel column chromatography. Hi FlashÔ silica gel
Table 5
Difference in reaction kinetics between microwave heating and oil bath for synthesis
Table 6
of 6.
Effect of microwave heating on concentration of ligands for synthesis of 6.
Method
Time (min)
Method
[Ligand] (M)
1
5
10
15
30
60
3 ꢁ 10ꢂ2 3 ꢁ 10ꢂ3 3 ꢁ 10ꢂ4 3 ꢁ 10ꢂ5 3 ꢁ 10ꢂ6 3 ꢁ 10ꢂ7
Microwavea
Oil bathb
93.1
6.4
90.7
51.7
90.7
71.5
91.2
83.6
93.6
88.9
92.0
89.5
Yield (%)
Microwavea 96.6
98.5
87.3
97.9
33.8
78.6
1.5
47.2
0.0
30.9
0.0
Yield (%)
Oil bathb
91.9
a
a
Heated by microwave radiation (300 W, 17 bar maximum pressure) at 110 ꢀC,
[Bn-IDAME] was 30 mM.
Heated by microwave radiation (300W, 17 bar maximum pressure) at 110 ꢀC for
30 min.
b
b
Heated by oil bath at 75 ꢀC, [Bn-IDAME] was 30 mM.
Heated by oil bath at 75 ꢀC for 30 min.

3748
N. Harada et al. / Journal of Organometallic Chemistry 696 (2011) 3745e3749
[Re(CO)3(H2O)3]Br
Re(CO)5Br
in H2O
reflux
1
O
O
CO
CO
HN
CO2Me
CO2Me
K2CO3
in DMF
1
N
CO2Me
N
Br
Re
in H2O/MeOH
(3/2)
O
CO2Me
CO
at 60 o
C
2
O
110 o
C
O
3
O
HN
CO2Et
N
1
HN
CO
CO
Re
in H2O
110 o
C
N
CO
4
N
Re
1
N
H
HN
CO
CO
N
N
in MeOH
100 o
N
CO
C
5
Scheme 1. Synthesis of rhenium tricarbonyl complexes.
CD3OD)
d
¼ 7.35 (d, J ¼ 7.4 Hz, 2H), 7.30 (dd, J ¼ 7.4, 6.9 Hz, 2H), 7.25
J ¼ 7.7 Hz, 2H), 7.42 (t, J ¼ 6.6 Hz, 2H), 4.79 (dd, J ¼ 17.5, 6.0 Hz, 2H),
(d, J ¼ 6.9 Hz, 1H), 3.87 (s, 2H), 3.70 (s, 6H), 3.51 (s, 4H). 13C NMR
4.74 (d, J ¼ 17.2 Hz, 2H). 13C NMR (125 MHz, CDCl3)
d
¼ 61.7, 123.3,
(125 MHz, CDCl3)
d
¼ 51.4, 54.0, 58.0,127.4,128.4,129.0,138.2,171.5.
125.4, 140.2, 151.7, 161.0, 196.0, 196.1. FABeHRMS; found: 470.0515
FABeHRMS; 252.1230 [M þ H]þ for C13H18NO4 calcd 252.1236.
[M]þ for C15H13N3O3Re calcd 470.0498.
4.3.3. Bn-IDAeRe (3) [Re(CO)3{NH(CH2COO)2}]H
4.3.6. Bn-IDAe99mTc (6)
To a solution of 2 (0.70 g) in 1,4-dioxane/water (6 mL/4 mL),
NaOH (0.29 g) was added. The mixture was stirred at 60 ꢀC for
0.4 h. To the mixture was added 6 N HCl to adjust the pH to 7. The
solvent was removed under reduced pressure. The crude sample
was added in a microwave vial and dissolved in 10 mL of water. To
the vial was added 1 (0.40 g). The reaction vial was crimp sealed
prior to microwave heating at 110 ꢀC for 5 min. The reaction
mixture was chilled, and then the precipitate was filtered and
washed with ice-cold water to yield 3 (0.11 mg; 22%). 1H NMR
In the present study, we used [99mTc(CO)3(H2O)3]þ prepared as
previously reported in Ref. [1]. Briefly, Na 99mTcO4 (Technescinti-
10MÒ, Nihon Medi-Physics, Japan) was added into an IsoLinkÒ kit
(Mallinckrodt, Netherlands), and the kit was heated at 100 ꢀC for
20 min (247 MBq/mL). First, 240
m
L of water and 80
99mTc(CO)3(H2O)3]þ were added to 240
L of a methanol solution
M, 7.0 M, or 0.70 M). Next,
mL of
[
m
of 2 (70 mM, 7.0 mM, 0.70 mM, 70
m
m
m
6 M hydrochloric acid was added to the mixture to adjust the pH to
8. The mixture was heated on a microwave reactor or in an oil bath.
HPLC tR; 11.8 min (methanol/water ¼ 80/20).
(500 MHz, DMSO-d6)
d
¼ 7.64 (m, 2H), 7.40 (m, 3H), 4.33 (s, 2H),
3.88 (d, J ¼ 14.89 Hz, 2H), 2.74 (d, J ¼ 14.89 Hz, 2H). ESI-MS; 492
[M]ꢂ for C14H11NO7Re.
4.3.7. PAMAe99mTc (7)
First, 240
added to 240
70 M). Next, 6 M hydrochloric acid was added to the mixture to
mL of water and 80
m
L of [99mTc(CO)3(H2O)3]þ were
4.3.4. PAMAeRe (4)
m
L of methanol solution of PAMAEE (0.70 mM or
1 (0.20 g) and 0.10 g of PAMAEE (Tokyo Chemical Industry,
Japan) were added to a microwave vial and dissolved in water/
methanol (3 mL/0.5 mL). The reaction vial was crimp sealed prior to
microwave heating at 110 ꢀC for 5 min. The reaction mixture was
chilled, and the precipitate was collected by filtration and washed
with dichloromethane to yield 4 (white powder; 0.13 g; 56% yield).
m
adjust the pH to 8. The mixture was heated in a microwave reactor
or in an oil bath. HPLC tR; 19.5 min (methanol/water ¼ from 40/60
to 60/40 over 30 min).
4.3.8. DPAe99mTc (8)
1H NMR (500 MHz, DMSO-d6)
d
¼ 8.81 (d, J ¼ 5.5 Hz, 1H), 8.12 (dt,
First, 40
mL of water and 160
m
L of [99mTc(CO)3(H2O)3]þ were
M or 3.75 M).
J ¼ 7.8, 1.1 Hz,1H), 7.75 (d, J ¼ 7.8 Hz,1H), 7.57 (t, J ¼ 6.6 Hz,1H), 7.22
(t, J ¼ 6.2 Hz, 1H), 4.58 (d, J ¼ 16.7 Hz, 1H), 4.50 (dd, J ¼ 5.1, 16.6 Hz,
1H), 3.65 (dd, J ¼ 8.1, 17.3 Hz, 1H), 3.25 (d, J ¼ 17.3 Hz, 1H). 13C NMR
added to 800
m
L of a methanol solution of DPA (37.5
m
m
Next, 6 M hydrochloric acid was added to the mixture to adjust the
pH to 8. The mixture was heated on a microwave reactor or in an oil
bath. HPLC tR; 33.3 min (methanol/water ¼ from 30/70 to 40/60
over 20 min and then from 40/60 to 80/20 over 20 min) (Scheme 1).
(125 MHz, DMSO-d6)
d
¼ 53.9, 62.0, 123.7, 125.4, 140.2, 152.0, 160.0,
179.5, 197.4, 197.5, 197.8. FABeHRMS; 437.0148 [M þ H]þ for
C11H10N2O5Re calcd 437.0131.
4.3.5. DPAeRe (5) [Re(CO)3{NH(CH2C5H4N)2}]Br
4.4. Analysis by radio-HPLC
1 (75 mg) and 0.37 g of DPA (Tokyo Chemical Industry) were
added to a microwave vial and dissolved with 1 mL of methanol.
The reaction vial was crimp sealed prior to microwave heating at
100 ꢀC for 5 min. 5 was recrystallized from ethyl acetate/hexane
(yellow solid; 69 mg; 77% yield). 1H NMR (500 MHz, DMSO-d6)
Radiochemical yields were calculated from the RI peak area of
the HPLC chart. After reactions, the reaction samples were purified
by HPLC. Then, radioactivity was dynamically plotted to obtain the
RI chart. We calculated (radioactivity of objective compound)/(total
radioactivity) as yield of 99mTc complexes.
d
¼ 8.86 (d, J ¼ 5.4 Hz, 2H), 8.00 (dt, J ¼ 7.7, 1.4 Hz, 2H), 7.62 (d,

N. Harada et al. / Journal of Organometallic Chemistry 696 (2011) 3745e3749
3749
4.5. Determination of reaction temperature
Acknowledgments
In the conventional method, reactions were conducted at 75 ꢀC
by heating in an oil bath [7]. Because this reaction temperature did
We thank FUJIFILM RI Pharma Co., Ltd., Tokyo, Japan, for
providing the IsoLinkÔ kit. This work was supported in part by
a Grant-in-Aid for General Scientific Research from the Japan
Society for the Promotion of Science.
not seem to be optimum, we investigated it further. First, 240
mL of
water and 80
m
L of [99mTc(CO)3(H2O)3]þ were added to 240
mL of
a methanol solution of 2 (0.70 mM), and then the mixture was
heated at 75 ꢀC in an oil bath or in a microwave reactor. We also
conducted reactions at 90 ꢀC and 110 ꢀC by using microwave
heating. Radiochemical yields were calculated at fixed time points
of 10, 15, and 30 min.
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4.6. Evaluation of effects of microwave heating on 99mTc reactions
We investigated whether 99mTc complexes can be rapidly
synthesized using microwave heating or the conventional method.
Several concentrations of 2, PAMAEE, and DPA were reacted with
[
99mTc(CO)3(H2O)3]þ for 1e60 min.
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4.7. Statistical test
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StatView 5.0 (SAS, USA) was used for statistical analysis. A
Bonferroni/Dunn test was used to assess the differences in the
radiochemical yield between oil-bath heating and microwave
heating. p < 0.05 was considered significant.
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