Synthesis and biological characterization of 99mTc(I) tricarbonyl cysteine complex, a potential diagnostic for assessment of renal function

Article abstract of DOI:10.1002/jlcr.897

Cysteine containing three functional groups, i.e. a carboxyl, sulfhydryl, and amino group, has been labelled with ^99mTc(I) tricarbonyl precursor (2) in order to study the renal characteristics of the resulting ^99mTc(I) tricarbonyl cy

Full text of DOI:10.1002/jlcr.897

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 63–73.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.897
Research Article
Synthesis and biological characterization of 99mTc(I)
tricarbonyl cysteine complex, a potential diagnostic for
assessment of renal function
Sang Hyun Park1,*, Beom Su Jang2 and Kyung Bae Park1
1 Division of Radioisotope Production and Application, Korea Atomic Energy Research
Institute, Daejeon, Republic of Korea
2 Division of Medicinal Science, Korea Research Institute of Chemical Technology,
Daejeon, Republic of Korea
Summary
Cysteine containing three functional groups, i.e. a carboxyl, sulfhydryl, and amino
group, has been labelled with 99mTc(I) tricarbonyl precursor (2) in order to study the
renal characteristics of the resulting 99mTc(I) tricarbonyl cysteine (3) versus the
reference 99mTc-MAG3 (1). The 99mTc(I) tricarbonyl cysteine (3) was prepared in good
yields and characterized by HPLC, eletrophoresis, and eletrospray mass spectrometry.
The plasma protein binding rate of 99mTc(I) tricarbonyl cysteine (3) was about 70 to
80%, and similar to that of 131I-OIH (70%) but lower than that of 99mTc-MAG3
(90%). The T1/2 of 99mTc(I) tricarbonyl cysteine (4.30 ꢀ 0.79 min) in the kidney was
higher than the one of 99mTc-MAG3 (2.43 ꢀ 0.70 min). The static image of 99mTc(I)
tricarbonyl cysteine at 5 min post injection showed high concentrated activity in the
kidney. And in the 15, 30 min post injection images, most activity appeared in the
bladder without a residue in other organs. The 99mTc(I) tricarbonyl cysteine exhibited
biological behavior comparable to 99mTc-MAG3 and it is expected to have diagnostic
potential for imaging renal function in nuclear medicine. Copyright # 2004 John
Wiley & Sons, Ltd.
Key Words: 99mTc(I) tricarbonyl complex; 99mTc(I) tricarbonyl cysteine; renal
function diagnostic; renal agents; tubular secretion
*Correspondence to: S. H. Park, Division of Radioisotope Production and Application, Korea
Atomic Energy Research Institute, 150 Dukjin-dong, Yuseong-gu, Daejeon 305–353, Republic of Korea.
E-mail: parksh@kaeri.re.kr
Contract/grant sponsor: Korean Ministry of Science and Technology
Contract/grant sponsor: International Atomic Energy Agency; contract/grant number: ROK 03002
Copyright # 2004 John Wiley & Sons, Ltd.
Received 20 March 2004
Revised 6 September 2004
Accepted 9 September 2004

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S. H. PARK ET AL.
Introduction
Various radiological methods are available to address anatomical questions
about kidneys. However, to determine the differential function of each kidney,
and to detect obstruction in urine flow, renography using radiotracers is the
method of choice.1 To date there has been found no compound that is
completely extracted by kidneys, and only para-aminohippuric acid (PAH)
comes close. Tubis et al. developed ortho-iodohippuric acid (OIH), a
radiolabelled analogue of PAH for measurement of ERPF and imaging.2
But, 131I-labelled-OIH involves poor image and high radiation dose, especially
in patients with urinary obstruction.3 Because of these disadvantages, many
new renal imaging agents labelled with 99mTc are being introduced. The
introduction of 99mTc-mercaptoacetyltriglycine (99mTc-MAG3, 1, Scheme 1)
into clinical use as a potential replacement of 123/131I-labelled-OIH has opened
up a new era in the field of renal radiopharmaceuticals.4 99mTc-MAG3 has
played an unchallenged role as a radiopharmaceutical of choice for dynamic
O
O
OH
OH
NaOH
S
Cl
HS
+
H O/Toluene
O
O
2
O
DCC
THF
HO
N
O
O
O
O
N
N
O
Triglycine
1N NaOH
O
N
S
S
N
O
O
O
Reflux, 2.5 h
O
O
COOH
SnCl
2
Sodium glucoheptonate
Sodium tartrate
O
N
O
N
99m
Tc
Lactose
O
S
N
99m
Na TcO
4
100¡É, 10 min
COOH
1
Scheme 1. Preparation of 99mTc-MAG3 (1)
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99MTC(I) TRICARBONYL CYSTEINE AS A RENAL FUNCTION DIAGNOSTIC
65
kidney function studies. However, the wide acceptance of 99mTc-MAG3 is
mainly due to the excellent scintigraphic imaging qualities of 99mTc rather than
its biological properties.4–6 Since, compared to 131I-OIH, 99mTc-MAG3
displays lower extraction efficiency, a significantly higher protein binding, a
smaller volume of distribution and consequently slower plasma clearance
(about 60–65% of OIH clearance),5–8 attempts have been made to develop a
99mTc-labelled renal agent with a more desirable biological behavior. As a
result of these attempts, 99mTc(I) tricarbonyl cysteine (3, Scheme 2) has been
prepared and evaluated in rabbits.
.
O
+
OH
Tc
2
H O
l-HSCH CH(NH )CO H
2
K [H BCO ]
2
2
2
OH
NH
Tc
2
3
3
2
2
99m
99m
S
[
TcO ]
4
O
99m
75° C, 30 min
OC
60° C, 15 min
CO
CO
OC
CO
CO
2
3
Scheme 2. Preparation of 99mTc(I) tricarbonyl cysteine complex (3)
Design of an improved 99mTc-labelled renal agent requires a systematic
identification of the physiological properties which are directly associated with
optimal tubular transport. For a long time, it was believed that the
carbonylglycine moiety was required for recognition by tubular proteins.9 In
view of this finding, it was of interest to prepare cysteine labelled with 99mTc
with low oxidation state. In general, 99mTc-radiopharmaceuticals are based on
99mTc(V) oxo or octahedral 99mTc(III) cores. 99mTc agents with low oxidation
state are less common, because of the difficulty of controlling the reduction of
the 99mTc(VII) to 99mTc(I). But, Alberto et al. synthesized the 99mTc(I)
tricarbonyl complex as a precursor with low oxidation state for the 99mTc(I)
radiolabelling of biomolecules.10–15 They reported that it was easily prepared
as the organometallic aqua complex [99mTc(OH2)3(CO)3]+ directly from
[
99mTcO4]ꢁ in saline which is stable at room temperature even though exposed
to air (Scheme 2).10,11 They concluded that this new peptide labelling approach
with the 99mTc(I) tricarbonyl precursor combines the highest possible specific
activities with a minimal influence on the biological properties of the peptide,
including receptor affinity and metabolism, and can be transferred to other
peptides of choice.12 Since synthesis of MAG3 (1) requires synthetic
procedures (Scheme 1), the development of a new 99mTc renal imaging agent
using a small molecule such as cysteine will be of interest.
Cysteine contains three functional groups such as carboxyl, sulfhydryl, and
amino group that are well known to be an efficient chelating moiety for 99mTc
labelling. Most of 99mTc-cysteine complexes are synthesized under various
reaction conditions as renal scintigraphic agents.16–19 However, the 99mTc(I)
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S. H. PARK ET AL.
tricarbonyl cysteine as a renal scintigraphic agent has not been reported for
present time.
In this paper, we describe the synthesis of 99mTc(I) tricarbonyl cysteine (3)
and evaluation of its biological characteristics as a potential diagnostic
radiopharmaceutical for renal function.
Results and discussion
99mTc(I) tricarbonyl precursor 2, [99mTc(OH2)3(CO)3]+, was successfully
prepared with 98% radiolabelling using a modification of the procedure
described by Alberto et al. (Scheme 2).10–12 The 99mTc(I) tricarbonyl cysteine
(3) was prepared by reacting 1 ml of 2 with 0.1 ml of l-cysteine solution (10 mM
in saline) for 30 min at a reaction temperature of 758C (Scheme 2). The HPLC
chromatograms of 99mTcO4ꢁ, 99mTc(I) tricarbonyl precursor 2 and 99mTc(I)
tricarbonyl cysteine (3) showed that retention times of those species are 8.3,
4.8, and 16.5 min, respectively. The radiolabelling yield of 3 in the reaction
mixture was determined by HPLC analysis and found to be 92%. The HPLC
chromatogram of 3 in the reaction mixture is shown in Figure 1. The complex
is stable (>90%) for approximately 3 h. After this time, decomposition of the
complex was observed. Paper electrophoresis investigations in aqueous
solution confirmed the anionic charge of 3 in neutral solution. To get mass
spectral data, 99/99mTc(I) tricarbonyl cysteine was prepared by reacting 1 ml of
99/99mTc(I) tricarbonyl precursor with 0.1 ml of l-cysteine solution (10 mM in
saline). The complexes revealed the same retention times on HPLC column
([99/99mTc(OH2)3(CO)3]+:4.9 min; 99/99mTc(I) tricarbonyl cysteine: 16.7 min) as
99/
the corresponding complexes 2 and 3. Analysis of the mass spectrum of
99mTc(I) tricarbonyl cysteine complex showed the corresponding molecular
weight.
0
5
10
15
20
25
30
Time [min]
Figure 1. HPLC chromatogram of complex 3
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99MTC(I) TRICARBONYL CYSTEINE AS A RENAL FUNCTION DIAGNOSTIC
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Table 1. Plasma protein binding rate of 99mTc(I) tricarbonyl cysteine (3) in rabbits
5 min
60 min
79.01 ꢀ 0.27
99mTc(I) tricarbonyl cysteine
69.20 ꢀ 1.74
Values are expressed as mean ꢀ SD of plasma protein binding percentage for three rabbits.
Table 2. Tmax and T1/2 of 99mTc(I) tricarbonyl cysteine (3) and 99mTc-MAG3 (1)
renography in rabbits with or without probenecid pretreatment
Control (min)
Probenecid (min)
Tmax
T1/2
Tmax
T1/2
99mTc(I) tricarbonyl cysteine
99mTc-MAG3
2.33 ꢀ 0.56
1.76 ꢀ 0.66
4.30 ꢀ 0.79
2.57 ꢀ 0.72
2.30 ꢀ 0.17
2.37 ꢀ 0.71
17.03 ꢀ 2.47**
3.57 ꢀ 0.39*
Values are expressed as mean ꢀ SD (min) for three rabbits. Probenecid dose was 20 mg/kg, and it was given
10 min prior to injection of test radiopharmaceutical 3 and 1. Statistically different from probenecid non-
treated control group (*:0.015p50.05, **p50.001).
The binding rates of 3 with plasma protein in rabbits at 5 and 60 min post
injection are summarized in Table 1. The plasma protein binding rate of 3 was
about 70 to 80%, and similar to that of 131I-OIH (70%) but lower than that of
99mTc-MAG3 (90%).20
The renograms of 3 with or without probenecid pretreatment are
summarized in Table 2. The Tmax of 3 in the kidney without probenecid
pretreatment was 2.33 ꢀ 0.56 min and the elapsed time of the Tmax to T1/2 was
4.30 ꢀ 0.79 min. The renogram of 3 in rabbits showed that the activity of the
kidney was rapidly reduced within 30 min post injection to the background
level (Figure 1), which indicates that 3 was rapidly excreted via the kidney and
radioactivity in kidney reached the background level within 30 min post
injection. The T1/2 of 99mTc tricarbonyl cysteine (4.30 ꢀ 0.79 min) was higher
than the one of 99mTc-MAG3 (2.43 ꢀ 0.70 min) but lower than that of 99mTc-
ECD (7.00 ꢀ 1.35 min) and 99mTc-EC (4.83 ꢀ 0.67 min) which contain
cysteine moiety21 (Figure 2).
The static image of 3 at 5 min post injection showed high concentrated
activity in the kidney. And in the 15, 30 min post injection images, most
activity appeared in the bladder without a residue in other organs (Figure 3).
The excretion mechanism of 3 was confirmed by the probenecid blocking
study. The Tmax of 3 in the kidney with probenecid pretreatment was
2.30 ꢀ 0.17 min and the elapsed time of Tmax to T1/2 was 17.03 ꢀ 2.47 min.
The Tmax of 3 in probenecid-pretreated rabbits was similar to that of untreated
ones. However, the T1/2 of 3 in rabbits pretreated with probenecid was
increased four-fold (409%) in comparison with that of untreated ones, which
means the excretion of 3 was extremely affected by probenecid.
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S. H. PARK ET AL.
Figure 2. The renogram of 99mTc tricarbonyl cysteine (3) in New Zealand white
rabbit for 24 min after injection
Figure 3. The images of a rabbit administered 99mTc-tricarbonyl cysteine (3) at
5, 15, and 30 min after injection
A probenecid blocking study of the 99mTc-MAG3 (1) was additionally
performed for comparison, and the results are summarized in Table 2. The
Tmax of 99mTc-MAG3 (1) in rabbits (n=3, each) with or without probenecid
pretreatment was similar, but the elapsed time of Tmax to T1/2 in rabbits with
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99MTC(I) TRICARBONYL CYSTEINE AS A RENAL FUNCTION DIAGNOSTIC
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probenecid pretreatment was 4.30 ꢀ 0.79 min, which is different from
2.57 ꢀ 0.71 min with no probenecid pretreatment (0.015p50.05). The T1/2
of 1 in rabbits pretreated with probenecid was increased to 145% of untreated
ones. This study proved the excretion of 3 was more extremely affected by
probenecid than 1. Thus, we concluded that 99mTc(I) tricarbonyl cysteine (3)
was principally excreted by active tubular transport, probably by the same
carrier proteins that are responsible for the renal excretion of 99mTc-MAG3
(1).1,20
In this study, it is shown that 3 exhibits desirable properties as a renal
function diagnostic agent in terms of its rapid renal excretion and non-
accumulation in other organs except the kidney. Furthermore, 99mTc
tricarbonyl cysteine complex is considered to be excreted principally by the
active tubular secretion through which commercially available 131I-OIH and
99mTc-MAG3 are secreted.
Experimental
Unless otherwise stated, all chemicals were of reagent grade. CO gas (99.5%)
was obtained from Daehan Gas Co. (Seoul, Korea) and pre-filtered with an
oxygen trap. Na99mTcO4 was obtained by solvent extraction from 99MoO3,
which was produced by irradiation of 98MoO3 using the high-flux advanced
neutron application reactor (HANARO) of the Korea Atomic Energy
Research Institute (KAERI) or from a commercial 99Mo/99mTc generator
(Mallinckrodt). l-Cysteine and probenecid were purchased from Sigma
Chemical Co. (St. Louis, USA). MAG3 labelling kit was obtained from
Mallinckrodt Medical, Inc. (St. Louis, USA). Potassium boranocarbonate was
synthesized by using the procedure described by Alberto et al.10 In this study,
labelling yield was checked by high performance liquid chromatography
(HPLC) equipped with a reversed phase mBondapak C-18 column
(3.9 ꢂ 300 mm, Waters, USA) or Jupiter 5m C-18 300A column
(4.6 ꢂ 250 mm, Phenomenex, UK), applying a gradient system with 0.05M
tetraethylammoniumphosphate (TEAP) buffer and 100% methanol. Anionic
99mTc species were characterized by paper electrophoresis (400 V, 20 V/cm,
45 min, paper chromatography (Whatman International Ltd, Maidstone,
England), 0.1M phosphate buffer (50/50 v/v, pH 7.4)). All solvents for the
mobile phase were of HPLC grade and pre-filtered with 0.2 mm pore size bottle
filter. Experimental animals were purchased from Bio Genomics, Inc. (Seoul,
Korea) that has technical cooperation with Charles River, experimental
animals, and they were allowed free access to food and water. The orbiter
gamma camera (Simens, Germany) with a low energy collimator was
positioned. The energy gate was set to 140 keV and the window width to
10%. Dynamic image acquisition was performed for 30 min according to the
dynamic procedure of the Microdelta System (Simens, Germany). The region
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S. H. PARK ET AL.
of interest (ROI) was drawn on the right and left kidney using 1–3 min
composition image and the time-activity curve was obtained.
Preparation of 99mTc tricarbonyl precursor, [99mTc(OH2)3(CO)3]+ (2)
The 99mTc tricarbonyl precursor 2 was prepared using a modification of the
procedure described by Alberto et al. (Scheme 2).10,11
Method A. A 10 ml-vial containing potassium boranocarbonate (5.9 mg,
0.043 mmol), sodium tetraborate (2.85 mg, 0.007 mmol), potassium sodium
tartrate (10.4 mg, 0.037 mmol) and sodium carbonate (7.15 mg, 0.067 mmol)
was capped with a rubber stopper and lyophilized. One ml of sodium
pertechnetate (Na99mTcO4) with up to 3.7 GBq was added into the vial by a
syringe and then heated to 908C in a boiling water bath for 20 min. After rapid
cooling down to room temperature, 0.15 ml of 0.1N HCl and 1.0 ml of
phosphate buffered saline (0.05M phosphate buffer, pH 7.4) were added to
neutralize 2. Yield: >98% determined by means of HPLC and TLC.
Method B. A 10 ml vial containing Na2CO3 (8 mg, 0.076 mmol) and NaBH4
(10 mg, 0.26 mmol) or tetrahydroborate exchange resin22 (10–20 mg) was
capped with a rubber stopper and then flushed with a stream of CO gas
(99.5%) at room temperature for 30 min. Six ml of sodium pertechnetate
(Na99mTcO4) with up to 3.7 GBq was added by a syringe and then heated to
758C for 30 min under the bubbling of CO gas. After rapid cooling down to
room temperature, 0.6 ml of phosphate buffered saline (0.05M phosphate
buffer, pH 7.4) was added to neutralize 2. Yield: >98% determined by means
of HPLC and TLC.
Preparation of 99mTc(I) tricarbonyl cysteine complex (3)
One ml of 99mTc(I) tricarbonyl precursor 2 was added into 0.1 ml of l-cysteine
solution (0.010M in saline) and the reaction mixture was heated 758C for
30 min. After cooling it to room temperature, 99mTc(I) tricarbonyl cysteine (3)
was characterized. Analytical data for yield: 92% (Rt=16.7 min) determined
by means of HPLC; stability: >90% for 3 h determined by means of HPLC;
charge: a negative charge of the complex determined by means of paper
eletrophoresis.
Preparation of 99/99mTc(I) tricarbonyl cysteine complex for mass spectrometry
99/99mTc(I) tricarbonyl precursor was prepared using method A except for
20 ml of 0.05M sodium pertechnetate (Na99TcO4)(1 ꢂ 10ꢁ7 mol) and a solution
of 0.5 ml of sodium pertechnate (Na99mTcO4)(120 MBq) in 1.5 ml of
physiological saline instead of 6 ml of sodium pertechnate (Na99mTcO4) with
up to 3.7 GBq. Preparation of 99/99mTc(I) tricarbonyl cysteine was prepared as
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99MTC(I) TRICARBONYL CYSTEINE AS A RENAL FUNCTION DIAGNOSTIC
71
described previously except for 99/99mTc(I) tricarbonyl precursor instead of
99mTc(I) tricarbonyl precursor. Analytical data for MS(ES): m/z 301.97 [M],
301.05 [M-1], 101.91, 103.08.
Plasma protein binding test
The extent of plasma protein binding was measured in triplicate. Three male
New Zealand white rabbits (3045.8 ꢀ 458.4 g) were injected with 3.7 MBq of 3
per head through the left ear vein. Blood samples were collected at 5 and
60 min after administration. The fresh heparinized whole blood was
centrifuged using a swing-out rotor at 4120 g for 10 min. The count rates of
plasma was measured in a well-type NaI(Tl) scintillation detector. For the
determination of plasma protein binding, the plasma protein was precipitated
by a method using trichloroacetic acid.23 The plasma protein is precipitated by
adding 0.2 ml of 50% trichloroacetic acid to 1 ml of plasma. The supernatant
and the precipitate were separated by centrifugation at 13 000 g for 10 min. The
activities of both phases were measured separately in a well-type NaI(Tl)
scintillation detector.
The percentage of protein binding was determined by the following
equation:
Plasma ðcpmÞ ꢁ supernatant ðcpmÞ
Plasma protein bound ð%Þ ¼
ꢂ 100
Plasma ðcpmÞ
Dynamic imaging studies and probenecid blocking studies
Dynamic imaging studies were performed with 6-week-old male New Zealand
white rabbits (1987.4 ꢀ 45.7 g, n ¼ 3) which were anesthetized with 25 mg/kg
of ketamine (Ketamine 50 inj., Yuhan Co., Korea) and 6 mg/kg of xylazine
(Rompun inj., Bayer-Korea, Korea). The effect of probenecid was studied by
the injection of probenecid (20 mg/kg) into the right ear vein of rabbits
(2004.6 ꢀ 72.3 g, n ¼ 3) at 10 min prior to the injection of either 3 or 1. The
rabbits were placed in a posterior position and injected with 37 MBq of test
complex per head (37 MBq, 1.0 mCi) via the left ear vein. In addition, the
static images of 3 were obtained at 5, 10, 30 min post injection with a microdot
imager (Simens, Germany). Data were expressed as mean ꢀ SD. Statistical
analyses were performed by the Student’s t-test. Differences were considered to
be significant at p50:05.
Conclusion
A novel radiosynthesis of 99mTc(I) tricarbonyl cysteine (3) for studying
dynamic kidney function has been developed. Biological evaluation of 3
showed an excellent renal excretion property. The 99mTc(I) tricarbonyl
cysteine is expected as a potential renal function diagnostic. Currently, we
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S. H. PARK ET AL.
are in the process of using this complex 3 for further comparison with 99mTc-
MAG3 (1) and evaluation in higher mammals before utilization for clinical
use, the results of which will be reported in due course.
Acknowledgements
This work was supported by the Mid- and Long-term Nuclear R&D Program
of the Korean Ministry of Science and Technology and the Technical
Cooperation Program of the International Atomic Energy Agency (ROK
03002). We would like to thank K. Landrock for her assistance in preparing
HPLC, electrophoresis, and MS data and Dr. H.-J. Pietzsch and Dr. S. Seifert,
Forschungszentrum Rossendorf, Germany for generously providing facilities.
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