Synthesis of S-thiomethyl MAG3, radiolabelling with technetium-99m and biological evaluation

Article abstract of DOI:10.1002/jlcr.2954

Protection of the thiolate function of the mercaptoacetyltriglycine (MAG₃) by S-thiomethyl group allows automatic deprotection of the protecting group during technetium-99m radiolabelling by transchelation using stannous chloride dihydrate as r

Full text of DOI:10.1002/jlcr.2954

Research Article
Received 28 February 2012,
Revised 9 July 2012,
Accepted 10 July 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.2954
Synthesis of S-thiomethyl MAG , radiolabelling
3
with technetium-99m and biological evaluation
a
b
a
Kasturi Sanyal, Sankha Chattopadhyay, and Mita Chatterjee Debnath *
3
Protection of the thiolate function of the mercaptoacetyltriglycine (MAG ) by S-thiomethyl group allows automatic deprotection
of the protecting group during technetium-99m radiolabelling by transchelation using stannous chloride dihydrate as
reductant. Protection of the thiolate group with S-thiomethyl increases the stability of the ligand, desired complex of high
radiochemical purity could be prepared under relatively mild labelling condition (at room temperature) omitting the aeration
step. The complex prepared from the S-thiomethyl protected MAG ligand were chromatographically (HPLC) and biologically
3
3
compared with the corresponding complex prepared from the S-benzoylated MAG precursor. This result suggests that
technetium-99m complex of MAG could be prepared from S-thiomethylated MAG precursor in comparatively higher purity
3
3
under relatively milder labelling condition and this method of radiolabelling could be used for the development of less
cumbrous single vial MAG kit.
3
Keywords: protecting group; S-thiomethyl MAG3; biodistribution; chelation
Introduction
be eliminated during complex preparation. All these workers were
99m
observed apart from the desired
3
Tc-MAG ; there were four other
The introduction of the technetium-99m complex of mercaptoace-
non-MAG components in varying proportion depending on the
3
9
9m
3
tyltriglycine ( Tc-MAG ) into clinical practices as a potential
method of complexation and purity of the ligand. These radioactive
1
31
131
replacement of I-orthoiodohipuran ( I-OIH) had opened up a
new era in the field of renal radiopharmaceuticals. This most
clinically successful renal tubular agent was first reported by
by products exhibited hepatobiliary accumulation interfered with
99m
the desired renal imaging pattern of
3
Tc-MAG . One of the minor
components obtained by using HPLC analysis was postulated to be
Fritzberg et al. in 1986, where the thiol functionality of the MAG
ligand was protected by benzoylation. This benzoyl functional
3
99m
99m
3
Tc(IV)-MAG , which on aerial oxidation furnished
3
Tc-MAG .
1
However, this by product could not be removed by HPLC purifica-
tion. Although thorough investigations were conducted by many
workers, no one could ascertain anything about the exact nature
of different intermediates and by products formed during the
group was removed during technetium-99m chelation of the
ligand under alkaline condition in presence of dithionite as reduc-
tant. But in spite of using protective group, the yield was found to
be >80% by reverse phase HPLC where apart from the desired
peak, another chelate with slightly shorter retention time was
observed which when isolated and heated was converted to the
99m
6,7
preparation of
Tc-MAG
3
.
Probably, the use of an S-protected
ligand during the preparation of the radiopharmaceutical may
complicate the complexation process that requires a boiling step
for the removal of the protective functionality and the resulting
complex may not attain desired kind of purity, and it is assumed
that all these discrepancies could be eliminated by using a suitable
protecting group.
1
main product. Fritzberg reported that the higher radiochemical
yield could be achieved by developing kit where radiolabelling of
99m
benzoyl MAG (Bz-MAG ) with
Tc was achieved by transchela-
3
3
tion approach using sodium gluconate as labile ligand and
stannous chloride as reductant. In both the cases to achieve
desired radiochemical purity heating at elevated temperature
Several attempts were undertaken to develop this radiopharma-
8
ceutical in well standardised kit form. Commercial kits of
ꢀ
(
95 C) was required. Immediately after this reporting, Muller-Suur
99m
Tc-MAG3 were developed in USA and Europe. Extensive
2
et al. conducted a detailed physicochemical and biological studies
131
comparative studies of the kits with I-OIH were carried out in
experimental animals, human volunteers and patients with
renal diseases in different nuclear medicine centres. It was
with HPLC purified and HPLC unpurified MAG complexes and
1,3
9
3
also MAG complex prepared from commercial kits developed
10
3
for routine clinical studies, where it was observed that all the
aforementioned preparations exhibited some extra renal clearance
approximated to be 10% of the total renal excretion in rat model
depending on the purity of the complexes.
accepted as the agent of choice for routine renal imaging and
a
Nuclear Medicine Division, Indian Institute of Chemical Biology (CSIR), 4, Raja
3
To understand the nature of the impurities, Brandau et al. first
S.C. Mullick Road, Jadavpur, Kolkata, 700032, India
initiated a thorough HPLC studies and biological investigations on
99m
b
Radiopharmaceuticals Lab, Variable Energy Cyclotron Centre, Kolkata, 700064, India
3
Tc-MAG and its impurities produced under different methods
of complexation reaction. The aforementioned studies on this
radiopharmaceutical were repeated by different workers too,
with the objective to determine whether those impurities could Kolkata-700032, India. E-mail: mitacd@iicb.res.in
a
*
Correspondence to: Debnath Mita Chatterjee, Nuclear Medicine Division,
4,5
Indian Institute of Chemical Biology (CSIR), 4, Raja S.C. Mullick Road, Jadavpur,
J. Label Compd. Radiopharm 2012
Copyright © 2012 John Wiley & Sons, Ltd.

K. Sanyal et al.
1
1,12
function studies.
Because of the poor chemical stability of Materials and methods
the thiol group, mercaptoacetyltriglycine was synthesised as the
S-benzoyl protected precursor and in this form, the ligand was
present in the various commercial labelling kits. Moreover, when
9
9
-
Molybdate ion ( MoO ) was purchased from the Bhabha Atomic
4
9
9m
-
Research Centre (Mumbai), and
TcO was obtained by using
4
99
-
1
31
99m
2-butanone extraction of a 5 (N) NaOH solution of MoO .
compared with I-OIH, the renal clearance of
Tc-MAG was
4
3
1
31
S-benzoyl mercaptoacetyltriglycine (1) was prepared as per the
5
0–60% of that of I-OIH and often exhibited sporadic uptake
in liver and gall bladder.
1
13,14
reported method. Methylsulphenyl chloride was prepared by
2
0
following the procedure described by us. HPLC analysis were per-
Researchers from all over the world performed extensive
research to minimise this unwanted physicochemical behaviour
of this radiopharmaceutical. The replacement of the benzoyl
group by other protective functionality is an important approach
towards the improvement of the physicochemical properties of
formed on a reverse phase C-18 column (4.6ꢁ 250 mm, particle size
5
mm) fitted to a Waters Associates HPLC system (Waters Corpora-
tion, MA, USA). Radioactivity in the eluate was monitored using
Beckman model 170 detector and integration was carried out using
1
99m
a Waters M-746 data Module. All H NMR spectra were recorded on
a 400-MHz Bruker VM-400 spectrometer (Bruker Biospin, MA, USA).
Tc-MAG3 kit. Attempts were also undertaken in modifying
the chemical structure of the ligand.
15–18
The benzoyl group as an
S-protected precursor is used to prolong the shelf life of MAG3
ligand during storage and also used as S-protective functionality Synthesis of S-thiomethylmercaptoacetyltriglycine (2)
in commercially available kits for routine clinical application.
99m
The synthesis comprises following three steps (Scheme 1)
The heating step included in the preparation of
3
Tc-MAG by
(a) Synthesis of S-thiomethylthioglycolic acid
transchelation can be considered as the most inconvenient step
in routine clinical practice. To avoid the inconvenience, attempts
were undertaken to replace the benzoyl with other different
protective functionalities, for example, benzyl, benzamidomethyl,
To the dry thioglycolic acid (5.69 g, 0.06mol) taken in dry
THF (30 ml), sodium bicarbonate (11 g, 0.1mol) was added. To
the aforementioned stirring mixture, 7.2 ml of freshly prepared
19
acetamidomethyl, acetyl, p-methoxy benzyl and others. The
labelling efficiency obtained by the direct labelling method
ꢀ
methylsulphenyl chloride was added drop by drop at 0 C under
nitrogen atmosphere. Stirring at room temperature was continued
until the reaction mixture became negative to nitroprusside. It was
then filtered, and the filtrate was neutralised with few drops of
pyridine and concentrated in vacuum, the oil obtained was
extracted with ethyl acetate (20 mlꢁ 3). Ethyl acetate layer on
evaporation furnished white solid. It was dissolved in ethyl acetate,
concentrated, dropwise addition of diethylether resulted crystalline
3
of the aforementioned different MAG precursors varied from
3
2–94%. In all the mentioned cases, radiolabelling efficiency was
sufficiently increased by exchange labelling and on heating the
complexes at elevated temperature. None of the aforementioned
protective groups appeared to be superior than benzoyl.
In the course of our study, S-thiomethyl (–S-CH ) has been devel-
3
oped as a sulfhydryl protecting group and was well studied on dif-
ꢀ
material (1.21 g, 14.18%), mp 96 C. Thin layer chromatography
ferent technetium binding –SH containing ligands, for example,
(
TLC) single spot, R
f
0.85 (chloroform: methanol: acetic acid; 7:3:1).
0
20–22
cysteine, L,L -EC, Dimercaptosuccinic acid and others.
In this
by
1
3
H NMR (CDCl ) d (ppm): 2.49 (s, 3H, -SCH ), 3.52 (s, 2H, -S-CH ).
3
2
study, we report the protection of the thiol function of MAG
3
S-thiomethylation that could be deprotected automatically during
(
b) Synthesis of succinimidyl-S-thiomethylthioglycolate
technetium-99m labelling at relatively mild reaction condition. The
99m
Tc-complexes prepared from protected and unprotected
precursors have been compared with HPLC and biological studies. 0.008 mol) in dry THF (5ml), N-hydroxysuccinimide (0.92 g,
To the solution of S-thiomethylthioglycolic acid (1.21g,
The results are discussed in the following section.
0.008 mol) in absolute THF (15 ml) was added followed by the drop
Scheme 1. Synthesis of the ligand S-thiomethylmercaptoacetyltriglycine.
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Council of scientific and industrial research
0
wise addition of N,N -dicyclohexylcarbodiimide (1.70 g,0.008 mol) (5 ml; pH 8.0) of triglycine (0.397 g, 0.002 mol) was added. The
ꢀ
dissolved in absolute THF (5ml) , at ꢂ5 C with constant stirring. two mixtures were mixed and stirred for 3 h. After removal of
The reaction mixture was stirred at room temperature for 18 h. the solvent, the crude material obtained was dissolved in water
Acetic acid (0.2 ml) was added and stirring was continued for one (0.2 mL) and few drops of 1(N) HCl was added to bring the pH
more hour. It was filtered, and filtrate was concentrated and between 2 and 3. A white solid which precipitated out on cooling
extracted with petroleum ether. Evaporation of the solvent created was separated by filtration. Further purification was carried out
colourless residue, which was finally recrystallised from isopropanol by dissolving the precipitate in aqueous ammonia (0.1mL) and
ꢀ
to produce pure solid product ( 1.13 g, 55%) mp 76 C. TLC single reprecipitation was carried out by adding 1(N) HCl (few drops).
1
spot, R 0.79 (chloroform: methanol: acetic acid; 7:3:1). H NMR Finally, it was recrystallised from isopropanol to produce white
f
ꢀ
(
3
CDCl ) d (ppm): 2.53(s, 3H, -SCH ), 2.86 (s, 4H, -CO-CH -CH -CO-), solid (0.30 g, 46%) mp 210 C. TLC single spot, R 0.12 (chloroform:
.71 (s, 2H, -S-CH -COO-).
3
3
2
2
f
1
methanol: acetic acid 7:3:1). H NMR at DMSO-d /D O shake),
2
6 2
2
.50 (s, -SCH ), 3.52 (s, 2H, -S-CH -CO-), 3.72 (s, 2H, -N-CH -CO),
3
2
2
(c) Synthesis of S-thiomethylmercaptoacetyltriglycine (2)
3.78 (s, 2H, -N-CH -COO-).
2
To the solution of succinimidyl-S-thiomethylthioglycolic
acid (0.500 g, 0.002 mol) in ethanol (20 ml), aqueous solution
Preparation of complexes
99m
99m
Preparation of
3
Tc-MAG3 (from S-benzoyl MAG ) ( Tc-1)
The complex was prepared by glucoheptanoate transchelation
1
process as per the reported method .
99m
99m
Preparation of
3
Tc-MAG (from S-thiomethyl MAG
3
) ( Tc-2)
To the aqueous solution of MAG
3
(1.5 m, 0.2 mL) adjusted to
pH 8.5 by N or N/10 NaOH, freshly prepared glucoheptanoate
solution ( 25 mg, in 0.6mL water) was added, followed by the
99m
-
addition of aqueous
4
TcO ( 0.1mL, 74–185 MBq) and freshly
prepared stannous chloride dihydrate solution (50mL, 25 mg) under
nitrogen atmosphere. The mixture was incubated for 30 min at
room temperature.
Chromatography
Instant thin layer chromatography was performed on precoated
silica-gel (SG) strips 1 ꢁ 12 cm (Merck) in acetone and saline to
9
9m
99m
determine the purity of the
Tc-MAG3 complexes ( Tc-1,
99m
Tc-2).
Technetium-99m complex of mercaptoacetyltriglycine complexes
99m
99m
(
Tc-1 and
reverse phase column. The column was eluted at a flow rate of
ml/min with an isocratic mixture of 0.01 M phosphate buffer
Tc-2) were subjected to HPLC analysis on C-18
1
(
1
pH 6.5):ethanol (95:5) as per the reported method.
Paper electrophoresis
9
9m
Paper electrophoresis of
Tc-chelates of 1 and 2, along
99m
-
with
TcO
4
was run on a Whatman No. 1 paper (26ꢁ 60 cm) in
9
9m
Figure 1. HPLC analysis of
Tc-MAG
3
chelate prepared from (a) S-benzoyl MAG
3
bicarbonate buffer (0.01 M, pH 7.0) across which a potential
difference of 3 kV was applied at a current strength of 10 mA for 1 h.
ligand and (b) S-thiomethyl MAG
3
ligand.
9
9m
99m
99m
Table 1. Biodistribution results of
Tc-MAG
3
complex prepared from S-thiomethyl MAG
3
(
Tc-2) and S-benzoyl MAG
3
(
Tc-1)
1
31
coinjected with I-orthoiodohippuran (results in parenthesis) at 30-min post injection expressed as percent dose/organ in mice
99m
99m
Tc-MAG
3
(ligand S-thiomethyl MAG
3
)
3 3
Tc-MAG (ligand S-benzoyl MAG )
Blood
Liver
Intestine
Kidney
Urine
1.86 ꢃ 0.80 (1.79 ꢃ 0.50 )
2.00 ꢃ 0.33 (1.67 ꢃ 0.13 )
2.26 ꢃ 0.45 (1.98 ꢃ 0.13)
2.30 ꢃ 0.35 (1.64 ꢃ 0.16 )
68.55 ꢃ 3.08 (77.56 ꢃ 1.18)
2.45 ꢃ 0.31 (1.69 ꢃ 0.72)
3.83 ꢃ 0.58 (1.23 ꢃ 1.09)
4.70 ꢃ 0.49 (1.45 ꢃ 0.99)
4.25 ꢃ 0.96 (1.99 ꢃ 0.39)
66.53 ꢃ 2.15 (76.89 ꢃ 0.52)
Results are expressed as mean ꢃ SD of six animals.
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K. Sanyal et al.
Biodistribution studies
Experiments using well hydrated Swiss Albino mice (20–25 g)
were carried out in compliance with the relevant national laws
99m
relating to the conduct of animal experimentation. Tc-MAG3
complexes prepared from the ligands 1 and 2 (8–12 MBq/Kg)
1
31
premixed with
I-OIH (2–4 MBq/Kg) were injected via tail
vein in mice. The animals were sacrificed either at 30 min or
at 10 min post-injection, the desired organs were collected,
rinsed with saline, blotted dry and weighed. Counting were
carried out in ECIL, NaI (Tl ) well counter (model LV4755) and
the results were expressed as the percentage of injected dose
per organ.
Inhibition studies
To hydrated mice an aqueous solution of probenecid (50 mg/Kg),
pH 7.4 was introduced via tail vein 10 min prior to the
radiopharmaceutical injection. The animals were sacrificed at
1
0 min post-injection, and biodistribution studies were carried
out following exactly the previously described procedure.
Results
Methane sulphur trichloride was produced on chlorination of
ꢀ
dimethyl disulfide under careful reaction condition at ꢂ15 C.
This reacted with dimethyl disulphide to give methyl sulphenyl
chloride used for S-thiomethylation without further purification
The preparation of S-thiomethyl MAG
reaction processes. Attempted preparation of S-thiomethyl
MAG from commercially available thioglycolic acid and freshly
3
involved three-step
3
prepared methyl sulphenyl chloride resulted in very poor yield
of the desired product. This was improved by the purification of
the commercial thioglycolic acid through Dean–Stark distillation
process. After purification, thioglycolic acid was treated with
ꢀ
methyl sulphenyl chloride at 0 C under nitrogen atmosphere to
give S-thiomethylthioglycolic acid. The product was crystallised
1
from diethylether and ethyl acetate and characterised by
H
NMR spectroscopy. S-thiomethylthioglycolic acid thus obtained
was reacted with N-hydroxysuccinimide in the presence of
dicyclohexylcarbodiimide at room temperature. The prepared
succinimidyl-S-thiomethylthioglycolate was recrystallised from
1
isopropanol and characterised by H NMR spectroscopy.
Succinimidyl-S-thiomethylthioglycolate was then reacted with
triglycine at room temperature to produce S-thiomethyl MAG3,
which was purified by recrystallisation from isopropanol and
1
analysed by H NMR spectroscopy.
Technetium-99m complex labelling of the S-thiomethyl MAG3
(
2) was carried out using stannous chloride reduction method in
presence of a labile ligand sodium glucoheptonate. Unlike the
99m
Tc labelling of the S-benzoyl MAG , the complexation was
3
allowed to proceed at room temperature. The analysis was carried
99m
-
out with TLC, HPLC and electrophoresis. In acetone,
TcO
4
moved to solvent front, whereas reduced hydrolysed technetium
(
3
Sn-Tc) and both MAG chelates were stayed at the origin. In saline
9
9m
MAG
3
chelates and
4
TcO - moved to the solvent front leaving
(Sn-Tc) at the origin. In all the cases, impurities accounted to be less
than 2% of the total activity in the instant thin layer chromatogra-
99m
phy plates. In electrophoretic field,
3
Tc-MAG chelates prepared
from the ligand 1 and the thiomethylated precursor 2 exhibited
sharp and rapid movement of 12cm (Fig. 2).
Technetium-99m complex of mercaptoacetyltriglycine chelate
3
prepared from S-benzoyl MAG ligand when subjected to HPLC
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Council of scientific and industrial research
analysis exhibited a major component (87.6% pure) at a retention
In this work, thiolate functionality of mercaptoacetyltri-
99m
time of 6.18 min, whereas under the similar condition,
complex prepared from S-thiomethyl MAG
Tc-MAG3 glycine was masked with thiomethyl group. Succinimidyl-S-
3
as starting ligand thiomethylthioglycolic was coupled with triglycine under mild
exhibited a major component of much higher purity (≥98%) at reaction condition to give S-thiomethyl MAG . After synthesising,
3
retention time 6.77 min. The HPLC chromatograms were depicted the ligand was purified and radiolabelled with technetium-99 m
in Figure 1.
by transchelation method using stannous chloride dehydrate as
The biodistribution studies in mice at 30-min post injection reductant. S-benzoyl-MAG3 was synthesised as per reported
9
9m
(Table 1) of
Tc-MAG complex prepared either from S-benzoyl method and radiolabelled with technetium-99 m by transchelation
3
MAG3 or S-thiomethyl MAG3 precursor exhibited appreciably method. Both the complexes were subjected to TLC analysis,
9
9m
-
high urinary excretion, which was in the range of 66.53 ꢃ 2.15 presence of radiochemical impurities, for example,
TcO and
4
99m
99m
(
Tc-1) and 68.55 ꢃ 3.08 ( Tc-2). Although their hepatobiliary reduced hydrolysed technetium were negligible (< 2%). HPLC
99m
excretion was not pronounced, but still, it was little higher in elution profile of (Figure 1)
Tc-MAG complexes prepared from
3
99m
Tc-MAG complex prepared from the benzoylated precursor S-thiomethyl MAG under transchelation method is similar to that
3
3
99m
99m
(
8.53 ꢃ 0.58) in comparison with that of the
Tc-MAG complex of
Tc-MAG complex prepared from S-benzoylated precursor.
3
3
9
9m
prepared from the thiomethylated precursor (4.26ꢃ 0.40). All the As per HPLC chromatograms,
Tc-MAG complex prepared from
3
131
experiments were carried out under I-OIH co administration. To S-benzoylated precursor exhibited a single radioactive component
99m
determine the exact pathway of renal elimination,
Tc-MAG3 (yield 87.6%). Above yield was much improved (98.7%) when the
complex prepared from 1 and 2 were subjected to probenecid same complex was prepared from thiomethylated precursor.
depression studies (Table 2) in mice pre-treated with probenecid However, the other workers in this area have reported that the
9
9m
(
pH 7.4, 50 mg/kg) 10 min prior to radiopharmaceutical injection. yield of the
Tc-MAG
3
complex prepared from S-benzoylated
1
31
In this study also, I-OIH was used as standard renal agent. The precursor could be increased (>90%) by boiling the complex for
24
renal excretion of all MAG
3
complexes was reduced by 11% with 10 min, after addition of pertechnetate to the kit vial. We have
99m
a concomitant rise in blood, liver, intestine and kidney uptake here attempted to prepare
Tc-MAG
chemical purity from S-thiomethyl-MAG
labelling condition (at room temperature) omitting both the
3
complex of high radio-
compared with that of the control.
3
under relatively mild
99m
heating and aeration step. The
3
Tc-MAG complex prepared rou-
Discussion
tinely in different radiochemical clinics from benzoylated precursor
necessitate the heating of the chelate at elevated temperature to
increase the labelling yield that cause much inconveniency and
may reduce the yield by forming some radioactive artefacts. This
In the field of organic synthesis, the high sensitivity of the thiolate
function for chemical reaction causes concern and often, the
reactants bearing free sulphhydryl groups are masked. Technetium
chelation of thiol-based ligands also resulted artefact formation,
chelate denaturation and subsequent polymerization. The high
reactivity of the thiolate donor therefore needs to be masked
while chelating with technetium. In the course of our study,
S-thiomethyl (S-CH ) has been developed as a sulphhydryl protect-
ing group and well studied using different technetium binding
ligand systems, for example, cysteine, ethylene dicysteine, DMSA
and others. All these thiomethylated precursor on radiolabelling
produced the desired technetium complex in quantitative yield.
could be avoided if thiomethylated precursor could be used
99m
instead of benzoylated one during preparation of
Tc-MAG
3
99m
complex. Biodistribution studies of the complexes
Tc-1 and
99m
Tc-2 showed almost similar uptake of the complexes by dif-
ferent organs of interest. The hepatobilliary excretion of
23
99m
Tc-2
99m
3
was little less than that of
Tc-1. During competitive inhibition
studies, renal excretion of the complex prepared from the
thiomethylated precursor was inhibited almost 11% by probene-
99m
cid, which was comparable with the
Tc-MAG3 complex
prepared from S-benzoyl MAG . All these studies were carried
3
131
out under I-OIH co-injection method and these confirmed a
common renal excretory pathway for both.
Technetium-99m complex of mercaptoacetyltriglycine complexes
prepared from S-benzoylMAG3 and S-thiomethylMAG3 also
exhibited similar electrophoretic movement (12 cm) towards
anode, indicating their identity and purity (Figure 2).
Conclusion
3
From this discussion, it is clear that thiomethyl group (–SCH ) could
be used for efficient protection of thiol functionality present in
mercaptoacetyltriglycine ligand to avoid by product formation
3
during complexation. S-thiomethylated MAG precursor resulted
in desired MAG complex under relatively mild condition (incuba-
3
tion at room temperature), with considerably high radiochemical
yield, leading to the simplification of the preparative method of
99m
the radiopharmaceuticals. The extrarenal uptake of
complex prepared from thiomethylated precursor was consider-
ably less than that prepared from S-benzoylated MAG . Lyophilised
can also be developed using
thiomethylated precursor as starting ligand.
Tc-MAG
3
Figure 2. Autoradiograph showing the electrophoretic movement of
3
(
a) 99mTc-MAG3 chelate prepared from S-benzoyl MAG3, (b) 99mTc-MAG3
99m
-
single vial kit for
Tc-MAG
3
chelate prepared from S-thiomethyl MAG3 and (c) 99mTcO
4
+ sign indicates
the anode, and the arrow indicates the direction of movement.
J. Label Compd. Radiopharm 2012
Copyright © 2012 John Wiley & Sons, Ltd.
www.jlcr.org

K. Sanyal et al.
[
9] A. Taylor Jr., D. Eshima, A. R. Fritzberg, P. E. Christian, S. Kasina, J. Nucl.
Med.1986, 27, 795.
Acknowledgement
[
10] A. Taylor Jr., D. Eshima, P. E. Christian , W. Milton, Radiology, 1987,
62, 365.
We acknowledge the Board of Radiation and Isotope Technology
1
-
131
(
BRIT) for providing MoO and I-OIH. The financial assistance
4
[11] R. A. Jafri, C. C. Nimmon, K. E. Britton, J. Nucl. Med.1987, 28, 647.
provided by the Indian Council of Medical Research (New Delhi) [12] D. Eshima, A. R. Fritzberg, A. Taylor Jr., Semin. Nucl. Med. 1990, 20, 28.
and BRNS (Mumbai) to carry this work is also gratefully [13] C. D. Russel, B. Thorstad, M. V. Yester, M. Stutzman, T. Baker,
acknowledged.
E. V. Dubvosky, J. Nucl. Med. 1988, 29, 1189.
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F. A. Latino, S. E. Payne, J. Nucl. Med. 1994, 35, 349.
[
Conflict of Interest
[15] G. Bormans, B. Cleynhens, P. Adriaens, M. De Roo, A. M. Verbruggen,
J. Label. Compd. Radiopharm. 1993, 33, 1065.
The authors did not report any conflict of interest.
[16] D. Eshima, A. Taylor Jr., A. R. Fritzberg, S. Kasina, L. Hansen,
J. F. Sorenson, J. Nucl. Med. 1987, 28, 1180.
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