Preliminary studies of a novel cyclopentadienyl tricarbonyl technetium-99m fatty acid derivative for myocardical imaging

Article abstract of DOI:10.1002/jlcr.2987

This study reports the synthesis and evaluation studies of 6′-cyclopentadienyl tricarbonyl technetium-99m 6′-oxo-11- (hexanamide)undecanoic acid (1). 1 was prepared with 26.5 ± 4.3% of radiochemical yield and more than 98% of radiochemical purity. Tissue distribution in mice showed that high radioactivity accumulated in the heart with moderate clearance. However, unfortunately, similar to those of other technetium-labeled fatty acid analogs, the biodistribution studies of 1 in mice showed poor heart-to-blood ratios, which suggested that 1 cannot be used as myocardial imaging agent, and it may provide a theoretical basis or a lab experience for corresponding fatty acid tracers studies. Tc-99m-labeled fatty acid is very important for the evaluation of myocardial metabolism. 1 was radiolabeled by a double ligand transfer reaction between ferrocene and 99mTc. Amidated 99mTc-labeling fatty acid is beneficial to prolonging retention in myocardium. Copyright

Full text of DOI:10.1002/jlcr.2987

Research Article
Received 20 September 2012,
Revised 24 October 2012,
Accepted 30 October 2012
Published online 7 December 2012 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.2987
Preliminary studies of a novel
cyclopentadienyl tricarbonyl technetium-99m
fatty acid derivative for myocardical imaging
a,b
b
c
a
Huahui Zeng, Huabei Zhang, Xiangxiang Wu, Fangfang Chao,
a
a
a
a
a
Gang Yu, Liqing Zhang, Han Jiang, Hongbiao Liu, Haifeng Hou,
a
a
a
Hongwei Zhan, Hong Zhang, * and Mei Tian *
0
0
This study reports the synthesis and evaluation studies of 6 -cyclopentadienyl tricarbonyl technetium-99m 6 -oxo-11-(hexanamide)
undecanoic acid (1). 1 was prepared with 26.5 ꢀ 4.3% of radiochemical yield and more than 98% of radiochemical purity.
Tissue distribution in mice showed that high radioactivity accumulated in the heart with moderate clearance. However,
unfortunately, similar to those of other technetium-labeled fatty acid analogs, the biodistribution studies of 1 in mice showed
poor heart-to-blood ratios, which suggested that 1 cannot be used as myocardial imaging agent, and it may provide a theoretical
basis or a lab experience for corresponding fatty acid tracers studies.
Keywords: fatty acid; technetium-99m; tissue distribution; myocardium
Introduction
the cyclotron. A technetium-99m-labeled fatty acid analog would
be highly desirable because of the ideal nuclear properties of
radiotechnetium (141 keV, t1/2 = 6 h) and its easy availability
through the Mo/ Tc generator system whenever needed.
In the past decade, many different Tc-99m complexes incorpor-
Fatty acids act as the most important energy sources in the normal
myocardium, accounting for 60–90% of aerobic metabolism, via
the beta-oxidation pathway. Disturbances in fatty acid metabolism
1
99
99m
often reflect myocardial damage, such as myocardial ischemia and
ating fatty acid chains of different lengths and structures have been
2
,3
cardiomyopathy. Accordingly, radiolabeled fatty acid analogs
have been utilized for diagnosis of myocardial ischemia and
other heart diseases using single-photon emission computed
12,13
reported,
but no compound has potential use in clinical prac-
99m
tice. Early researches on
Tc-labeled fatty acid analogs were
unsuccessful for poor radiotracers accumulation in myocardium.
4
–7 11
18
tomography or positron emission tomography.
C-, F-, and
I-labeled long chain fatty acid derivatives have been reported
as useful radiopharmaceuticals for the estimation of myocardial
6
99m
Recently, the Magata et al. found that [ Tc]MAMA-hexadecanoic
123
acid (HDA) shows high initial heart uptake and subsequent rapid
99m
clearance, and detected the fatty acid is metabolized to [ Tc]
11
fatty acid metabolism. 1-[ C]Palmitate showed biexponential
clearance in the heart with rapid washout through b-oxidation and
slow washout for slow turnover of the intracellular lipid pool,
99m
MAMA-butyric acid via b-oxidation in the body.
(
3
Tc(CO) -15-[N-
7
Acetyloxy)-2-picolylamino]pentadecanoic acid showed that high
3,7
radioactivity accumulated in the heart with rapid clearance via
which the biexponential clearance, intracellular lipid turnover,
and short half-life of radiocarbon were unfavorable for myocardical
14
b-oxidation in the body. Adriano Duatti et al. reported a series
99m
99m
0/+
of
Tc-labeled fatty acid complexes, [ Tc(N)(PNP)(L)] (PNP,
18
imaging. 16-[ F]Fluoropalmitic acid showed a same initial myocar-
diphosphane ligand; long chains fatty acids). The monocationic
complexes have almost identical accumulation values in the heart
11
dial uptake and a longer retention compared with 1-[ C]palmitate.
18
Methylbranched o-[ F]fluoroheptadecanoic acids (3-MFHA or 5-
1
8
MFHA) and 14-[ F]fluoro-6-thiaheptadecanoic acid were designed
8
for prolonged myocardial retention. However, short half-life of
radiofluorine and rapid washout of those tracers in the heart
a
Department of Nuclear Medicine, Second Affiliated Hospital of Zhejiang
University School of Medicine, Hangzhou, China, 310009
1
23
were unfavorable for clinical diagnosis. 17-[ I]Iodoheptadecanoic
123
123
b
Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of
acid, 15-(p-[ I]iodophenyl)pentadecanoic acid, and 15-(p-[ I]
9
–11
Chemistry, Beijing Normal University, Beijing, China, 100875
iodophenyl)-3-methylpentadecanoic acid
gated as successful radiopharmaceuticals for the estimation of
had been investi-
c
Pharmacy College, Henan University of Traditional Chinese Medicine,
7
myocardial fatty acid metabolism. But shedding radioiodine Zhengzhou, China, 450008
and easy deiodination were disadvantageous to use and prepare
those tracers. In addition, the cyclotron-produced C-11, F-18, and
I-123 have inherent economic and logistic disadvantages,
*
Correspondences to: Prof. Hong Zhang, Prof. Mei Tian, Department of Nuclear
Medicine, Second Hospital of Zhejiang University School of Medicine, 88 Jiefang
Road, Hangzhou, Zhejiang 310009, China.
particularly in nuclear medicine centers located far away from E-mail: hzhang21@gmail.com; meitian@gmail.com
J. Label Compd. Radiopharm 2013, 56 1–5
Copyright © 2012 John Wiley & Sons, Ltd.

H. Zeng et al.
and while the neutral complexes were not efficiently accumulated temperature, the remainder thionyl chloride and methanol sol-
99m
15
in the heart and rapidly washed out.
Tc-CpTT-16-oxo-HDA
vent were removed in vacuo; the residue was dissolved in water
was synthesized by a double ligand transfer reaction, which (50 mL) and dripped with saturated sodium bicarbonate solution
showed that high radioactivity accumulated in the heart (9.03 % until no bubbles were visible, and then extracted with dichloro-
ID/g at 1-min postinjection) with rapid clearance, and the fatty acid methane (50 mL ꢁ 3) to afford methyl 11-aminoundecanoate
9
9m
1
is metabolized to
Tc-CpTT-4-oxobutyric acid via b-oxidation in (4.87 g, 91%) as a white solid. H-NMR (CDCl , 400 MHz) d 1.27–133
3
myocardium. All those tracers were developed by long linear (m, 12H), 1.58–170 (m, 4H), 1.97 (s, 2H), 2.27 (t, J= 12.1, 2H), 2.68
+
chains fatty acids (containing 12, 15, and 16 carbon atoms) inter- (t, J= 12.2, 2H), 3.67 (s, 3H); LC-MS (ESI): m/z (%) = 216.20 (M + H ).
connected with variety of Tc-99m-labeled bifunctional chelating
Thionyl chloride (5 mL, 82.18 mmol) was added dropwise to
ꢂ
groups, which showed different accumulation values and washed adipic acid (3.63 g, 24.88 mmol) and heated at 90 C overnight.
99m
out rate in the heart. Especially,
Tc-CpTT-16-oxo-HDA showed After thionyl chloride had been removed in vacuo, the resulting
the most efficient radioactivity accumulation in the heart and the adipoyl chloride was used without further purification. The
lowest blood radioactive background among those tracers.
reaction flask was charged with ferrocene (4.63, 24.88 mmol)
99m
In the chelating group of
Tc-CpTT-16-oxo-HDA, cyclopenta- and adipoyl chloride in dichloromethane (30 mL) and chilled in
99m
+
dienyl group was chosen to chelate the fac- Tc(CO) (H O) com- an ice bath. To this solution was added anhydrous aluminum
3
2
3
plex because of the stability and significantly smaller molecular size chloride (3.32, 24.88 mmol) carefully over 30 min. The reaction
of the technetium-99m complex. The effect of the chelating group mixture, which turned a deep-violet color, was stirred for 2 h in
99m
of
Tc-CpTT-16-oxo-HDA on the biodistribution has not been clar- an ice bath. At the end of the reaction, the mixture was filtered
ified. In the present study, combining the cyclopentadienyl chelating in vacuo, and the solution was removed. The flask added with
9
9m
+
group and small fac- Tc(CO)
3
complex with 11-amidoundecanoic dry dichloromethane (10 mL) was placed again in an ice bath.
0
acid linked by the adipic acid, tricarbonyl technetium-99m 6 - The previous methyl 11-aminoundecanoate and triethylamine
oxo-6 -cyclopentadienyl-11-(hexanamide)undecanoic acid ( Tc- (3.46 mL) in 7-mL dichloromethane were slowly added and
CpTT-6 -oxo-HAUA, 1) was synthesized by a double ligands transfer stirred for 4 h at room temperature. After solvent had been
0
99m
0
reaction between the ferrocene adduct of methyl 11-(hexanamido) removed under reduced pressure, the crude mixture was diluted
9
9m
undecanoate (3) and Na TcO
4
in the presence of Cr(CO)
6
and with water and extracted with dichloromethane (3 ꢁ 15 mL). The
CrCl , followed by hydrolysis of the methyl ester group. The chemi- organic layer was dried over anhydrous Na
3
2
SO , and solvent was
4
cal characterization and biodistribution in mice of 1 were investi- removed in vacuo. The residue obtained was purified by flash
gated to evaluate the molecular specificity for myocardial imaging. column chromatography (20:80 ethyl acetate–hexane) to give 3
1
(
4.92 g, 41%) as a red oil. H-NMR (CDCl
3
, 400 MHz) d 1.25–130
(
2
m, 12H), 1.57–1.69 (m, 8H), 2.27 (t, J= 12.1, 2H), 2.58 (t, J= 12.2,
Materials and methods
Chemicals and equipment
H), 2.68 (t, J= 12.2, 2H), 3.25 (m, 2H), 3.65 (s, 3H), 4.22 (s, 5H), 4.55
+
(s, 2H), 4.79 (s, 2H), 6.39 (br, 1H); LC-MS (ESI): m/z (%) = 511.24 (M ).
0
0
Synthesis of 6 -cyclopentadienyltricarbonylrhenium-6 -oxo-11-
(
4
All reagents were of commercial grade. KReO was purchased from
0
hexanamide)undecanoic acid (CpRT-6 -oxo-HAUA, 2)
Alfa Aesar Chemical Company (London, UK), and other A.R. Grade
chemical reagents were all purchased from Sinopharm Group Co.
A mixture of the ester 3 (70.8 mg, 0.147 mmol), KReO (13.6mg,
.047 mmol), Cr(CO) (58.3 mg, 0.265 mmol), and CrCl (15.2mg,
.096 mmol) was placed in a pressure tube containing a magnetic
stir bar. Dry methanol (300 mL) was added to the vial that was
sealed and heated at 170 C for 1 h. At the end of the reaction,
the mixture was cooled in an ice bath for 6 min, and the solvent
2 2
was removed in vacuo. The residue was dissolved in CH Cl , passed
through a short silica plug, and the solvent was removed. The
product (20.2 mg, 0.032 mmol) was added in 3 mL of 0.3 N NaOH
4
99m
99
99m
4
Ltd. (BJ, China). Na TcO was eluted from an in-house Mo- Tc
0
0
6
3
column generator, using normal saline (Beijing Atomic High-tech
Co. Ltd., BJ, China). HPLC was performed on a Gold HPLC System
(Beckman Coulter, Inc., Brea, USA) equipped with a ultraviolet detec-
ꢂ
tor (254 nm) and a radioisotope detector. HPLC analysis was carried
out using a reversed-phase Alltima Amino 100A (250 ꢁ 4.6 mm, 5 m)
(Beckman Coulter, Inc., Brea, USA) at flow rate of 1 mL/min. Proton
nuclear magnetic resonance (NMR) spectra were recorded on a
00-MHz Varian VXR (Palo Alto, CA, USA) 300S spectrophotometer.
4
ꢂ
and methanol (1:3) and heated at 60 C for 20 min. After removing
Mass spectra were recorded on a QTOE (Waters, MA, USA) micro-
mass instrument, using ESI in positive mode. Radioactivity was
measured in a dose calibrator (CRC-15R, Capintec, Stanwood,
Washington, USA) and tissue radioactivity in a Bioscan-g-detector
methanol under reduced pressure, the solution was cooled and
acidified with 0.1 N HCl in an ice bath. The reaction mixture was then
extracted with dichloromethane, and the organic layer was dried
over anhydrous Na
purified by flash column chromatography (20:80 ethyl acetate–
hexane) to give 2 (19 mg, 21%) as a gray solid. H-NMR (CDCl
00 MHz) d 1.28–131 (m, 12H), 1.57–1.70 (m, 8H), 2.23 (t, J= 12.2, 2H),
.55 (t, J= 12.2, 2H), 2.70 (t, J= 12.2, 2H), 3.22 (m, 2H), 5.39 (s, 2H),
2 4
SO and concentrated. The crude product was
2D-6000. Animal experiments were carried out by using normal
Kunming mice (the laboratory animal centre of Zhejang University
of TCM, HZ, China). All the animal experiments were carried out in
compliance with the relevant national laws, as approved by the local
committee on the conduct and ethics of animal experimentation.
1
3
,
4
2
5
187
+
.98 (s, 2H), 6.54 (br, 1H); LC-MS (ESI): m/z (%) = 648.4(Re , M+H ).
Chemical synthesis
Radiochemical synthesis
0
0
0
0
Synthesis of methyl 6 -ferrocenyl-6 -oxo-11-(hexanamide)unde- Preparation of 6 -cyclopentadienyl tricarbonyl technetium-99m 6 -
canoate (3)
99m
0
oxo-11-(hexanamide)undecanoic acid ( Tc-CpTT-6 -oxo-HAUA, 1)
Thionyl chloride (5 mL, 82.18 mmol) was dissolved in methanol Radiotracer 1 was synthesized as described in Scheme 1. A solution
9
9m
(
(
7 mL), and to this solution was added 11-aminoundecanoic acid of Na TcO
4
(370 MBq, 0.2 mL) eluted from a generator was placed
ꢂ
5 g, 24.88 mmol) in an ice bath. After stirring for 3 h at room in a pressure tube and dried at 100 C. Ester 3 (3.4 mg, 5.34 mmol),
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Copyright © 2012 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 1–5

H. Zeng et al.
ꢂ
900 mL). The resulting mixture was incubated at 37 C for 4 h.
(
The mixture was filtered with a 0.2-mm Millipore filter, and the
radiochemical purity was analyzed by radio-HPLC.
Tissue distribution studies
Female Kunming mice (22–25 g) were housed for a week under a
12-h light/12-h dark cycle with free access to food and water for
subsequent tissue distribution studies. Animals were fasted
before experiments for 12 h. The radiotracer 1 (0.1 mL, 10 mCi)
was injected via the tail vein. At the indicated time points (1, 5,
15, 30, and 60 min), mice (n = 5) were sacrificed by cervical
dislocation, and samples of blood were immediately obtained
Scheme 1. Synthetic route of Tc-CpTT-6 -oxo-HAUA (1) and CpRT-6 -oxo-HAUA (2). from the myocardial tissue via a syringe, and samples of whole
99m
0
0
organ and tissue (heart, brain, lung, liver, spleen, kidney, intes-
Cr(CO)
300 mL) were then added, and the reaction mixture was sealed with counted. Data are expressed as the percent injected dose per
6 3
(2.1 mg, 9.64 mmol), CrCl
(0.5 mg, 3.21 mmol), and methanol tine, muscle, and bone) were also removed, weighed, and
(
ꢂ
a Teflon cap/O-ring and heated at 170 C (oil bath) for 1 h. At the gram of tissue (%ID/g). All experiments were carried out follow-
end of the reaction, the mixture was cooled in an ice bath, and ing the principles of laboratory animal care and the Chinese
methanol was then removed under a stream of N
was dissolved in CH Cl , passed through a 0.2-mm Millipore filter,
2
. The residue law on the protection of animals.
2
2
and the solvent was removed. The residue was redissolved in
methanol (200 mL) and treated with 0.3 N NaOH (50 mL) at 60 C for
Results and discussion
ꢂ
2
0 min. The solution was cooled, acidified with 0.1 N HCl (150 mL),
Chemistry
and extracted with CH Cl . The reaction mixture was purified by
2
2
The precursor 3 was prepared by Friedel–Crafts acylation from
reversed phase HPLC at a flow 2 mL/min using a 60:40:0.09 mixture
of methyl cyanide–phosphoric acid (aq). An aliquot was analyzed by
reversed phase HPLC at a flow 1 mL/min using a 60:40 mixture of
methyl cyanide–0.1% phosphoric acid (aq), and 1 was eluted
between 3.87 ꢀ 1.30 min.
ferrocene and adipoyl chloride in the presence of AlCl
3
and then
amidation with methyl 11-aminoundecanoate. A double ligand
9
9m
transfer reaction between the precursor 3 and KReO
4 4
/Na TcO
using CrCl and Cr(CO) and subsequent methyl ester hydrolysis
3
6
were carried out to provide compound 2 or radiotracer 1. The
structure of the product was assigned with the aid of NMR spec-
troscopic data and ESI mass spectra data (Scheme 1). In those
Partition coefficient determination
ꢃ 99m
ꢃ
The partition coefficients of 1 was measured by mixing 10 mL (5mCi) reactions, the ReO
4
/
TcO
4
are reduced and carbonylated,
of 1 with 3 g each of n-octanol and phosphate buffer (0.1 M, pH 7.4) which undergoes a cyclopentadienyl (Cp) ligand transfer
in a test tube. The test tube was vortexed for 3 min at room reaction with the ferrocenyl precursor. Moreover, incorporation
99m
temperature, followed by centrifugation for 5 min at 3500 rpm. of Re/ Tc into the Cp-fatty acid analog was quantitative.
Weighted sample from the n-octanol and buffer layers were However, during the hydrolysis of the methyl ester, unknown
counted. The partition coefficient was expressed as the logarithm peaks were observed on HPLC, which were probably derived
99m
of the ratio of the counts per gram from n-octanol versus that of from cleavage of the
Tc core or amide hydrolysis of radiotra-
phosphate buffer. Sample from n-octanol layer was repartitioned cer 1; therefore, mild conditions were employed to reduce side
99m
until consistent partition of coefficient value was obtained. The product formation. Hydrolysis of the
Tc-labeled compound
measurement was carried out in triplicate and repeated three times. was attempted in 0.3 N NaOH (aq) and methanol (volume, 1:3)
ꢂ
at 60–70 C, which gave a maximal yield of the desired product.
Subsequent HPLC purification furnished the radiotracer 1 in
In vitro stability
overall radiochemical yield of 26.5 ꢀ 4.3% (decay-corrected,
The radiotracer 1 (100 mL) was added to a test tube (5.0 mL) n = 5) and radiochemical purity of more than 98%. Total
containing Kunming rat serum (900 mL) or, alternatively, saline synthesis time including HPLC purification was 200–240 min.
Figure 1. HPLC analyses of radiotracer 1 (A) and the Re complex (B).
J. Label Compd. Radiopharm 2013, 56 1–5
Copyright © 2012 John Wiley & Sons, Ltd.
www.jlcr.org

H. Zeng et al.
99m
The retention times of
similar to the corresponding Re-labeled fatty acids on HPLC:
.87 min versus 3.56 min (Figure 1).
Tc-labeled fatty acids analogs were Tissue distribution studies
The Kunming mice were fasted for 12 h before experiments
because fatty acids are predominantly metabolized in the fasting
state. High radioactivity levels accumulated in blood, heart, lung,
liver, and kidneys at 1-min postinjection, and cleared rapidly with
3
In vitro stability
The radiotracer 1 was incubated in Kunming rat serum or saline time from blood (Table 1). However, there was an increase in
ꢂ
for 4 h at 37 C and analyzed by radio-HPLC. The percentage of liver uptake with time, indicating liver metabolism of 1 was
the remaining radiotracer 1 was 96% in saline and 92% in another important metabolic pathway. The injection of 1 in mice
Kunming mice serum, indicating high in vitro stability.
led to the heart initial uptake of 4.37 ꢀ 0.09 %ID/g at 1 min,
99m
0
Tc-CpTT-6 -oxo-HAUA (1) in normal Kunming Mice
Table 1. Distribution of
Tissues
1 min
5 min
15 min
30 min
60 min
Blood
Brain
Heart
Liver
Spleen
Lung
Kidney
Intestine
Muscle
Bone
4.73 ꢀ 0.11
0.43 ꢀ 0.02
4.37 ꢀ 0.09
10.62 ꢀ 0.99
2.68 ꢀ 0.23
4.79 ꢀ 0.73
4.24 ꢀ 0.4
1.32 ꢀ 012
0.73 ꢀ 0.05
1.27 ꢀ 0.10
0.92
2.76 ꢀ 0.19
0.24 ꢀ 0.01
3.28 ꢀ 0.36
16.88 ꢀ 0.65
4.99 ꢀ 0.31
3.64 ꢀ 0.17
5.26 ꢀ 0.15
1.29 ꢀ 0.16
0.59 ꢀ 0.06
0.89 ꢀ 0.06
1.19
1.88 ꢀ 0.10
0.18 ꢀ 0.01
2.49 ꢀ 0.23
18.04 ꢀ 0.54
3.13 ꢀ 0.15
2.79 ꢀ 0.17
6.40 ꢀ 0.42
1.12 ꢀ 0.06
0.53 ꢀ 0.04
1.10 ꢀ 0.07
1.32
1.65 ꢀ 0.06
0.15 ꢀ 0.00
2.38 ꢀ 0.28
17.79 ꢀ 0.89
5.78 ꢀ 0.44
2.95 ꢀ 0.30
6.84 ꢀ 0.31
0.52 ꢀ 0.11
0.54 ꢀ 0.11
1.22 ꢀ 0.16
1.44
1.02 ꢀ 0.09
0.10 ꢀ 0.01
1.42 ꢀ 0.15
12.7 ꢀ 1.07
5.00 ꢀ 0.52
2.27 ꢀ 0.22
5.53 ꢀ 0.44
0.43 ꢀ 0.06
0.47 ꢀ 0.05
0.76 ꢀ 0.04
1.39
Heart/blood
Heart/liver
0.41
0.19
0.14
0.13
0.11
Values are mean ꢀ SD (n = 5, %ID/g) after tail vein injection of 1 (10 mCi, 0.1 mL).
99m
Table 2. Comparison in vivo data of
Tc-labeled fatty acid analogs
a
b
b
Radiotracer
Heart
Heart/blood
Heart/liver
Animal
9
9
9
9m
9m
9m
0
Tc-CpTT-6 -oxo-HAUA
4.37 (1 min)
0.92
1.19
1.32
1.44
1.39
1.14
1.51
0.82
0.77
0.86
0.69
0.85
1.87
1.65
4.65
24.25
29.5
1.64
2.13
3.27
3.72
0.98
0.27
0.28
0.23
0.21
0.53
0.21
0.09
0.03
0.02
0.46
0.20
0.02
0.02
0.06
0.17
0.34
0.35
0.16
0.11
0.06
Kunming mice
3
2
2
1
.28 (5 min)
.49 (15 min)
.38 (30 min)
.42 (60 min)
6
Tc-MAMA-HDA
11.22 (0.5 min)
ddY mice
5
2
0
0
.46 (2 min)
.40 (5 min)
.60 (20 min)
.32 (60 min)
Tc(CO) -15-[N-(Acetyloxy)-2-
12.67 (0.5 min)
6.38 (1 min)
ICR mice
3
7
picolylamino]pentad ecanoic acid
0
0
.73 (5 min)
.28 (30 min)
9
9m
+ 14
[
Tc(N)(PNP3)(L)]
1.07 (5 min)
SD mice
ICR mice
0
0
.97 (30 min)
.59 (60 min)
9
9m
15
Tc-CpTT-16-oxo-HDA
9.03 (1 min)
5
4
2
.41 (5 min)
.12 (10 min)
.16 (30 min)
HAUA: 11-(hexanamide)undecanoic acid; HDA, hexadecanoic acid; PNP, diphosphane ligand; L, 12-aminoundecanoic acid; Cp,
cyclopentadienyl; ICR, Institute of Cancer Research; SD, Sprague Dawley.
a
%
%
ID/g,
ID/g ratio,
b
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J. Label Compd. Radiopharm 2013, 56 1–5

H. Zeng et al.
which was eliminated with a half-life of about 30 min (2.38ꢀ 0.28 % myocardial evaluation, but 1 cannot be used as myocardical
ID/g at 30-min postinjection) (Table 1). The maximum heart- imaging agent for the poor heart-to-blood ratios, which may
to-blood uptake ratio of 1 was 1.44 at 30-min postinjection, and provide a theoretical basis or a lab experience for corresponding
the heart to blood uptake ratios increased with time (0.92 at studies and investigations aiming at the activation of other fatty
1
min, 1.19 at 5 min, 1.32 at 10 min, and 1.44 at 30 min). No signifi- acid tracers.
99m
cant uptake in the intestine indicated that
Tc-pertechnetate was
not regenerated during the time of the study.
Acknowledgements
99m
0
Tc-CpTT-6 -oxo-HAUA (1) a new compound for single-
photon emission computed tomography imaging of myocardium
was evaluated. Tissue distribution studies showed higher concen-
The authors are gratefully acknowledged financial support
from the Natural Science Foundation of China (No. 81101023,
tration in the heart with moderate clearance and a higher target 81170306, 81173468), the Open Fund of the Key Laboratory of
to nontarget ratio. It is likely that the amidation of fatty acid chain Radiopharmaceuticals of Ministry of Education of Beijing Normal
contributed to myocardial accumulation and prolong retention University, Zhejiang Provincial Natural Science Foundation of China
(
Z2110230), Health Bureau of Zhejiang Province (2010ZA075,
011ZDA013), Science and Technology Bureau of Zhejiang
because the amidation group is more hydrophilic than the alkyl
chain and that the compositions of cardiomyocytes are more
hydrophilic than that of hepatocytes in rats. The logP (partition
coefficients) of the radiotracer 1 was determined to be
2
Province (2012R10040), Ministry of Science and Technology of
China (2011CB504400, 2012BAI13B06) and Qianjiang Talents
Project of Zhejiang Province (No. 2011R10079).
1
.01 ꢀ 0.12 in n-octanol/buffer. The heart-to-blood uptake ratio
and myocardium retention time of 1 had significant enhance than
Conflict of Interest
9
9m
the classical
Tc-MAMA-HDA, whereas the heart-to-liver uptake
ratio of 1 was similar to or higher than the others (Table 2).
The authors did not report any conflict of interest.
99m
Compared with
.32 %ID/g at 60-min postinjection) and
Tc-MAMA-HDA (11.22 %ID/g at 0.5 min and
99m
0
2
0
3
Tc(CO) -15-[N-(Acetyloxy)-
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Tc-
4
MAMA-HDA in heart-to-liver and heart-to-blood uptake ratio (after
[
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9m
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(
(
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+
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[
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3
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[
[
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2
008, 19, 450.
1
in mice showed that the higher initial myocardial uptake and
[
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J. Label Compd. Radiopharm 2013, 56 1–5
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