Initial evaluation of 99mTc-tricarbonyl-cyclopentadienyl fatty acids derivatives as SPECT tracers for myocardium

Article abstract of DOI:10.1002/jlcr.3497

Fatty acids are myocardial metabolic agent for detecting myocardial ischemia and infraction. However, no ^99mTc-labeled fatty acids had potential use in clinical practice. In this study, ^99mTc-CpTT-10-oxo-para-PPA (1d), ^99mTc-CpTT-11-oxo-para-PPA (2d), ^99mTc-CpTT-12-oxo-para-PPA (3d), ^99mTc-CpTT-11-oxo-ortho-PPA (4d), and ^99mTc-CpTT-11-oxo-meta-PPA (5d) were synthesized by a double ligand transfer reaction, and their biological behaviors were investigated. Compound 2d achieved good heart to blood ratio (3.39 at 5?min after intravenous), and 2d showed high-heart uptake of 6.20%?ID/g at 5?minutes after injection. Compound 3d displayed a prolonged retention in the myocardium (1.43%?ID/g at 60?min after injection). Radioactivity accumulation in the lungs, spleen, and blood was eliminated rapidly. In vivo, metabolite analysis presented that compound 6d may be metabolite of 2d through β-oxidation in tissue. Unfortunately, the biodistribution studies of 1d, 2d, 3d, 4d, and 5d showed fast heart clearance and poor heart to liver ratios, which suggested that the 5 ^99mTc-labeled fatty acid analogues cannot be used for diagnosis.

Full text of DOI:10.1002/jlcr.3497

Received: 8 December 2016
DOI 10.1002/jlcr.3497
Revised: 5 February 2017
Accepted: 7 February 2017
R E S E A R C H A R T I C L E
Initial evaluation of 99mTc‐tricarbonyl‐cyclopentadienyl fatty acids
derivatives as SPECT tracers for myocardium
Jianping Liu | Huan Wang | Shuxia Wang | Qianqian Xue | Dawei Wang | Hang Wang |
Huabei Zhang
Key Laboratory of Radiopharmaceuticals of
Ministry of Education, College of Chemistry,
Beijing Normal University, Beijing, China
Fatty acids are myocardial metabolic agent for detecting myocardial ischemia and
infraction. However, no 99mTc‐labeled fatty acids had potential use in clinical
practice. In this study, 99mTc‐CpTT‐10‐oxo‐para‐PPA (1d), 99mTc‐CpTT‐11‐oxo‐
para‐PPA (2d), 99mTc‐CpTT‐12‐oxo‐para‐PPA (3d), 99mTc‐CpTT‐11‐oxo‐ortho‐
PPA (4d), and 99mTc‐CpTT‐11‐oxo‐meta‐PPA (5d) were synthesized by a double
ligand transfer reaction, and their biological behaviors were investigated. Compound
2d achieved good heart to blood ratio (3.39 at 5 min after intravenous), and 2d
showed high‐heart uptake of 6.20% ID/g at 5 minutes after injection. Compound
3d displayed a prolonged retention in the myocardium (1.43% ID/g at 60 min after
injection). Radioactivity accumulation in the lungs, spleen, and blood was
eliminated rapidly. In vivo, metabolite analysis presented that compound 6d may
be metabolite of 2d through β‐oxidation in tissue. Unfortunately, the biodistribution
studies of 1d, 2d, 3d, 4d, and 5d showed fast heart clearance and poor heart to liver
ratios, which suggested that the 5 99mTc‐labeled fatty acid analogues cannot be used
for diagnosis.
Correspondence
Huabei Zhang, Laboratory of
Radiopharmaceuticals of Ministry of
Education, College of Chemistry, Beijing
Normal University, Beijing 100875, China.
Email: hbzhang@bnu.edu.cn
Funding Information
Significant New Drugs Development, Grant/
Award Number: 2014ZX09507007001;
Natural Science Foundation of China, Grant/
Award Number: 21371026; Science and
Technology Support Program, Grant/Award
Number: 2014BAA03B03
KEYWORDS
fatty acid, myocardial imaging, SPECT tracers, β‐oxidation
1 | INTRODUCTION
was introduced to hinder FAs metabolic and enhance myo-
cardial retention. However, the nuclear features of 11C and
Radiolabeled fatty acids (FAs) are used for cardiac imaging,
because the oxidation of FAs is suppressed in the ischemic
heart. Radiolabeled FAs are valuable tools for the assessment
of ischemic heart disease through the use of single photon
emission computed tomography.1,2 15‐(p‐[123I]iodophenyl)
pentadecanoic acid3 ([123I]‐IPPA) and [11C]‐palmitate4 are two
representative myocardial imaging agents that have been suc-
cessfully used for clinical diagnosis. 15‐(p‐[123I]iodophenyl)
3‐methylpentadecanoic acid5 (BMIPP) is eliminated slowly
from the myocardium by introducing a methyl branch in
the β‐position of [123I]‐IPPA. Another branched FA analogue
123I limit the application of those tracers, such as the high
cost of the accelerator‐produced radionuclide 123I, the short
half‐life of 11C radioisotope (t1/2 = 20 min). 99mTc‐labeled
FA analogues are attractive because of the ideal physical
properties of 99mTc radioisotope (141 keV, t1/2 = 6 h), and
99mTcO4 is easily obtained from 99Mo/99mTc generator
−
system. Magata7 showed that 99mTc‐labeled N‐[[[2‐mercap-
toethyl)amino]carbonyl]methyl]‐N‐(2‐mercap‐toethyl)‐con-
jugated hexadecanoic acid
(
99mTc‐MAMA‐HDA) was
metabolized to 99mTc‐labeled N‐[[[2‐mercaptoethyl)amino]
carbonyl]methyl]‐N‐(2‐mercaptoethyl)‐conjugated butyric
acid (99mTc‐MAMA‐butyric acid) acid via β‐oxidation in the
myocardium. Studies of a new class of strongly electrophilic
metal fragment [99mTc(N)(PNP)(L)]0/+ (PNP = diphosphane
is
iodine‐123‐labeled‐15‐(p‐iodophenyl)‐9‐(R,S)‐methyl-
pentadecanoic acid (9MPA),6 which inserted a methyl branch
in the ninth carbon location of [123I]‐IPPA. A methyl branch
J Label Compd Radiopharm. 2017;1–13.
wileyonlinelibrary.com/journal/jlcr
Copyright © 2017 John Wiley & Sons, Ltd.
1

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LIU ET AL.
ligand; L = dianionic or monoanionic bifunctional ligands)
conjugated to FA chains of different lengths,8,9 indicated that
monocationic 99mTc‐labeled complexes accumulated in the
myocardium highly, respectively. Among 99mTc‐labeled FAs,
16‐cyclopentadienyl tricarbonyl technetium‐99 m 16‐oxo‐
meta‐PPA,
5d),
[
99mTc]‐Tricarbonyl
(3‐(4‐(11‐
cyclopentadineyl‐11‐oxodecyl)oxy)phenyl)benzoic acid) tech-
netium (99mTc‐CpTT‐11‐oxo‐para‐PBA, 6d) were prepared
using a double ligand transfer reaction. The biological charac-
teristics of the 5 compounds (1d, 2d, 3d, 4d, and 5d) were eval-
uated in vitro and in vivo. In addition, the metabolic
mechanism of compound 2d was studied in vivo.
hexadecanoic acid10 99mTc‐CpTT‐16‐oxo‐HDA) displayed
(
high‐radioactivity accumulation in the heart of 9.03% ID/g at
1 minute after intravenous administration. Zeng11 introduced
a heterocyclic group at the β‐position of the FA that exhibited
maximumhearttobloodratioof5.7at15minutesafterinjection
of 15‐cyclopentadienyl tricarbonyl technetium‐99 m 15‐oxo‐
pentadecanoyl thiopheneacetic acid (99mTc‐CpTT‐15‐oxo‐
PTA). The findings suggested that 99mTc‐labeled FA
analogues were recognized and metabolized in the heart.
Several FA radiotracers with different 99mTc‐cores and
complex structures, such as 99mTc‐3 + 1 (3 = tridentate S,E,S
donor ligand cap [S = thiol S,E = thioether S, ether O or
substituted N], 1 = monodentate mercaptide),12,13 99mTc‐
2 | EXPERIMENTAL SECTION
2.1 | Materials and methods
Chemicals and solvents were obtained from commercial
suppliers and used without further purification. Na99mTcO4
was obtained by elution with saline from a 99Mo‐99mTc
generator (Beijing Atomic High‐tech Co, Beijing). All
reactions were monitored by thin layer chromatography,
using silica gel plates with fluorescent indicator F254 and
ultraviolet (UV) light visualization. Silica gel 60 (230‐400
mesh) was used for flash column chromatography. High‐
performance liquid chromatography (HPLC) was performed
using a Shimadzu SCL‐10AVP System equipped with a
4 + 1 (4 = tripodal tetradentate, 1 = monodentate),14
[
99mTc
and
(CO)3(H2O)3]+,15,16 99mTc‐O,7
[ ,
99mTcN(PNP)]2+ 8,9
99mTc(CO)3‐cyclopentadienyl10,11
(
99mTc‐CpTT) have been
reported. However, poor myocardial accumulation and short
retention of the 99mTc‐labeled FAs12–18 may be the major bio-
logical factors negatively affecting their further application.
Therefore, efforts have been made to develop 99mTc‐labeled
FA analogues with the advantages of high heart to liver ratio,
quick blood washout, low‐lungs uptake, and long myocardial
retention. Among the different cores of 99mTc,
cyclopentadienyl tricarbonyl technetium FAs derivatives
displayed excellent in vivo characteristics, the high stability,
lipophilicity, andrelativesmallmolecularsizeofTc‐99mcores
semipreparative column (Venusil MP C‐18,
5 μm,
10 mm × 250 mm) or an analytical column (Alltech C‐18,
5 μm, 4.6 mm × 250 mm) with a UV detector (254 nm)
and NaI radioisotope detector. Nuclear magnetic resonance
(NMR) spectra were obtained using a Bruker ARX‐400 spec-
trometer with CDCl3 as the solvent. Mass spectra (EI‐MS)
were obtained using a Trance MS‐2000 mass spectrometer
(Finnigan). Radioactivity was measured using a dose calibra-
tor (Beijing Nuclear Instrument Factory, Beijing), and tissue
radioactivity was measured using a Bioscang‐detector
B‐FC3200. All animal experiments were performed using
normal mice (Vital River Laboratory Animal Technology
Co Ltd, Beijing) in compliance with the relevant national
laws, as approved by the local committee on the conduct
and ethics of animal experimentation.
(
99mTc‐CpTT) were beneficial to improve the biological activ-
ity of FAs. Therefore, cyclopentadienyl tricarbonyl technetium
FAs derivatives were expected to be designed and synthesized
as myocardial imaging. Several similar FAs with phenyl group
exhibited that phenyl group was uptake by myocytes, such as
[
123I]‐IPPA, [123I]‐BMIPP, and [123I]‐9MPA.
In this study, 99mTc‐CpTT core was chosen because of
its lipophilicity and diminutive size. A phenyl group
(with the aromatic properties) was introduced to the γ‐
position of the chain to impede β‐oxidation of FAs and
prolong retention in the myocardium. [99mTc]‐Tricarbonyl
(3‐(4‐(10‐cyclopentadineyl‐10‐oxodecyl)oxy)phenyl)propanoic
acid) technetium (99mTc‐CpTT‐10‐oxo‐para‐PPA, 1d), [99mTc]‐
3 | CHEMICAL SYNTHESIS
3.1 | Synthesis of 10‐ferrocenyl‐oxo‐
bromodecan (1a)
Tricarbonyl
(3‐(4‐(11‐cyclopentadineyl‐11‐oxodecyl)oxy)
Sulphoxide chloride (50 mL) was added dropwise to 10‐
bromodecanoic acid (5.0 g, 19.9 mmol) and heated at 85°C
overnight. After the sulphoxide chloride was removed,
dichloromethane (10 mL) and ferrocene (3.5 g, 18.8 mmol)
were added. Thereafter, anhydrous aluminium chloride
(2.5 g, 18.8 mmol) was added slowly in an ice bath. The reac-
tion was stopped with hydrochloric acid (30 mL, 1 mol/L)
and extracted with dichloromethane (3 × 30 mL). Compound
1a was obtained as an orange solid (2.6 g, 6.2 mmol, 33.0%).
phenyl)propanoic acid) technetium (99mTc‐CpTT‐11‐oxo‐para‐
PPA, 2d) , [99mTc]‐Tricarbonyl (3‐(4‐(12‐cyclopentadiney
l‐12‐oxodecyl)oxy)phenyl)propanoic acid) technetium (99mTc‐
CpTT‐12‐oxo‐para‐PPA, 3d) , [99mTc]‐Tricarbonyl (3‐(2‐(11‐
cyclopentadineyl‐11‐oxodecyl)oxy)phenyl)propanoic
technetium (99mTc‐CpTT‐11‐oxo‐ortho‐PPA, 4d), [99mTc]‐
Tricarbonyl (3‐(3‐(11‐cyclopentadineyl‐11‐oxodecyl)oxy)
phenyl)propanoic acid) technetium
99mTc‐CpTT‐11‐oxo‐
acid)
(

LIU ET AL.
3
1HNMR (400 MHz, CDCl3) δ 4.77 (s, 2H, ‐Fe‐Cp‐H(α)),
4.48 (s, 2H, ‐Fe‐Cp‐H(β)), 4.18 (s, 5H, Cp‐H), 3.40
(t, J = 6.9 Hz, 2H, ‐CH2‐Br), 2.68 (t, J = 7.4 Hz 2H,
‐C = O‐CH2‐), 1.81 to 1.88 (m, 2H, CH2‐CH2‐Br), 1.66 to
1.73 (m, 2H, CH2‐CH2‐C = O), 1.23 to 1.44 (m, 10H,
‐CH2‐), 13CNMR(100 MHz, CDCl3) δ 203.28[‐Fe‐Cp‐
C = O], 78.10[‐Fe‐C‐C = O], 71.04[‐Fe‐Cp(α)], 68.65
[‐Fe‐Cp(β)], 68.24[‐Cp], 38.56[‐CH2‐Br], 32.94[‐CH2‐CH2‐
C = O‐], 31.72 [‐CH2‐CH2‐C = O‐], 28.37 [‐CH2‐], 28.33
[‐CH2‐], 28.21[‐CH2‐], 27.63[‐CH2‐], 27.05[‐CH2‐], 23.43
[‐CH2‐]; MS(ESI) m/z: calcd for [C20H27FeOBr] 419.37;
found (M++H, 79Br) 419.1, (M++H, 81Br) 421.1.
3.4 | Synthesis of methyl 3‐(4‐((10‐ferrocenyl‐
10‐oxodecyl)oxy)phenyl)propanoate (1b)
Compound 1a (800 mg, 1.9 mmol) was dissolved in
dimethylformamide (DMF, 100 mL), then K2CO3 (235 mg,
1.9 mmol) was added. The mixture was stirred at room
temperature for 10 minutes. After a solution of methyl 3‐(4‐
hydroxyphenyl)propanoate (340 mg, 1.9 mmol) was added
dropwise at room temperature, the solution was heated to
80°C for 4 hours. After cooling to room temperature, the
solvent was removed via vacuum. The resultant solution
was extracted with dichloromethane and saturated NaCl, then
dried with anhydrous Na2SO4. The crude product was
obtained by silica gel column chromatography (ethyl
acetate‐petroleum ether 80:20) to yield compound 1b
(680 mg, 1.3 mmol, 69%). 1HNMR (400 MHz, CDCl3)
δ 7.10 (d, J = 8.4 Hz, 2H, ‐phenyl), 6.82 (d, J = 8.4 Hz, 2H,
‐phenyl), 4.78 (s, 2H, ‐Fe‐Cp‐H(α)), 4.48 (s, 2H, ‐Fe‐Cp‐H
(β)), 4.20 (s, 5H, Cp‐H), 3.92 (t, J = 6.5 Hz, 2H, ‐CH2‐O‐),
3.66 (s, ‐CH3), 2.88 (t, J = 7.6 Hz 2H, ‐C = O‐CH2‐), 2.69
(t, J = 7.4 Hz 2H, ‐C = O‐CH2‐), 2.59 (t, J = 7.9 Hz 2H, ‐
phenyl‐CH2‐), 1.68 to 1.77 (m, 4H, ‐CH2‐CH2‐), 1.35 to
1.44 (m, 10H, ‐CH2‐), 13CNMR(100 MHz, CDCl3) δ 203.55
[‐Fe‐Cp‐C = O], 172.36[‐COOCH3], 156.63[‐phenyl], 131.32
[‐phenyl], 128.13 [‐phenyl], 113.51[‐phenyl], 78.21[‐Fe‐C‐
3.2 | Synthesis of 11‐ferrocenyl‐oxo‐
bromoundecan (2a)
Prepared using the procedure stated as for 1a, starting from
11‐bromoundecanoic acid (5.3 g), thionyl chloride (10 mL),
ferrocene (3.5 g), AlCl3 (2.5 g) to give 2a as an orange solid
1
(5.0 g, 11.5 mmol, 61.2%). HNMR (400 MHz, CDCl3)
δ
4.87 (s, 2H, ‐Fe‐Cp‐H(α)), 4.57 (s, 2H, ‐Fe‐Cp‐H(β)), 4.29
(s, 5H, Cp‐H), 3.40 (t, J = 6.9 Hz, 2H, ‐CH2‐Br), 2.64
(t, J = 7.4 Hz 2H, ‐C = O‐CH2‐), 1.82 to 1.89 (m, 2H,
CH2‐CH2‐Br), 1.68 to 1.75 (m, 2H, CH2‐CH2‐C = O), 1.30
to 1.42 (m, 12H, ‐CH2‐), 13CNMR(100 MHz, CDCl3)
δ 203.21[‐Fe‐Cp‐C = O], 78.17[‐Fe‐C‐C = O], 71.03[‐Fe‐
Cp(α)], 68.67[‐Fe‐Cp(β)], 68.25[‐Cp], 38.61[‐CH2‐Br],
32.96[‐CH2‐CH2‐C = O‐], 31.77[‐CH2‐CH2‐C = O‐], 28.44
[‐CH2‐], 28.42[‐CH2‐], 28.33[‐CH2‐], 27.68[‐CH2‐], 27.09[‐
CH2‐], 23.49[‐CH2‐]; MS(ESI) m/z: calcd for [C21H29FeOBr]
433.40; found (M++H, 79Br) 433.2, (M++H, 81Br) 435.2.
C
=
O], 71.07[‐Fe‐Cp(α)], 68.71[‐Fe‐Cp(β)], 68.31
[‐Cp], 66.94[‐O‐CH2‐] 50.51[‐COO‐CH3], 38.70[‐CH2‐
C = O‐], 34.99[‐CH2‐C = O‐], 29.10[‐CH2‐CH2‐C = O‐],
28.49[‐CH2‐], 28.41[‐CH2‐], 28.32[‐CH2‐], 25.02[‐CH2‐],
23.58[‐CH2‐]; MS(ESI) m/z: calcd for [C30H38FeO4] 518.68;
found (M++H,) 519.2. HRMS (ESI) m/z: found (M++H,)
519.2187. Elemental analysis, found: C, 68.75; H, 7.66.
Calculated for C30H38FeO4: C, 69.46; H, 7.40.
3.3 | Synthesis of 12‐ferrocenyl‐oxo‐
3.5 | Synthesis of methyl 3‐(4‐((11‐ferrocenyl‐
11‐oxoundecyl)oxy)phenyl)propanoate (2b)
bromododecan (3a)
Prepared using the procedure stated as for 1a, starting from
12‐bromoundecanoic acid (5.6 g), thionyl chloride (10 mL),
ferrocene (3.5 g), AlCl3 (2.5 g) to give 3a as an orange solid
Prepared using the procedure stated as for 1b, starting from
Compound 2a (824 mg) in 100 mL DMF, K2CO3 (235 mg,
1.9
mmol),
methyl
3‐(4‐hydroxyphenyl)propanoate
1
(4.6 g, 10.6 mmol, 56.4%). HNMR (400 MHz, CDCl3) δ
(340 mg, 1.9 mmol) to give 2b as an orange solid (760 mg,
1.43 mmol, 75.2%). 1HNMR (400 MHz, CDCl3) δ 7.10
(d, J = 8.4 Hz, 2H, ‐phenyl), 6.82(d, J = 8.4 Hz, 2H, ‐phe-
nyl), 4.81 (s, 2H, ‐Fe‐Cp‐H(α)), 4.52 (s, 2H, ‐Fe‐Cp‐H(β)),
4.23 (s, 5H, Cp‐H), 3.92 (t, J = 6.6 Hz, 2H, ‐CH2‐O‐), 3.66
(s, ‐CH3), 2.88 (t, J = 7.6 Hz 2H, ‐C = O‐CH2‐), 2.67
(t, J = 7.2 Hz 2H, ‐C = O‐CH2‐), 2.59 (t, J = 8.1 Hz 2H, ‐
phenyl‐CH2‐), 1.68 to 1.77 (m, 4H, ‐CH2‐CH2‐), 1.26 to
1.44 (m, 12H, ‐CH2‐), 13CNMR(100 MHz, CDCl3)
δ 204.54[‐Fe‐Cp‐C = O], 173.34[‐COOCH3], 157.63[‐
phenyl], 132.32[‐phenyl], 129.14[‐phenyl], 114.51[‐phenyl],
4.77 (s, 2H, ‐Fe‐Cp‐H(α)), 4.48 (s, 2H, ‐Fe‐Cp‐H(β)), 4.19
(s, 5H, Cp‐H), 3.40 (t, J = 6.8 Hz, 2H, ‐CH2‐Br), 2.69
(t, J = 7.4 Hz 2H, ‐C = O‐CH2‐), 1.81 to 1.88 (m, 2H,
CH2‐CH2‐Br), 1.66 to 1.71 (m, 2H, CH2‐CH2‐C = O), 1.29
to 1.43 (m, 14H, ‐CH2‐), 13CNMR(100 MHz, CDCl3)
δ 204.72[‐Fe‐Cp‐C = O], 79.18[‐Fe‐C‐C = O], 72.09[‐Fe‐
Cp(α)], 69.71[‐Fe‐Cp(β)], 69.33[‐Cp], 39.73 [‐CH2‐Br],
34.01[‐CH2‐CH2‐C = O‐], 32.82[‐CH2‐CH2‐C = O‐], 29.51
[‐CH2‐], 29.47 [‐CH2‐], 29.43[‐CH2‐], 29.39[‐CH2‐], 28.72
[‐CH2‐], 28.14[‐CH2‐], 24.61[‐CH2‐]; MS(ESI) m/z: calcd
for [C22H31FeOBr] 447.43; found (M++H, 79Br) 447.1,
(M++H, 81Br) 449.1.
79.22[‐Fe‐C‐C
= O], 72.07[‐Fe‐Cp(α)], 69.71[‐Fe‐Cp
(β)], 69.32[‐Cp], 67.94[‐O‐CH2‐] 50.50[‐COO‐CH3], 39.71

4
LIU ET AL.
[‐CH2‐C = O‐], 35.99[‐CH2‐C = O‐], 30.10[‐CH2‐CH2‐
C = O‐], 29.52[‐CH2‐], 29.49 [‐CH2‐], 29.43[‐CH2‐], 29.36
[‐CH2‐], 29.30[‐CH2‐], 26.04[‐CH2‐], 24.59[‐CH2‐]; MS
(ESI) m/z: calcd for [C31H40FeO4] 532.71; found (M++H,)
533.2. HRMS (ESI) m/z: found (M++H,) 533.2337.
Elemental analysis, found: C, 69.76; H, 7.48. Calculated for
C30H38FeO4: C, 69.82; H, 6.99.
CH2‐] 51.43[‐COO‐CH3], 39.71[‐CH2‐C = O‐], 34.02[‐
CH2‐C = O‐], 29.54[‐CH2‐CH2‐C = O‐], 29.47[‐CH2‐],
29.36[‐CH2‐], 29.31[‐CH2‐], 26.24[‐CH2‐], 26.15[‐CH2‐],
24.61[‐CH2‐]; MS(ESI) m/z: calcd for [C31H40FeO4]
532.71; found (M++H,) 533.2. HRMS (ESI) m/z: found
(M++H,) 533.2340. Elemental analysis, found: C, 69.22;
H, 7.58. Calculated for C31H40FeO4: C, 69.82; H, 6.99.
3.6 | Synthesis of methyl 3‐(4‐((12‐ferrocenyl‐
12‐oxododecyl)oxy)phenyl)propanoate (3b)
3.8 | Synthesis of methyl 3‐(3‐((11‐ferrocenyl‐
11‐oxoundecyl)oxy)phenyl)propanoate (5b)
Prepared using the procedure stated as for 1b, starting
from Compound 3a (850 mg) in 100 mL DMF, K2CO3
(235 mg, 1.9 mmol), methyl 3‐(4‐hydroxyphenyl)propanoate
(340 mg, 1.9 mmol) to give 3b as an orange solid (520 mg,
0.95 mmol, 50.0%). 1HNMR (400 MHz, CDCl3) δ 7.10
(d, J = 7.9 Hz, 2H, ‐phenyl), 6.82(d, J = 7.9 Hz, 2H, ‐phenyl),
4.77 (s, 2H, ‐Fe‐Cp‐H(α)), 4.48 (s, 2H, ‐Fe‐Cp‐H(β)), 4.19
(s, 5H, Cp‐H), 3.91 (t, J = 6.2 Hz, 2H, ‐CH2‐O‐), 3.66
(s, ‐CH3), 2.88 (t, J = 7.4 Hz 2H, ‐C = O‐CH2‐), 2.69
(t, J = 7.2 Hz 2H, ‐C = O‐CH2‐), 2.59 (t, J = 7.6 Hz 2H,
‐phenyl‐CH2‐), 1.68 to 1.77 (m, 4H, ‐CH2‐CH2‐), 1.30 to
1.43 (m, 14H, ‐CH2‐), 13CNMR(100 MHz, CDCl3) δ
Prepared using the procedure stated as for 1b, starting
from Compound 2a (824 mg) in 100 mL DMF, K2CO3
(235 mg, 1.9 mmol), methyl 3‐(3‐hydroxyphenyl)propanoate
(340 mg, 1.9 mmol) to give 5b as an orange solid (600 mg,
1.13 mmol, 59.4%). 1HNMR (400 MHz, CDCl3) δ 7.19
(t, J = 7.1 Hz, 1H, ‐phenyl), 6.77(d, J = 13.5 Hz, 3H, ‐phenyl),
4.78 (s, 2H, ‐Fe‐Cp‐H(α)), 4.49 (s, 2H, ‐Fe‐Cp‐H(β)), 4.19 (s,
5H, Cp‐H), 3.92 (t, J = 6.0 Hz, 2H, ‐CH2‐O‐), 3.67 (s, ‐CH3),
2.91 (t, J = 7.4 Hz 2H, ‐C = O‐CH2‐), 2.69 (t, J = 7.1 Hz 2H,
‐C = O‐CH2‐), 2.62 (t, J = 7.5 Hz 2H, ‐phenyl‐CH2‐), 1.68 to
1.77 (m, 4H, ‐CH2‐CH2‐), 1.26 to 1.44 (m, 12H, ‐CH2‐),
13CNMR(100 MHz, CDCl3) δ 204.67[‐Fe‐Cp‐C = O],
204.45[‐Fe‐Cp‐C
=
O], 173.27[‐COOCH3], 157.62
173.38[‐COOCH3],
159.37[‐phenyl],
142.12[‐phenyl],
[‐phenyl],132.30[‐phenyl], 129.11[‐phenyl], 114.50[‐phenyl],
79.22[‐Fe‐C‐C = O], 72.05[‐Fe‐Cp(α)], 69.70[‐Fe‐Cp(β)],
69.30[‐Cp], 67.92[‐O‐CH2‐] 51.46[‐COO‐CH3], 39.68[‐CH2‐
C = O‐], 35.96[‐CH2‐C = O‐], 30.08[‐CH2‐CH2‐C = O‐],
29.51[‐CH2‐], 29.36[‐CH2‐], 29.30[‐CH2‐], 26.04[‐CH2‐],
24.58[‐CH2‐]; MS(ESI) m/z: calcd for [C32H42FeO4] 546.74;
found (M++H,) 547.3. HRMS (ESI) m/z: found (M++H,)
547.3342. Elemental analysis, found: C, 69.89; H, 7.61.
Calculated for C32H42FeO4: C, 60.21; H, 7.76.
129.52[‐phenyl], 120.47[‐phenyl], 114.70[‐phenyl], 112.25
[‐phenyl], 79.31[‐Fe‐C‐C = O], 72.17[‐Fe‐Cp(α)], 69.81
[‐Fe‐Cp(β)], 69.42[‐Cp], 67.92[‐O‐CH2‐], 51.69[‐COO‐
CH3], 39.83[‐CH2‐C = O‐], 35.70[‐CH2‐C = O‐], 30.08
[‐CH2‐CH2‐C = O‐], 29.79[‐CH2‐], 29.64[‐CH2‐], 29.61
[‐CH2‐], 29.55[‐CH2‐], 29.48[‐CH2‐], 29.40[‐CH2‐], 26.15
[‐CH2‐], 24.71[‐CH2‐]; MS(ESI) m/z: calcd for [C31H40FeO4]
532.71; found (M++H,) 533.2. HRMS (ESI) m/z: found
(M++H,) 533.2338 Elemental analysis, found: C, 68.97;
H, 7.55. Calculated for C31H40FeO4: C, 69.82; H, 6.99.
3.7 | Synthesis of methyl 3‐(2‐((11‐ferrocenyl‐
11‐oxoundecyl)oxy)phenyl)propanoate (4b)
3.9 | Synthesis of methyl 3‐(4‐((11‐ferrocenyl‐
11‐oxoundecyl)oxy)benzoate (6b)
Prepared using the procedure stated as for 1b, starting
from Compound 2a (824 mg) in 100 mL DMF, K2CO3
(235 mg, 1.9 mmol), methyl 3‐(2‐hydroxyphenyl)propanoate
(340 mg, 1.9 mmol) to give 4b as an orange solid (860 mg,
1.05 mmol, 55.4%). 1HNMR (400 MHz, CDCl3) δ 7.18
(q, J = 7.6 Hz, 2H, ‐phenyl), 6.87(q, J = 7.4 Hz, 2H, ‐phe-
nyl), 4.81 (s, 2H, ‐Fe‐Cp‐H(α)), 4.52 (s, 2H, ‐Fe‐Cp‐H(β)),
4.23 (s, 5H, Cp‐H), 3.92 (t, J = 6.6 Hz, 2H, ‐CH2‐O‐), 3.66
(s, ‐CH3), 2.88 (t, J = 7.6 Hz 2H, ‐C = O‐CH2‐), 2.67
(t, J = 7.2 Hz 2H, ‐C = O‐CH2‐), 2.59 (t, J = 8.1 Hz 2H, ‐
phenyl‐CH2‐), 1.68 to 1.77 (m, 4H, ‐CH2‐CH2‐), 1.26 to
1.44 (m, 12H, ‐CH2‐), 13CNMR(100 MHz, CDCl3)
δ 204.54[‐Fe‐Cp‐C = O], 173.76[‐COOCH3], 156.93[‐phe-
nyl], 129.88[‐phenyl], 128.85[‐phenyl], 127.54[‐phenyl],
120.14[‐phenyl], 111.93[‐phenyl], 79.21[‐Fe‐C‐C = O],
72.09[‐Fe‐Cp(α)], 69.73[‐Fe‐Cp(β)], 69.33[‐Cp], 67.68[‐O‐
Prepared using the procedure stated as for 1b, starting from
Compound 2a (824 mg) in 100 mL DMF, K2CO3
(235 mg, 1.9 mmol), methyl 3‐(4‐hydroxyphenyl) benzoate
(287 mg, 1.9 mmol) to give 6b as an orange solid
1
(520 mg, 0.95 mmol, 50.0%). HNMR (400 MHz, CDCl3)
δ 7.99 (t, J = 8.8 Hz, 2H, ‐phenyl), 6.91(d, J = 8.8 Hz,
2H, ‐phenyl), 4.79 (s, 2H, ‐Fe‐Cp‐H(α)), 4.50 (s, 2H, ‐Fe‐
Cp‐H(β)), 4.20 (s, 5H, Cp‐H), 3.98 (t, J = 6.5 Hz, 2H,
‐CH2‐O‐), 3.88 (s, ‐CH3), 2.68 (t, J = 7.3 Hz 2H,
‐C = O‐CH2‐), 1.68 to 1.83 (m, 4H, ‐CH2‐CH2‐), 1.26
to 1.33 (m, 12H, ‐CH2‐), 13CNMR(100 MHz, CDCl3)
δ 204.60[‐Fe‐Cp‐C = O], 166.86[‐COOCH3], 162.93[‐phe-
nyl], 131.53[‐phenyl], 122.25[‐phenyl], 114.04[‐phenyl],
79.18[‐Fe‐C‐C = O], 72.08[‐Fe‐Cp(α)], 69.71[‐Fe‐Cp(β)],
69.30[‐Cp], 68.15[‐O‐CH2‐] 51.78[‐COO‐CH3], 39.70

LIU ET AL.
5
[‐CH2‐C = O‐], 29.49[‐CH2‐CH2‐C = O‐], 29.41[‐CH2‐],
29.32[‐CH2‐], 29.08[‐CH2‐], 29.36[‐CH2‐], 25.95[‐CH2‐],
24.58[‐CH2‐]; MS(ESI) m/z: calcd for [C29H36FeO4]
504.65; found (M++H,) 505.3. HRMS (ESI) m/z:
found (M++H,) 505.3106. Elemental analysis, found: C,
68.51; H, 7.18. Calculated for C29H36FeO4: C, 69.02;
H, 7.20.
(CO)6 (102.4 mg, 0.5 mmol), and CrCl3 (24 mg,
0.15 mmol) with dry methanol (1 mL) to give 2c
(26 mg, 0.04 mmol, 26.0%) as a gray solid. 1HNMR
(400 MHz,CDCl3) δ 7.12(d, J = 8.4 Hz, 2H, ‐phenyl),
6.83 (d, J = 8.4 Hz, 2H, ‐phenyl), 5.98 (s, 2H, ‐Re‐Cp‐H
(α)), 5.38 (s, 2H, ‐Re‐Cp‐H(β)), 3.92 (t, J = 6.5 Hz, 2H,
‐O‐CH2‐), 2.89 (t, J = 7.6 Hz, 2H, ‐C = O‐CH2‐), 2.64
(t, J = 7.8 Hz, 2H, ‐O‐CH2‐CH2‐), 2.58 (t, J = 7.2 Hz,
2H, ‐C = O‐CH2‐), 1.66 to 1.79 (m, 4H, ‐C = O‐CH2‐
CH2‐), 1.26 to 1.43 (m, 12H, ‐CH2‐); 13CNMR(100
MHz, CDCl3) δ 195.42[‐Re‐C = O], 191.88[‐Re‐C = O],
178.57[‐COOH], 157.71[phenyl], 132.04[phenyl], 129.19
[phenyl], 114.58[phenyl], 96.21[‐Re‐C‐C = O], 87.93[‐Re‐
Cp(α)], 85.16[‐Re‐Cp(β)], 67.99[‐O‐CH2‐], 38.85[‐C = O‐
CH2‐], 35.87[‐C = O‐CH2‐], 29.80[‐CH2‐], 29.47[‐CH2‐],
29.36[‐CH2‐], 29.35[‐CH2‐], 29.30[‐CH2‐], 29.08[‐CH2‐],
26.03[‐CH2‐], 24.43[‐CH2‐]; MS (ESI) m/z: calcd for
[C28H33185ReO7] 666.61; found (M+H+,185 Re) 667.2,
(M+H+,187 Re) 669.2. HRMS (ESI) m/z: found
(M+Na+,185 Re) 689.1642 (M+Na+,187 Re) 691.1670.
Elemental analysis, found: C, 50.26; H, 5.43. Calculated
for C28H33185ReO7: C, 50.05; H, 5.00.
3.10 | Synthesis of tricarbonyl 3‐(4‐((10‐
cyclopentadienyl‐10‐oxodecyl)oxy)phenyl)
propanoic acid) rhenium (1c)
Compound 1b (78 mg, 0.15 mmol), NH4ReO4 (24 mg,
8.8 mmol), Cr(CO)6 (102.4 mg, 0.5 mmol), and CrCl3
(24 mg, 0.15 mmol) with dry methanol (1 mL) were placed
in a 10‐mL high‐pressure tank at a temperature of 180°C.
The mixture was allowed to react for 1 hour, and the
residue was passed through a 0.22 μm Millipore filter.
After the solvent was removed, 10 mL of methanol and
4 mL of 0.3 M NaOH were heated to 80°C for 40 minutes.
The pH was adjusted to 7 with 0.1M HCl, and the organic
layer was extracted with dichloromethane, dried over
anhydrous Na2SO4, then concentrated. The crude products
were purified by flash column chromatography (acetate‐
petroleum ether with 1% acetic acid, 10:30) to yield
compound 1c (20 mg, 0.03 mol, 20.4%), a gray solid.
1HNMR(400 MHz,CDCl3) δ 7.16 (d, J = 8.4 Hz, 2H, ‐
phenyl), 6.83 (d, J = 8.4 Hz, 2H, ‐phenyl), 5.98 (s, 2H, ‐
Re‐Cp‐H(α)), 5.38 (s, 2H, ‐Re‐Cp‐H(β)), 3.92 (t, J = 6.5 Hz,
2H, ‐O‐CH2‐), 2.89 (t, J = 7.6 Hz, 2H, ‐C = O‐CH2‐),
2.64 (t, J = 7.9 Hz, 2H, ‐O‐CH2‐CH2‐), 2.58 (t, J = 7.3 Hz,
2H, ‐C = O‐CH2‐), 1.67 to 1.79 (m, 4H, ‐C = O‐CH2‐
CH2‐), 1.32 to 1.43 (m, 10H, ‐CH2‐); 13CNMR(100
MHz, CDCl3) δ 195.45[‐Re‐C = O], 191.87[‐Re‐C = O],
178.15[‐COOH], 157.69[phenyl], 132.08[phenyl], 129.19
[phenyl], 114.58[phenyl], 96.18[‐Re‐C‐C = O], 87.93[‐Re‐
Cp(α)], 85.16[‐Re‐Cp(β)], 67.99[‐O‐CH2‐], 38.83[‐C = O‐
CH2‐], 35.83[‐C = O‐CH2‐], 29.81[‐CH2‐], 29.34[‐CH2‐],
29.28[‐CH2‐], 29.05[‐CH2‐], 26.01[‐CH2‐], 24.40[‐CH2‐];
MS (ESI) m/z: calcd for [C27H31185ReO7] 652.58;
found (M+H+,185 Re) 653.1, (M+H+,187 Re) 655.1.
HRMS (ESI) m/z: found (M+H+,185 Re) 653.1668
(M+H+,187 Re) 655.1692. Elemental analysis, found:
C, 49.76; H, 5.12. Calculated for C27H31185ReO7:
C, 49.69; H, 4.80.
3.12 | Synthesis of tricarbonyl 3‐(4‐((12‐
cyclopentadienyl‐12‐oxodecyl)oxy)phenyl)
propanoic acid) rhenium (3c)
Prepared using the procedure stated as for 1c, starting from
Compound 3b (82 mg), NH4ReO4 (24 mg, 8.8 mmol), Cr
(CO)6 (102.4 mg, 0.5 mmol), and CrCl3 (24 mg,
0.15 mmol) with dry methanol (1 mL) to give 3c
(18 mg, 0.03 mmol, 17.6%) as a gray solid. 1HNMR
(400 MHz,CDCl3) δ 7.12(d, J = 8.4 Hz, 2H, ‐phenyl),
6.83 (d, J = 8.4 Hz, 2H, ‐phenyl), 5.98 (s, 2H, ‐Re‐Cp‐H
(α)), 5.38 (s, 2H, ‐Re‐Cp‐H(β)), 3.92 (t, J = 6.5 Hz, 2H, ‐
O‐CH2‐), 2.89 (t, J = 7.6 Hz, 2H, ‐C = O‐CH2‐), 2.64 (t,
J = 7.8 Hz, 2H, ‐O‐CH2‐CH2‐), 2.58 (t, J = 7.2 Hz, 2H, ‐
C = O‐CH2‐), 1.66 to 1.77 (m, 4H, ‐C = O‐CH2‐CH2‐),
1.29 to 1.44 (m, 14H, ‐CH2‐); 13CNMR(100 MHz, CDCl3)
δ 195.42[‐Re‐C = O], 191.88[‐Re‐C = O], 178.57[‐COOH],
157.71[phenyl], 132.03[phenyl], 129.19[phenyl], 114.58
[phenyl], 96.22[‐Re‐C‐C = O], 87.92[‐Re‐Cp(α)], 85.14[‐
Re‐Cp(β)], 68.02[‐O‐CH2‐], 38.85[‐C = O‐CH2‐], 35.87
[‐C = O‐CH2‐], 29.79[‐CH2‐], 29.47[‐CH2‐], 29.36[‐CH2‐],
29.35[‐CH2‐], 29.30[‐CH2‐], 29.08[‐CH2‐], 26.03[‐CH2‐],
24.42[‐CH2‐]; MS (ESI) m/z: calcd for [C29H35185ReO7]
680.64; found (M+H+,185 Re) 681.3 (M+H+,187 Re)
683.3. HRMS (ESI) m/z: found (M+H+,185 Re) 681.1979
(M+H+,187 Re) 683.2008. Elemental analysis, found:
C, 50.51; H, 5.98. Calculated for C29H35185ReO7: C, 51.17;
H, 5.19.
3.11 | Synthesis of tricarbonyl 3‐(4‐((11‐
cyclopentadienyl‐11‐oxodecyl)oxy)phenyl)
propanoic acid) rhenium (2c)
Prepared using the procedure stated as for 1c, starting from
Compound 2b (80 mg), NH4ReO4 (24 mg, 8.8 mmol), Cr

6
LIU ET AL.
3.13 | Synthesis of tricarbonyl 3‐(2‐((11‐
cyclopentadienyl‐11‐oxodecyl)oxy)phenyl)
propanoic acid) rhenium (4c)
3.14 | Synthesis of tricarbonyl 3‐(3‐((11‐
cyclopentadienyl‐11‐oxodecyl)oxy)phenyl)
propanoic acid) rhenium (5c)
Prepared using the procedure stated as for 1c, starting from
Compound 4b (80 mg), NH4ReO4 (24 mg, 8.8 mmol), Cr
(CO)6 (102.4 mg, 0.5 mmol), and CrCl3 (24 mg, 0.15 mmol)
with dry methanol (1 mL) to give 4c (28 mg, 0.04 mmol,
Prepared using the procedure stated as for 1c, starting from
Compound 5b (80 mg), NH4ReO4 (24 mg, 8.8 mmol), Cr
(CO)6 (102.4 mg, 0.5 mmol), and CrCl3 (24 mg, 0.15 mmol)
with dry methanol (1 mL) to give 5c (32 mg, 0.05 mmol,
1
1
28.0%) as a gray solid. HNMR(400 MHz,CDCl3) δ 7.17(q,
32.0%) as a gray solid. HNMR(400 MHz,CDCl3) δ 7.18 (t,
J = 6.4 Hz, 2H, ‐phenyl), 6.86 (q, J = 7.4 Hz, 2H, ‐phenyl),
5.98 (s, 2H, ‐Re‐Cp‐H(α)), 5.38 (s, 2H, ‐Re‐Cp‐H(β)), 3.94
(t, J = 6.5 Hz, 2H, ‐O‐CH2‐), 2.93 (t, J = 7.5 Hz, 2H, ‐
C = O‐CH2‐), 2.65 (t, J = 8.0 Hz, 2H, ‐O‐CH2‐CH2‐), 2.57
(t, J = 7.2 Hz, 2H, ‐C = O‐CH2‐), 1.66 to 1.81 (m, 4H, ‐
C = O‐CH2‐CH2‐), 1.25 to 1.46 (m, 12H, ‐CH2‐); 13CNMR
(100 MHz, CDCl3) δ 195.69[‐Re‐C = O], 191.95[‐Re‐
C = O], 178.66[‐COOH], 156.95[phenyl], 129.91[phenyl],
128.56[phenyl], 127.63[phenyl], 120.14[phenyl], 110.93
[phenyl], 96.07[‐Re‐C‐C = O], 88.03[‐Re‐Cp(α)], 85.24[‐
Re‐Cp(β)], 67.70[‐O‐CH2‐], 38.82[‐C = O‐CH2‐], 33.84[‐
C = O‐CH2‐], 29.42[‐CH2‐], 29.30[‐CH2‐], 29.26[‐CH2‐],
29.00[‐CH2‐], 26.13[‐CH2‐], 26.02[‐CH2‐], 24.36[‐CH2‐];
MS (ESI) m/z: calcd for [C28H33185ReO7] 666.61; found (M
+H+,185 Re) 667.5 (M + H+,187 Re) 669.5. HRMS (ESI)
m/z: found (M+Na+,185 Re) 689.1642 (M+Na+,187 Re)
691.1667. Elemental analysis, found: C, 50.44; H, 5.56.
Calculated for C28H33185ReO7: C, 50.05; H, 5.00.
J = 6.4 Hz, 1H, ‐phenyl), 6.79(m, 3H, ‐phenyl), 5.98 (s,
2H, ‐Re‐Cp‐H(α)), 5.38 (s, 2H, ‐Re‐Cp‐H(β)), 3.97 (t,
J = 6.5 Hz, 2H, ‐O‐CH2‐), 2.90 (t, J = 7.7 Hz, 2H, ‐
C = O‐CH2‐), 2.69 (t, J = 7.8 Hz, 2H, ‐O‐CH2‐CH2‐), 2.61
(t, J = 7.2 Hz, 2H, ‐C = O‐CH2‐), 1.67 to 1.80 (m, 4H, ‐
C = O‐CH2‐CH2‐), 1.30 to 1.41 (m, 12H, ‐CH2‐); 13CNMR
(100 MHz, CDCl3) δ 196.68[‐Re‐C = O], 192.45[‐Re‐
C = O], 175.58[‐COOH], 159.54[phenyl], 142.50[phenyl],
129.23[phenyl], 120.30[phenyl], 114.58[phenyl], 112.08
[phenyl], 96.32[‐Re‐C‐C = O], 88.65[‐Re‐Cp(α)], 85.94[‐
Re‐Cp(β)], 67.68[‐O‐CH2‐], 38.36[‐C = O‐CH2‐], 35.53[‐
C = O‐CH2‐], 30.89[‐CH2‐], 29.38[‐CH2‐], 29.32[‐CH2‐],
29.27[‐CH2‐], 29.25[‐CH2‐], 28.88[‐CH2‐], 25.96[‐CH2‐],
24.47[‐CH2‐]; MS (ESI) m/z: calcd for [C28H33185ReO7]
666.61; found (M+H+,185 Re) 667.3 (M + H+,187 Re)
669.3. HRMS (ESI) m/z: found (M+Na+,185 Re) 689.1641
(M+Na+,187 Re) 691.1670. Elemental analysis, found: C,
50.16; H, 5.30. Calculated for C28H33185ReO7: C, 50.05; H, 5.00.
SCHEME 1 The synthetic route of the rhenium and technetium‐99 m complexes. aReaction conditions: (a) NH4ReO4, Cr(CO)6, CrCl3,
CH3OH, 180°C, 1 h; (b) 0.3N NaOH‐CH3OH(1:3), 80°C, 40 min; (c) Na99mTcO4, Mn(CO)5Br, DMF, 150°C, 1 h; (d) 0.3N NaOH‐CH3OH
(1:3), 80°C, 10 min

LIU ET AL.
7
[phenyl], 96.20[‐Re‐C‐C = O], 87.90[‐Re‐Cp(α)], 85.14[‐
Re‐Cp(β)], 68.25[‐O‐CH2‐], 38.81[‐C = O‐CH2‐], 31.90
[‐CH2‐], 29.76[‐CH2‐], 29.60[‐CH2‐], 29.54[‐CH2‐], 29.51
[‐CH2‐], 29.41[‐CH2‐], 29.27[‐CH2‐], 29.04[‐CH2‐], 27.20
[‐CH2‐], 25.92[‐CH2‐], 24.36[‐CH2‐], 22.68[‐CH2‐]; MS
(ESI) m/z: calcd for [C26H29185ReO7] 638.55; found (M+H
+,185 Re) 639.1 (M+H+,187 Re) 641.1. HRMS (ESI) m/z:
found (M+Na+, 185 Re) 661.1330 (M+Na+,187 Re)
653.1361. Elemental analysis, found: C, 48.16; H, 5.52.
Calculated for C26H29185ReO7: C, 48.90; H, 4.59.
3.15 | Synthesis of tricarbonyl 3‐(4‐((11‐
cyclopentadienyl‐11‐oxodecyl)oxy) benzoic acid)
rhenium (6c)
Prepared using the procedure stated as for 1c, starting from
Compound 6b (76 mg), NH4ReO4 (24 mg, 8.8 mmol), Cr
(CO)6 (102.4 mg, 0.5 mmol), and CrCl3 (24 mg, 0.15 mmol)
with dry methanol (1 mL) to give 6c (25 mg, 0.04 mmol,
1
26.1%) as a gray solid. HNMR(400 MHz,CDCl3) δ 7.12(d,
J = 8.4 Hz, 2H, ‐phenyl), 6.83 (d, J = 8.4 Hz, 2H, ‐phenyl),
5.98 (s, 2H, ‐Re‐Cp‐H(α)), 5.38 (s, 2H, ‐Re‐Cp‐H(β)), 3.92
(t, J = 6.5 Hz, 2H, ‐O‐CH2‐), 2.89 (t, J = 7.6 Hz, 2H, ‐
C = O‐CH2‐), 2.64 (t, J = 7.8 Hz, 2H, ‐O‐CH2‐CH2‐), 2.58
(t, J = 7.2 Hz, 2H, ‐C = O‐CH2‐), 1.66 to 1.77 (m, 4H, ‐
C = O‐CH2‐CH2‐), 1.29 to 1.44 (m, 12H, ‐CH2‐); 13CNMR
(100 MHz, CDCl3) δ 195.31[‐Re‐C = O], 191.86[‐Re‐
C = O], 169.95[‐COOH], 163.55[phenyl], 132.25[phenyl],
129.90[phenyl], 121.27[phenyl], 116.36[phenyl], 114.18
4 | RADIOCHEMICAL SYNTHESIS
The synthesis of the radiotracers (1d, 2d, 3d, 4d, 5d, and 6d)
and the corresponding rhenium compounds were outlined in
Scheme 1. A quantity of 1.5 mg of precursors and 4.5 mg of
Mn(CO)5Br in 1 mL of DMF were placed in a 10‐mL sealed
FIGURE 1 HPLC profiles of 99mTc/Re‐labeled fatty acids
TABLE 1 HPLC retention time of 99mTc/Re‐labeled fatty acids
Compound
Retention time, min
Compound
Retention time, min
1c
2c
3c
4c
5c
6c
18.57
20.05
24.87
22.67
19.43
18.67
1d
2d
3d
4d
5d
6d
20.49
22.40
26.93
23.33
20.62
19.94

8
LIU ET AL.
vial. A 99mTcO4− aqueous solution (20 mCi) was added, then
the mixture was maintained at 150°C for 1 hour. After cooled
to room temperature in an ice bath, the residue was extracted
with dichloromethane, and the solvent was removed under a
stream of N2. Hydrolysis of the 99mTc‐labeled complex was
performed in methanol (1 mL) and 0.3M NaOH at 80°C for
10 minutes. After the pH was adjusted to 7 with 1M HCl
and extraction was performed with dichloromethane, the final
99mTc‐labeled compounds were purified using HPLC after
passing through a 0.22 μm Millipore filter. ([Semipreparative
column, Venusil MP C‐18, 5 μm, 10 mm × 250 mm] using
isocratic elution system [CH3CN/H2O = 90/10: mobile phase
A is water at a rate of 0.2 mL/min, while mobile phase B is
acetonitrile at a rate of 1.8 mL/min] and UV [254 nm])
aReaction conditions: A, NH4ReO4, Cr(CO)6, CrCl3,
CH3OH, 180°C, 1 hour; B, 0.3 N NaOH‐CH3OH(1:3), 80°C,
40 minutes; C, Na99mTcO4, Mn(CO)5Br, DMF, 150°C, 1 hour;
D, 0.3 N NaOH‐CH3OH(1:3), 80°C, 10 minutes
6 | BIODISTRIBUTION STUDIES
Normal female mice (Chinese Kunming, 18‐22 g, n = 5)
were fasted for 12 hours, then purified 99mTc‐labeled
complex (1d, 2d, 3d, 4d, or 5d) (100 μL, 10 μCi) dissolved
in saline was injected into the tail veins. The mice were
sacrificed at predetermined time points (1, 5, 15, 30, or
60 min). Organs and tissue samples of interest were obtained,
weighed, and counted. Data were expressed as the percentage
of injected dose per gram of tissue (% ID/g).
7 | DISTRIBUTION COEFFICIENT
(LogD7.4
)
Purified labeled complex (1d, 2d, 3d, 4d, or 5d) (100 μL,
10 μCi) was vortexed for 5 minutes with 1 mL of n‐octanol
and 0.9 mL of phosphate‐buffered saline (PBS; pH 7.4).
After centrifugation for 5 minutes at 3500 rpm, samples from
the 2 separated layers were collected, and radioactivity and
weight were measured. The logD(7.4) value of the complex
was calculated as the logarithm of the ratio of counts per
5 | SERUM STABILITY
For us to evaluate the stability of the 99mTc‐labeled complexes
(1d, 2d, 3d, 4d, or 5d) in rat serum, in vitro 200 μCi
radiotracers was added to 1 mL of rat serum. The mixture
was incubated at 37°C for 3 hours, and then 300 μL of cold
acetonitrile was added to precipitate the serum proteins. After
centrifugation (10 min, 3500 rpm), the supernatant was
passed through a 0.22 μm Millipore filter and analysed using
radio‐HPLC.
TABLE 2 The distribution coefficient of 99mTc‐labeled fatty acids
Compound
LogD(7.4)
Compound
LogD(7.4)
1d
2d
3d
1.26 Æ 0.04
1.42 Æ 0.01
1.65 Æ 0.01
4d
5d
6d
1.39 Æ 0.01
1.40 Æ 0.03
Not determined
FIGURE 2 Serum stability of 99mTc‐labeled complexes (1d, 2d, 3d, 4d, and 5d)

LIU ET AL.
9
TABLE 3 Biodistribution of radioactivity after intravenous injection of 1d, 2d, 3d, 4d, and 5d (expressed as % injected dose per gram. Average for
5 mice Æ standard deviation)
1d
1 min
5 min
15 min
30 min
60 min
Blood
13.47 Æ 0.90
0.86 Æ 0.01
11.07 Æ 0.07
22.44 Æ 1.00
5.11 Æ 0.29
27.02 Æ 2.12
8.69 Æ 0.06
2.41 Æ 0.11
2.23 Æ 0.001
0.82
1.74 Æ 0.13
0.66 Æ 0.03
3.34 Æ 0.37
44.73 Æ 1.99
11.57 Æ 0.39
10.73 Æ 0.44
10.77 Æ 0.38
1.52 Æ 0.01
1.68 Æ 0.18
1.92
0.92 Æ 0.05
0.59 Æ 0.04
2.18 Æ 0.21
47.03 Æ 1.01
8.06 Æ 0.68
9.18 Æ 0.47
11.74 Æ 0.28
0.87 Æ 0.31
1.07 Æ 0.16
2.37
0.77 Æ 0.07
0.45 Æ 0.04
1.40 Æ 0.004
40.83 Æ 2.09
4.84 Æ 0.31
9.37 Æ 0.23
10.21 Æ 0.66
0.45 Æ 0.02
0.52 Æ 0.02
1.81
0.56 Æ 0.006
0.25 Æ 0.003
0.50 Æ 0.03
35.21 Æ 1.08
3.16 Æ 0.42
7.08 Æ 0.27
9.28 Æ 0.28
0.41 Æ 0.12
0.59 Æ 0.12
0.89
Brain
Heart
Liver
Spleen
Lung
Kidney
Muscle
Bone
Heart to blood
Heart to liver
Heart to lung
2d
0.49
0.07
0.05
0.03
0.01
0.41
0.31
0.24
0.15
0.07
1 min
5 min
15 min
30 min
60 min
Blood
7.18 Æ 0.25
0.51 Æ 0.04
9.59 Æ 0.15
23.19 Æ 1.40
3.65 Æ 0.08
9.75 Æ 0.18
9.31 Æ 0.75
2.63 Æ 0.03
2.04 Æ 0.26
1.33
1.21 Æ 0.04
0.35 Æ 0.03
6.20 Æ 0.55
36.89 Æ 3.05
1.55 Æ 0.32
2.63 Æ 0.25
9.52 Æ 0.98
1.85 Æ 0.22
1.05 Æ 0.05
5.12
0.66 Æ 0.24
0.37 Æ 0.01
2.19 Æ 0.33
42.77 Æ 0.62
0.99 Æ 0.01
1.65 Æ 0.10
10.64 Æ 0.66
0.75 Æ 0.17
0.63 Æ 0.22
3.32
0.45 Æ 0.02
0.31 Æ 0.02
1.25 Æ 0.13
35.00 Æ 0.40
0.62 Æ 0.05
1.41 Æ 0.13
9.64 Æ 0.27
0.72 Æ 0.20
0.81 Æ 0.05
2.78
0.46 Æ 0.15
0.30 Æ 0.02
0.63 Æ 0.03
25.26 Æ 1.64
0.94 Æ 0.26
1.11 Æ 0.11
9.96 Æ 0.12
0.36 Æ 0.001
0.35 Æ 0.02
1.37
Brain
Heart
Liver
Spleen
Lung
Kidney
Muscle
Bone
Heart to blood
Heart to liver
Heart to lung
3d
0.41
0.17
0.05
0.04
0.02
1.00
2.36
1.33
0.89
0.57
1 min
5 min
15 min
30 min
60 min
Blood
16.11 Æ 0.70
0.44 Æ 0.01
8.31 Æ 0.58
46.62 Æ 3.14
4.38 Æ 0.82
14.66 Æ .036
6.95 Æ 0.33
2.44 Æ 0.20
3.68 Æ 0.35
0.52
1.39 Æ 0.02
0.80 Æ 0.31
4.71 Æ 0.24
50.60 Æ 1.10
20.03 Æ 0.57
4.84 Æ 0.24
6.29 Æ 0.17
1.90 Æ 0.39
2.19 Æ 0.02
3.39
0.91 Æ 0.09
0.22 Æ 0.03
3.06 Æ 0.25
51.86 Æ 2.95
9.57 Æ 0.93
2.09 Æ 0.25
6.82 Æ 0.03
0.92 Æ 0.02
1.31 Æ 0.50
3.36
0.73 Æ 0.03
0.33 Æ 0.05
2.99 Æ 0.17
61.14 Æ 4.61
5.84 Æ 0.24
1.24 Æ 0.05
9.53 Æ 0.41
1.04 Æ 0.10
1.22 Æ 0.34
4.09
0.70 Æ 0.01
0.23 Æ 0.03
1.43 Æ 0.05
48.39 Æ 0.51
1.71 Æ 0.12
1.63 Æ 0.06
10.69 Æ 0.18
0.46 Æ 0.15
0.54 Æ 0.08
2.04
Brain
Heart
Liver
Spleen
Lung
Kidney
Muscle
Bone
Heart to blood
Heart to liver
Heart to lung
0.18
0.09
0.06
0.05
0.03
0.57
0.97
1.46
2.41
0.88
(Continued)

10
LIU ET AL.
TABLE 3 (Continued)
4d
1 min
5 min
15 min
30 min
60 min
Blood
16.81 Æ 0.77
0.80 Æ 0.09
10.22 Æ 0.98
25.62 Æ 2.69
3.27 Æ 0.63
17.16 Æ 0.57
9.45 Æ 0.59
2.30 Æ 0.51
2.38 Æ 0.39
0.61
3.63 Æ 0.54
0.44 Æ 0.05
3.54 Æ 0.65
43.42 Æ 0.92
4.21 Æ 0.41
6.91 Æ 0.34
8.52 Æ 0.94
1.73 Æ 0.14
2.02 Æ 0.41
0.98
1.44 Æ 0.005
0.31 Æ 0.02
1.25 Æ 0.06
45.89 Æ 0.62
1.92 Æ 0.09
3.38 Æ 0.38
8.91 Æ 0.11
1.22 Æ 0.10
1.19 Æ 0.27
0.89
1.10 Æ 0.18
0.59 Æ 0.05
1.66 Æ 0.006
37.93 Æ 0.72
3.14 Æ 0.28
3.44 Æ 0.74
9.08 Æ 0.02
2.19 Æ 0.06
3.25 Æ 0.67
1.51
0.40 Æ 0.15
0.37 Æ 0.03
1.12 Æ 0.10
42.12 Æ 1.58
2.29 Æ 0.27
2.64 Æ 0.10
10.98 Æ 0.92
1.01 Æ 0.13
2.96 Æ 0.35
2.80
Brain
Heart
Liver
Spleen
Lung
Kidney
Muscle
Bone
Heart to blood
Heart to liver
Heart to lung
5d
0.40
0.08
0.03
0.04
0.03
0.60
0.51
0.37
0.48
0.42
1 min
5 min
15 min
30 min
60 min
Blood
9.21 Æ 0.33
0.69 Æ 0.03
10.57 Æ 0.63
27.02 Æ 2.93
3.06 Æ 0.35
13.64 Æ 0.74
7.80 Æ 0.58
2.04 Æ 0.16
1.68 Æ 0.46
1.15
1.32 Æ 0.08
0.39 Æ 0.02
3.43 Æ 0.51
43.32 Æ 2.42
1.43 Æ 0.29
3.84 Æ 0.18
7.98 Æ 0.15
1.37 Æ 0.05
1.05 Æ 0.03
2.60
0.57 Æ 0.10
0.45 Æ 0.06
1.45 Æ 0.13
42.58 Æ 0.94
1.20 Æ 0.14
1.93 Æ 0.07
8.50 Æ 0.19
2.45 Æ 0.40
0.82 Æ 0.50
2.54
0.47 Æ 0.03
0.40 Æ 0.05
0.84 Æ 0.10
36.74 Æ 1.14
0.70 Æ 0.04
1.55 Æ 0.03
11.46 Æ 0.68
0.61 Æ 0.02
0.66 Æ 0.07
1.79
0.23 Æ 0.01
0.29 Æ 0.01
0.60 Æ 0.06
32.29 Æ 1.53
0.65 Æ 0.007
1.57 Æ 0.25
10.70 Æ 0.05
0.54 Æ 0.02
0.59 Æ 0.12
2.61
Brain
Heart
Liver
Spleen
Lung
Kidney
Muscle
Bone
Heart to blood
Heart to liver
Heart to lung
0.39
0.08
0.03
0.02
0.02
0.77
0.89
0.75
0.54
0.38
gram of n‐octanol to those of PBS. The distribution coeffi-
cient experiment was performed in triplicate.
9 | RESULTS AND DISCUSSION
The retention time of 99mTc‐labeled FAs was verified by
comparison with nonradioactive rhenium (Re) compounds
using HPLC (Figure 1). HPLC retention times of Re‐
and 99mTc‐labeled FA analogue were outlined in
Table 1. Stability studies (Figure 2) demonstrated that
the Tc‐99 m complexes were highly stable in rat serum
at 37°C for 3 hours. The logD7.4 values were used to
evaluate the lipophilicity of the compounds.19,20 Usually,
the lipophilic radiotracers such as 99mTc‐Cp‐TT‐15‐oxo‐
PTA (logD7.4 = 1.10 Æ 0.03) have high‐myocardial selec-
tivity. The logD7.4 values of the 5 Tc‐99 m complexes
(Table 2) showed that they were lipophilic radiotracers.
Strong correlation was observed between lipophilicity of
the 99mTc‐labeled FAs and the FA chain length. 3d exhib-
ited a slightly higher logD7.4 value than other compounds,
8 | ANALYSIS OF METABOLITES
Radiotracer 2b (500 μCi, 200 μL) was injected into the tail
vein of 12 hours fasted mice (Sprague Dawley, 200‐250 g).
Mice were sacrificed at predetermined time points (5, 30, or
60 min). Samples of the heart, blood, liver, and urine were
collected. After being washed with saline, the samples were
placed in 500 μL of cold PBS and homogenized for
2 minutes, then the blood was centrifuged at 3500 rpm for
5 minutes. Cold acetonitrile (500 μL) was added to precipi-
tate the proteins. After centrifugation, the supernatant was
passed through a 0.22 μm organic Millipore filter and
analyzed using radio‐HPLC.

LIU ET AL.
11
which indicated that 3d was more lipophilic. The
biodistribution results showed that 3d presented the best
myocardial retention.
compound 2d had superior heart to blood ratio and heart to
liver ratio. Those 99mTc‐complexes presented fast heart wash-
out with time like in the blood and the lungs. Heart retention
and heart to liver ratio of all the complexes in this study
remained unsatisfactory similar to other 99mTc‐labled FAs.
Cyclopentadienyl tricarbonyl 99mTc‐branched FA analogues
10 | BIODISTRIBUTION STUDIES
(
99mTc‐CpTT‐16‐oxo‐HDA (Table 4) and compound 2d)
Biodistribution data (Table 3) confirmed that the complexes
exhibited rapid blood with lung washout and high initial
heart uptake. Because liver washout was considered as an
important issue for the development of a suitable metabolic
myocardial imaging agent, it was unfortunate that liver wash-
out was poor. Compound 3d displayed a suitable heart uptake
with slow clearance. Radioactivity accumulation in the kid-
ney remained constant over time, and there was low radioac-
tivity observed in the brain, spleen, muscle, and bone. The
results (Figure 3) indicated that compound 3d exhibited
prolonged heart retention, and compound 2d showed higher
initial heart uptake (heart uptake % ID/g ratio of 2d:3d:
9.59:8.31 at 1 min after injection, 6.20:4.71 at 5 min after
injection, 2.19:3.06 at 15 min after injection, 1.25:2.99 at
30 min after injection, 0.63:1.43 at 60 min after injection;
heart to blood ratio of 2d:3d: 1.33:0.52 at 1 min after injec-
tion, 5.12:3.39 at 5 min after injection, 3.32:3.36 at 15 min
after injection, 2.78:4.09 at 30 min after injection, 1.37:2.04
at 60 min after injection). The most important characteristics
for myocardial SPECT imaging were high uptake and reten-
tion, and the rate of clearance from nontarget organs was also
essential, such as blood, lungs, and liver. Figure 3 showed the
heart to blood ratio, heart to liver ratio, and heart to lungs
ratio. All the 5 99mTc‐complexes exhibited a similar biologi-
cal behavior in rapid blood clearance, which leaded to high
heart to blood ratio. Compared with other complexes,
showed optimal characteristics in the rate of elimination from
blood and slightly prolonged myocaidial retention, the possi-
ble reason was that the advantages of 99mTc‐CpTT core.
11 | METABOLIC ANALYSIS
The analysis of radioactive metabolites was performed with
urine samples using previously reported methods.21,22
Magata7 first demonstrated that FAs were metabolized via
beta‐oxidation in the myocardium. The in vivo metabolic sta-
bility was analyzed using radio‐HPLC, the results was shown
in Figure 4. It indicated that there was one metabolite with
the retention time of 4.39 minutes in the myocardium and
liver; the other radioactivity peak was that for compound
2d. The observed radioactive peak at retention time of
4.39 minutes was similar to that of 6d. It is likely that 6d
may be present as a metabolite of 2d as a result of β‐oxidation
in tissue, as described previously for [99mTc]Tricarbonyl(15‐
cyclopentadienyl pentadecanoic acid) technetium (99mTc‐
CpTT‐PA).23 Five minutes after intravenous administration
of compound 2d, more than 50% of compound 2d was found
in the heart and liver. Radioactivity in blood washed out
quickly, which was consistent with the results of the
biodistribution study. The amount of metabolized product
increased with time and a small amount of compound 2b
FIGURE 3 Comparison of (A) heart to blood ratio, (B) heart to lung ratio and (C) heart to liver ratio of 1d, 2d, 3d, 4d, with 5d
TABLE 4 Myocardial uptake data of 99mTc‐CpTT‐16‐oxo‐HDA10
Radiotracer
Heart
Heart to blood ratio
Heart to liver ratio
Animal
99mTc‐CpTT‐16‐oxo‐HDA
9.03 (1 min)
5.41 (5 min)
4.12 (10 min)
2.16 (30 min)
1.64
2.13
3.27
3.72
0.35
0.16
0.11
0.06
ICR mice

12
LIU ET AL.
FIGURE 4 Metabolite analysis of heart, urine, blood, and liver samples after administration 2d. (A) HPLC analyses of 2d and 6d A, (B) 5 min
tissue samples, (C) 30 min tissue samples, (D) 60 min tissue samples. (Analytical column, Agela Venusil MP C18, 150*4.6 mm, 5 μm) using
isocratic elution system (mobile phase A is water at a rate of 0 mL/min, while mobile phase B is acetonitrile at a rate of 0.7 mL/min) and UV (254 nm)
remained 60 minutes after injection. The radioactive metabo-
lite and compound 2b were excreted into urine.
additional CH2‐group displayed the most prolonged retention
time. However, because liver uptake was high and elimination
was slow, these 99mTc‐labeled FAs were unsuitable for
diagnostic application. Biological evaluation of the metabolic
analysis results demonstrated that compound 2d may the
final radio‐metabolite by β‐oxidation and was eliminated
in urine.
12 | CONCLUSIONS
New Tc‐99 m complexes were successfully prepared and eval-
uated. The final radiochemical yield was 32.65% to 38.56%,
and radiochemical purity was more than 95% after HPLC
purification. The stability and molecular size of the
cyclopentadienyl tricarbonyl technetium‐99 m branched FAs
were suitable for the myocardium. The FA analogues
displayed high‐heart uptake with rapid clearance from lung,
blood, and spleen. Compound 2d (n = 10) exhibited a
superior initial heart uptake and compound 3d with an
ACKNOWLEDGEMENTS
We gratefully acknowledged the Significant New Drugs
Development (grant 2014ZX09507007001), Natural Science
Foundation of China (21371026) and Science and
Technology Support Program (2014BAA03B03) for finan-
cial support.

LIU ET AL.
13
14. Mirtschink P, Stehr SN, Pietzsch HJ, et al. Modified “4 + 1” mixed
ligand technetium‐labeled fatty acids for myocardial imaging: evalu-
ation of myocardial uptake and biodistribution. Bioconjug Chem.
2008;19:97‐108.
CONFLICT OF INTEREST
The authors did not report any conflict of interest.
15. Alberto R. The chemistry of technetium‐water complexes within the
manganese triad: challenges and perspectives. Eur J Inorg Chem.
2009;1:21‐31.
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