Preparation and biodistribution of [18F]FP2OP as myocardial perfusion imaging agent for positron emission tomography

Article abstract of DOI:10.1016/j.bmc.2009.12.022

Myocardial extractions of pyridaben, a mitochondrial complex I (MC-I) inhibitor, is well correlated with blood flow. Based on the synthesis and characterization of pyridaben analogue 2-tert-butyl-5-[2-(2-[¹⁸F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([¹⁸F]FP2OP), this study assessed its potential to be developed as myocardial perfusion imaging (MPI) agent. Methods: The tosylate labeling precursor 2-(2-(4-(tert-butyl-5-chloro-6-oxo-1,6-dihydro-pyridazin-4-yloxymethyl)benzyloxy)ethoxy)ethyl ester (OTs-P2OP) and the nonradioactive 2-tert-butyl-5-[2-(2-[¹⁹F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([¹⁹F]FP2OP) were synthesized and characterized by IR, ¹H NMR, ¹³C NMR and MS analysis. By substituting tosyl of precursor OTs-P2OP with ¹⁸F, the radiolabeled complex [¹⁸F]FP2OP was prepared and further evaluated for its in vitro physicochemical properties, in vivo biodistribution, the metabolic stability in mice, ex vivo autoradiography and cardiac PET/CT imaging. Results: Starting with [¹⁸F]F^- Kryptofix 2.2.2./K₂CO₃ solution, the total reaction time for [¹⁸F]FP2OP was about 100 min, with final high-performance liquid chromatography purification included. Typical decay-corrected radiochemical yield stayed at 41 ± 5.3%, the radiochemical purity, 98% or more. Biodistribution in mice showed that the heart uptake of [¹⁸F]FP2OP was 41.90 ± 4.52%ID/g at 2 min post-injection time, when the ratio of heart/liver, heart/lung and heart/blood reached 6.83, 9.49 and 35.74, respectively. Lipophilic molecule was further produced by metabolized [¹⁸F]FP2OP in blood and urine at 30 min. Ex vivo autoradiography demonstrates that [¹⁸F]FP2OP may have high affinity with MC-I and that can be blocked by [¹⁹F]FP2OP or rotenone (a known MC-I inhibitor). Cardiac PET images were obtained in a Chinese mini-swine at 5, 15, 30 and 60 min post-injection time with high quality. Conclusion: [¹⁸F]FP2OP was synthesized with high radiochemical yield. The promising biological properties of [¹⁸F]FP2OP suggest high potential as MPI agent for positron emission tomography in the future.

Full text of DOI:10.1016/j.bmc.2009.12.022

Bioorganic & Medicinal Chemistry 18 (2010) 1312–1320
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Preparation and biodistribution of [18F]FP2OP as myocardial perfusion
imaging agent for positron emission tomography
Tiantian Mou a, Huihui Jing a, Wenjiang Yang a, Wei Fang b, Cheng Peng c, Feng Guo b,
a
c
Xianzhong Zhang a, , Yan Pang , Yunchuan Ma
*
a Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, 19 Xinjiekou Outer St., Beijing 100875, China
b Department of Nuclear Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences, Beijing 100037, China
c PET Center of Xuan Wu Hospital, Capital Medical University, Beijing 100053, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Myocardial extractions of pyridaben, a mitochondrial complex I (MC-I) inhibitor, is well correlated with
Received 15 October 2009
Revised 6 December 2009
Accepted 8 December 2009
Available online 26 December 2009
blood flow. Based on the synthesis and characterization of pyridaben analogue 2-tert-butyl-5-[2-(2-
[
potential to be developed as myocardial perfusion imaging (MPI) agent.
Methods: The tosylate labeling precursor 2-(2-(4-(tert-butyl-5-chloro-6-oxo-1,6-dihydro-pyridazin-4-
yloxymethyl)benzyloxy)ethoxy)ethyl ester (OTs-P2OP) and the nonradioactive 2-tert-butyl-5-[2-(2-
18F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([18F]FP2OP), this study assessed its
Keywords:
[
19F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([19F]FP2OP) were synthesized and
Positron emission tomography
Myocardial perfusion imaging
characterized by IR, 1H NMR, 13C NMR and MS analysis. By substituting tosyl of precursor OTs-P2OP with
18F, the radiolabeled complex [18F]FP2OP was prepared and further evaluated for its in vitro physico-
chemical properties, in vivo biodistribution, the metabolic stability in mice, ex vivo autoradiography
and cardiac PET/CT imaging.
[
18F]FP2OP
Mitochondria complex I
Results: Starting with [18F]FÀ Kryptofix 2.2.2./K2CO3 solution, the total reaction time for [18F]FP2OP was
about 100 min, with final high-performance liquid chromatography purification included. Typical
decay-corrected radiochemical yield stayed at 41 5.3%, the radiochemical purity, 98% or more. Biodis-
tribution in mice showed that the heart uptake of [18F]FP2OP was 41.90 4.52%ID/g at 2 min post-injec-
tion time, when the ratio of heart/liver, heart/lung and heart/blood reached 6.83, 9.49 and 35.74,
respectively. Lipophilic molecule was further produced by metabolized [18F]FP2OP in blood and urine
at 30 min. Ex vivo autoradiography demonstrates that [18F]FP2OP may have high affinity with MC-I
and that can be blocked by [19F]FP2OP or rotenone (a known MC-I inhibitor). Cardiac PET images were
obtained in a Chinese mini-swine at 5, 15, 30 and 60 min post-injection time with high quality.
Conclusion: [18F]FP2OP was synthesized with high radiochemical yield. The promising biological proper-
ties of [18F]FP2OP suggest high potential as MPI agent for positron emission tomography in the future.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
emission computed tomography (SPECT), including higher spatial
resolution, improved attenuation correction, and the capability to
Coronary artery disease (CAD) is the leading cause of death in
developed countries and is a serious health problem worldwide.
Myocardial perfusion imaging (MPI), an aid in clinical diagnosis,
plays an important role in noninvasive measurement of CAD. Cur-
rently, MPI is performed with six agents in clinic use: [201Tl]TlCl,
perform quantitative measurements at the peak of stress. Given
this situation, there is a well-recognized need for the development
of new perfusion tracers with more ideal properties for PET imag-
ing. Cardiac PET, accordingly, has an opportunity to become the
standard for evaluation of myocardial perfusion in coming years.3
Mitochondria, known as the powerhouse of the cell, are abun-
dant in tissues with large energy requirements, such as the heart,
where they take up 20–30% of the myocardial intracellular vol-
99mTc-sestamibi, 99mTc-tetrofosmin,
[ [
82Rb]RbCl, 13N]NH3, and
[
15O]H2O.1 The first three of these tracers being single-photon-
emitting agents, which serve as the mainstay of myocardial perfu-
sion imaging (MPI) tests.2 However, positron emission tomography
(PET) imaging provides certain advantages versus single-photon
ume.4 Therefore,
a
couple of MPI agents, such as 18FTPP,
[
18F]FBnTP, BMS-747158–02, take mitochondria as their target.2,5,6
Four electron transport complexes are located in the inner mito-
chondrial membrane, of which MC-I is the first enzyme. Recent
studies showed that 18F- or 125I-labeled MC-I inhibitors was highly
* Corresponding author. Tel.: +86 10 58802038; fax: +86 10 62208126.
E-mail addresses: zhangxzh@gmail.com, zhangxzh@bnu.edu.cn (X. Zhang).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.12.022

T. Mou et al. / Bioorg. Med. Chem. 18 (2010) 1312–1320
1313
correlated with flow.7–9 Accordingly, we designed a new [18F]-
labeled tracer based on pyridaben, one of MC-I inhibitors, for myo-
cardial perfusion imaging.
Here we report the synthesis and characterization of pyridaben
analogue 2-tert-butyl-5-[2-(2-[18F]fluroethoxy)ethoxy]benzyloxy]-
4-chloro-2H-pyridazin-3-one ([18F]FP2OP) as a potential myocar-
dial perfusion imaging (MPI) agent.
experiments were carried out using 0.025 mol/L phosphate buffer
(pH 7.4) and Xinhua 1# filter paper at 150 V for 180 min. Re-
versed-phase high-pressure liquid chromatography (RP-HPLC)
was performed on an Alltech system with Alltech HPLC pump
Model 626, LINEAR UVIS-201, and BIOSCAN flow-counter. The C-
18 reverse-phase Semi-Preparative HPLC column (10 Â 250 mm,
5 lm particle size, Venusil MP-C18, Agela Technologies Inc., USA)
was eluted at a flow rate of 5 mL/min. Labgen 7 homogenizer
was purchased from Cole-Parmer Instrument (USA).
2. Materials and methods
2.1. Materials
1H NMR spectra were recorded on a Bruker (400 MHz) spec-
trometer, while 13C NMR spectra were recorded on a Bruker
(100 MHz) spectrometer. Chemical shifts are reported in d (ppm)
values. Infrared spectra were measured on a Nicolet 360 Avatar
instrument using a potassium bromide (KBr) disk, scanning from
400 to 4000 cmÀ1. Mass spectra were recorded using a Brucker
Apex IV FTM instrument.
[
18F]FÀ was obtained from PET Center of Xuanwu Hospital (Bei-
jing, China). No-carrier-added [18F]FÀ was trapped on a QMA car-
tridges and eluted with 0.3 mL K2CO3 solution (10 mg/mL in H2O)
combined with 1 mL Kryptofix2.2.2. solution (Sigma–Aldrich)
(13 mg/mL in acetonitrile).10,11 Instant lyophilized Kit for 99mTc-
MIBI (MIBI = 2-methoxyisobutylisonitrile) preparation was do-
nated by Beijing SHIHONG Pharmaceutical Co., Ltd (Beijing, China).
99mTc-MIBI injection was prepared under Kit instruction. Rotenone
with 95% purity was purchased from Sigma–Aldrich. Other re-
agents and solvents were purchased from commercial suppliers
and were used without further purification. Paper electrophoresis
2.2. Preparation of 2,3-dichloro-4-oxo-2-butenoicacid (DCA)
The synthesis route of DCA, shown in Figure 1, is a slight mod-
ification of the procedure described by Feng et al.12
MnO2 (80 g, 0.9 mol) was added to concentrated hydrochloric
acid (480 mL, 5.8 mol) in portions with ice-bath cooling. Furfural
O
KI,K2CO3
Cyclohexanone,reflux
O
HO
Cl
O
O
OH
2
O
O
O
MB-PEG2
HO
O
CHO
HO
TBSCl
Imidazole
DMF
O
O
HO
DCA
LAH
Ether
OTBS
2
O
O
OTBS
2
SPE-PEG2
O
TBAF
THF
t-BuHNNH2 HCl
CH3COOH
MSB-PEG2
O
N
O
Cl
O
Cs2CO3
DMF
N
N
N
Cl
Cl DCP
OTBS
2
SB-P2OP
O
O
TBAF
THF
Cl
N
N
O
TsCl
DMAP
DIEA
DCM
Cl
O
N
OTs
n
N
O
O
OTs-P2OP
HB-P2OP
OH
n
O
[
18F]KF/K222
ACN, 90 oC
TBAF
ACN, 90 oC
O
O
Cl
Cl
N
N
N
N
O
O
19F
2
18F
2
[
19F]FP2OP
O
O
[
18F]FP2OP
Figure 1. The synthesis route of OTs-P2OP, nonradioactive [19F]FP2OP and [18F]FP2OP .

1314
T. Mou et al. / Bioorg. Med. Chem. 18 (2010) 1312–1320
(24 g, 0.25 mol) slowly dropped into the reaction flask at 0–10 °C,
stirring for 30 min, then heated to 60 °C. MnO2 (42 g, 0.5 mol)
was added in portion at 60–80 °C, heated to 100 °C, stirred until
the solution turned to orange, then cooled to room temperature.
After filtration, filter residue was dissolved in ether (40 mL), and
filtered again. Filtrate was concentrated in vacuo. The residue
was recrystalled from water (40 mL) to get DCA as a white crystal
(yield: 25 g, 59%). 1H NMR, 13C NMR and IR for DCA: 1H NMR
(400 MHz, CDCl3) d: 6.085 (s, 1H, HO–C–H); 13C NMR (100 MHz,
CDCl3) d: 98.56, 123.87, 151.25, 165.15; IR (KBr, cmÀ1) v: 3407
(O–H), 1770 (C@O), 1638 (C@C).
saturated NaHCO3 (20 mL for each extraction). The organic phase
was dried with MgSO4, filtered, and concentrated under reduced
pressure to give MSB-PEG2 as buff oil (yield: 1.07 g, 70%). 1H
NMR and IR for MSB-PEG2: 1H NMR (400 MHz, CDCl3) d: 0.000
(s, 6H, OSi(CH3)2), 0.824 (s, 9H, SiC(CH3)3), 3.567 (t, 2H, CH2CH2O-
Si), 3.726 (t, 2H, CH2CH2OSi), 3.813 (s, 3H, OCH3), 3.815 (t, 2H, phe-
nyl-O-CH2CH2), 4.099 (t, 2H, phenyl-O-CH2), 6.862 (d, 2H, O-
phenyl), 7.911 (d, 2H, CO-phenyl); IR (KBr, cmÀ1) v: 1723 (C@O),
1250 (@C–O–C), 1087 (C–O–C).
2.6. Preparation of 4-[2-(2-(tert-butyldimethylsiloxy)ethoxy)-
ethoxy]phenylethanol (SPE-PEG2)
2.3. Preparation of 2-tert-butyl-4.5-dichloro-2H-pyridazin-3-
one (DCP)
The synthesis route of SPE-PEG2 is based on the procedure de-
scribed by Caesbier et al.14 with a slight modification (Fig. 1).
The solution of MSB-PEG2 (1.07 g, 3 mmol in 15 mL ether) was
dropped slowly into the mixture of anhydrous ether (10 mL) and
LiAlH4 (0.28 g, 7.2 mmol), stirring in the ice bath for 2 h, then stir-
ring for another 2 h at room temperature. The water was dropped
slowly into the flask until no gas produced, and then the pH was
adjusted to 6. After filtered, filtrate was dried with MgSO4, filtered,
and concentrated to give SPE-PEG2 as buff oil (yield: 0.93 g, 95%).
1H NMR for SPE-PEG2: 1H NMR (400 MHz, CDCl3) d: 0.000 (s, 6H,
OSi(CH3)2), 0.815 (s, 9H, SiC(CH3)3), 3.580 (t, 2H, CH2CH2OSi),
3.672 (t, 2H, CH2CH2OSi), 3.775 (t, 2H, phenyl-O-CH2CH2), 4.046
(t, 2H, phenyl-O-CH2CH2), 4.466 (s, 2H, CH2–O–C@C–Cl), 6.807 (d,
2H, O-phenyl), 7.211 (d, 2H, CO-phenyl).
The synthesis route of DCP is shown in Figure 1. DCA (15 g,
0.09 mol) and Na2CO3 (4.5 g, 0.04 mol) were added to 150 mL
water in an ice bath, stirred until the reaction mixture became clar-
ifying. tert-Butyl hydrazine hydrochloride (11 g, 0.09 mol) was
added into the reaction flask and stirred for 2.5 h, then filtered.
The filter residue was washed by cool water, and transferred into
a 100 mL flask. Benzene (50 mL) and acetic acid (7 g) were added
to the flask above, and then the mixture was heated to 35–45 °C
and stirred for 4 h. The mixture was washed by 20 mL water and
then the organic phase was separated and washed by 20 mL NaOH
solution (1.25 mol/L), 20 mL HCl solution (3 mol/L) and 20 mL
water successively. The organic layer was dried with MgSO4, fil-
tered, and most of solvent removed under reduced pressure. The
residue was crystalled to get DCP as a buff crystal (yield: 7.6 g,
38%). 1H NMR and IR for DCP: 1H NMR (400 MHz, CDCl3) d: 1.648
(s, 9H, N(CH3)3), 7.729 (s, 1H, N@C–H); IR (KBr, cmÀ1) v: 3461
(O–H), 1658 (C@O).
2.7. Preparation of 2-tert-butyl-5-[2-(2-(tert-butyldimethylsiloxy)-
ethoxy)ethoxy]benzyloxy-4-chloro-2H-pyridazin-3-one (SB-P2OP)
The synthesis route of SB-P2OP, shown in Figure 1, is a slight
modification of the procedure described by Caesbier et al.14
Anhydrous DMF (10 mL) was added to the mixture of SPE-
PEG2 (0.38 g, 1.2 mmol), DCP (0.93 g, 4.2 mmol) and Cs2CO3
(1.37 g, 4.2 mmol), and stirred for 12 h at 68 °C in an oil bath.
After cooled to temperature, the reaction solution was diluted
with ethyl acetate (20 mL), and washed five times by saturated
NaCl solution (20 mL for each time). The organic phase was dried
with MgSO4, filtered, and concentrated under reduced pressure.
The residue was chromatographed over a column of silica gel
and eluted with the mixture of hexane and ethyl acetate 3:1 (v/
v). After removal of the solvents under vacuum, SB-P2OP was ob-
tained as buff oil (yield: 0.55 g, 90%). 1H NMR and IR for SB-P2OP:
1H NMR (400 MHz, CDCl3) d: 0.000 (s, 6H, OSi(CH3)2), 0.824
(s, 9H, SiC(CH3)3), 1.558 (s, 9H, N(CH3)3), 3.566 (t, 2H, CH2CH2OSi),
3.727 (t, 2H, CH2CH2OSi), 3.802 (t, 2H, phenyl-O-CH2CH2), 4.057
(t, 2H, phenyl-OCH2CH2), 5.177 (s, 2H, CH2–O–C@C–Cl), 6.876
(d, 2H, O-phenyl), 7.255 (d, 2H, CO-phenyl), 7.663 (s, 1H,
2.4. Preparation of methyl 4-[2-(2-hydroxyethoxy)ethoxy]-
benzoate (MB-PEG2)
The synthesis route of MB-PEG2, shown in Figure 1, is a slight
modification of the procedure described by Bender et al.13
Cyclohexanone (20 mL) was added to a mixture of methyl-4-
hydroxybenzoate (1 g, 6.57 mmol), KI (0.55 g, 3.29 mmol), and
K2CO3 (1.81 g, 13.1 mmol) with stirring under nitrogen. 2-(2-Chlo-
roethoxy)ethanol (1.8 mL, 17.0 mmol) was added into the reaction
flask, and refluxed with stirring for 1 d under nitrogen. The suspen-
sion was cooled to room temperature and filtered to remove the
solids. The yellow-orange filtrate was concentrated in vacuo. After
that, CH2Cl2 (15 mL) was added to the residue, filtered, and the fil-
trate was concentrated in vacuo again. The residue was chromato-
graphed over a column of silica gel and eluted with ether to give
the MB-PEG2 as buff oil (yield: 1.04 g, 66%). 1H NMR and IR for
MB-PEG2: 1H NMR (400 MHz, CDCl3) d: 2.072 (s, 1H, OH), 3.677
(t, 2H, CH2CH2OH), 3.769 (t, 2H, CH2CH2OH), 3.883 (s, 3H, OCH3),
3.886 (t, 2H, phenyl-O-CH2CH2), 4.191 (t, 2H, phenyl-O-CH2),
N@C-H); IR (CH2Cl2, cmÀ1
) v: 1649 (C@O), 1250 (@C–O–C),
1132 (C–O–C).
6.934 (d, 2H, O-phenyl), 7.986 (d, 2H, CO-phenyl); IR (KBr, cmÀ1
v: 3461 (O–H), 1715 (C@O), 1102 (C–O–C).
)
2.8. Preparation of 2-tert-butyl-5-[2-(2-hydroethoxy)ethoxy]-
benzyloxy]-4-chloro-2H-pyridazin-3-one (HB-P2OP)
2.5. Preparation of methyl 4-[2-(2-(tert-butyldimethylsiloxy)-
ethoxy)ethoxy]benzoate (MSB-PEG2)
The synthesis route of HB-P2OP, shown in Figure 1, is a slight
modification of the procedure described by Caesbier et al.14
Anhydrous tetrahydrofuran (3 mL) was added to the mixture
of SB-P2OP (552 mg, 1.1 mmol) and tert-butylammonium fluoride
(3 mmol in 3 mL tetrahydrofuran). After stirring for 2 h, the reac-
tion solution was diluted with ethyl acetate (20 mL), and ex-
tracted two times with saturated NaCl solution (20 mL for each
extraction). The organic layer was separated and dried with
MgSO4, filtered, and concentrated under reduced pressure. The
residue was chromatographed over a column of silica gel and
eluted with the mixture of CH2Cl2 and CH3OH 7:1 (v/v). After re-
The synthesis route of MSB-PEG2, shown in Figure 1, is a slight
modification of the procedure described by Caesbier et al.14
Anhydrous DMF (10 mL) was added into the mixture of imidaz-
ole (0.50 g, 7.2 mmol), MB-PEG2 (1.04 g, 4.3 mmol) and tert-butyl-
dimethylsilyl chloride (1.08 g, 7.4 mmol). After stirring in an oil
bath for 4 h at 80 °C, the reaction mixture was diluted with ethyl
acetate (20 mL) and extracted five times with saturated NaCl solu-
tion (20 mL for each extraction), then extracted two times with

T. Mou et al. / Bioorg. Med. Chem. 18 (2010) 1312–1320
1315
moval of the solvents under vacuum, HB-P2OP was obtained as
2.11. Preparation of 2-tert-butyl-5-[2-(2-[18F]fluroethoxy)-
ethoxy]benzyloxy-4-chloro-2H-pyridazin-3-one ([18F]FP2OP)
yellow oil (yield: 361 mg, 83%). 1H NMR and IR for HB-P2OP:
1H NMR (400 MHz, CDCl3) d: 1.532 (s, 9H, N(CH3)3), 3.586 (t,
2H, CH2CH2OH), 3.678 (t, 2H, CH2CH2OH), 3.785 (t, 2H, phenyl-
O-CH2CH2), 4.059 (t, 2H, phenyl-OCH2CH2), 5.153 (s, 2H, CH2–O–
C@C–Cl), 6.857 (d, 2H, O-phenyl), 7.240 (d, 2H, CO-phenyl),
7.636 (s, 1H, N@C–H); IR (CH2Cl2, cmÀ1) v: 3239 (O–H), 1643
(C@O), 1251 (@C–O–C), 1137 (C–O–C).
[
18F]FÀ was eluted from the QMA cartridges with the solution of
K2CO3 (3 mg in 0.3 mL H2O) combined with the solution of Krypto-
fix2.2.2 (13 mg in 1 mL acetonitrile). The liquid evaporated under a
stream of nitrogen at 110 °C. The labeling precursor OTs-P2OP
(2 mg, 3.6 lmol) was dissolved in anhydrous acetonitrile (1 mL)
and added to the above evaporation residue. After stirring for
30 min at 90 °C, it was cooled to room temperature and the solu-
tion was diluted with 9 mL water, and trapped on a C-18 Sep-Pak
cartridge. [18F]FP2OP was eluted to a 10 mL vial with 3 mL CH2Cl2.
After the solvent CH2Cl2 was removed under a stream of nitrogen
at 60 °C, the residue was dissolved in 0.5 mL acetonitrile and in-
jected onto a semi-HPLC column for purification. The column
was eluted with water (solvent A) and acetonitrile (solvent B) at
a flow rate of 5.0 mL/min. Gradient: 0–5 min: 95% A, 5.01–8 min:
95–60% A, 8.01–16 min: 60–35% A, 16.01–30 min: 0% A. The de-
sired product was collected from HPLC and the solvent evaporated
using a rotary evaporator. The product was redissolved in 5% eth-
2.9. Preparation of toluene-4-sulfonic acid 2-tert-butyl-4-
chloro-5-[2-(2-(tert-butyldimethylsilanyloxy)ethoxy)ethoxy]-
benzyloxy-2H-pyridazin-3-one (OTs-P2OP)
The synthesis route of OTs-P2OP, shown in Figure 1, is a
slight modification of the procedure described by Caesbier
et al.14
Anhydrous CH2Cl2 (3 mL) was added to the mixture of HB-P2OP
(361 mg, 0.91 mmol), TsCl (252 mg, 1.32 mmol), 4-dimethylami-
nopyridine (167 mg, 1.37 mmol) and N,N-diisopropylethylamine
(175 mg, 1.35 mmol). After stirring for 2 h, the reaction mixture
was diluted with ethyl acetate (20 mL), and filtered. The filtrate
was washed with 0.1 mol/L HCl (20 mL) and saturated NaCl solu-
tion (20 mL). The organic phase was separated and dried with
MgSO4, filtered, and concentrated under reduced pressure. The res-
idue was chromatographed over a column of silica gel and eluted
with the mixture of CH2Cl2 and CH3OH 100:1 (v/v). After removal
of the solvents under vacuum, OTs-P2OP was obtained as yellow
solid (yield: 260 mg, 51%). 1H NMR, ESI-MS and IR for OTs-P2OP:
1H NMR (400 MHz, CDCl3) d: 1.558 (s, 9H, N(CH3)3), 2.341 (s, 3H,
phenyl-CH3), 3.695 (t, 2H, CH2CH2OS), 3.729 (t, 2H, CH2CH2OS),
3.990 (t, 2H, phenyl-O-CH2CH2), 4.122 (t, 2H, phenyl-OCH2CH2),
5.180 (s, 2H, CH2–O–C@C–Cl), 6.850 (d, 2H, O-phenyl), 7.235 (d,
2H, CO-phenyl), 7.265 (d, 2H, phenyl-CH3), 7.666 (s, 1H, N@C–H),
7.723 (d, 2H, phenyl-SO3); ESI-MS calculated for C26H31ClN2O7S:
550.1. Found 551.2 [M+1]+; IR (CH2Cl2, cmÀ1) v: 1652 (C@O),
1249 (@C–O–C), 1092 (C–O–C).
anol solution, and filtered through a 0.22 lm Millipore filter.
Specific activity was calculated by measuring the radioactivity
of the product fraction in the dose calibrator and dividing the value
by the mass of the product as determined by the area under the UV
curve measured at 254 nm. Chemical and radiochemical purity was
checked by re-injection of the product onto a radio-HPLC, the
radioactive fraction was collected and radioactivity was measured.
2.12. Octanol/water partition coefficient15,16
The octanol/water partition coefficient of [18F]FP2OP was mea-
sured following 1 min vigorous vortex mixing of 500
and 500 L phosphate buffer (0.025 mol/L, pH 7.4), with approxi-
mately 74 kBq of radiotracer in a microcentrifuge tube. The tube
was centrifuged at 6000 rpm for 5 min and the counts in 100
lL octanol
l
lL
aliquots of both organic and aqueous layers were determined using
a 1470 Wizard™ Automatic Gamma Counter (Perkin-Elmer). The
measurement was repeated three times. Care was taken to avoid
cross contamination between the phases. The partition coefficient
(P) was calculated using the following equation: P = (cpm in the
octanol phase À background cpm)/(cpm in the aqueous phase À
background cpm). The partition coefficient value was expressed
as log P.
2.10. Preparation of nonradioactive 2-tert-butyl-5-[2-(2-
fluroethoxy)ethoxy]benzyloxy-4-chloro-2H-pyridazin-3-one
([19F]FP2OP)
The synthesis route of [19F]FP2OP, shown in Figure 1, is a slight
modification of the procedure described by Caesbier et al.14
The solution of tert-butylammonium fluoride (1 mmol in 1 mL
tetrahydrofuran) was added to a 25 mL flask. After evaporation in
a stream of nitrogen at 110 °C, the labeling precursor OTs-P2OP
(260 mg, 0.47 mmol in 3 mL anhydrous CH3CN) was added to the
above evaporation residue, and refluxed for 40 min at 90 °C. Then
the reaction solution was evaporated again and the residue was di-
luted with CH2Cl2 (15 mL), and washed with saturated NaCl solu-
tion (20 mL). After concentrated under reduced pressure, the
residue was chromatographed over a column of silica gel and
eluted with the mixture of CH2Cl2 and CH3OH 100:1 (v/v).
2.13. Stability study
Purified [18F]FP2OP solution (ꢀ3.7 MBq, in 100
lL water) was
incubated at room temperature for 1 h. The radiochemical purity
(RCP) was assayed by HPLC at 1 h after preparation. In order to test
the stability of
[
[
18F]FP2OP in organic solvent, the purified
18F]FP2OP (ꢀ3.7 MBq) was dissolved in 100
lL of 80% ethanol
solution and incubated at room temperature for 4 h. The radio-
chemical purity was assayed by HPLC at 4 h after preparation.
The stability in mouse plasma was determined by incubating
ꢀ3.7 MBq purified [18F]FP2OP in the solution of 0.5 mL murine
plasma at 37 °C for 1 h. Plasma proteins were precipitated by add-
[
19F]FP2OP was obtained as brown solid (yield: 150 mg, 80%). 1H
NMR, 13C NMR, 19F NMR, ESI-MS and IR for [19F]FP2OP: 1H NMR
(400 MHz, CDCl3) d: 1.554 (s, 9H, N(CH3)3), 3.744 (dt, 2H,
CH2CH2OF), 3.820 (t, 2H, phenyl-O-CH2CH2), 4.081 (t, 2H, phenyl-
OCH2CH2), 4.514 (dt, 2H, CH2CH2OF), 5.167 (s, 2H, CH2–O–C@C-
Cl), 6.873 (d, 2H, O-phenyl), 7.252 (d, 2H, CO-phenyl), 7.656 (s,
1H, N@C–H); 13C NMR (100 MHz; CDCl3) d: 26.87, 65.33, 66.57,
68.86, 69.60 (d, J = 9 Hz), 70.80, 82.11 (d, J = 84 Hz), 114.06,
117.32, 124.35, 126.20, 127.94, 152.78, 158.07, 158.17; 19F NMR
d: À222.86; ESI-MS calculated for C19H24ClFN2O4: 398.1. Found
399.1 [M+1]+; IR (CH2Cl2, cmÀ1) v: 1641 (C@O), 1242 (@C–O–C),
1091 (C–O–C).
ing 100 lL acetonitrile and removed by centrifugation at 6000 rpm
for 5 min at room temperature. The radiochemical purity was ana-
lyzed by HPLC.
2.14. Paper electrophoresis15
Paper electrophoresis experiments were performed on Xinhua
filter papers (10 cm  1 cm) which were pre-treated with phos-
phate buffer (0.025 mol/L, pH 7.4). The analyses were carried out
using phosphate buffer (0.025 mol/L, pH 7.4) at 150 V for

1316
T. Mou et al. / Bioorg. Med. Chem. 18 (2010) 1312–1320
180 min. The developed paper strips were left to dry and the distri-
bution of radioactivity on the strip was determined using a 1470
Wizard™ Automatic Gamma Counter.
2.18. Cardiac PET/CT imaging
All the animal protocols were approved by the Institute’s Ani-
mal Care and Use Committee. For PET study, a healthy Chinese
mini-swine (weight 15 kg) was anesthetized with an intravenous
of a mixture of ketamine (25 mg/kg) and diazepam (1.1 mg/kg).
Anesthesia was supplemented as needed.
2.15. Biodistribution study
All the animal studies were carried out in compliance with
relevant national laws relating to the conduct of animal experi-
mentation.
PET data were obtained using a PET/CT system (Biograph 64; Sie-
mens Healthcare). The animal was placed in a prone position on the
PET/CT bed, and a venous catheter was established for imaging agent
injection. 85 MBq of [18F]FP2OP in 2 mL 5% ethanol solution was in-
jected intravenously. The PET/CT scan was performed at 5, 15, 30 and
60 min after the tracer injection, respectively. After CT low dose scan
for attenuation correction (Tube voltage 120 kV, Tube Current 50
mAs with CareDose4D, Collimation 24 Â 1.2 mm, Rotation time 0.5
s, Pitch 1.2, Slice 3 mm), PET imaging for myocardial uptake evalua-
tion was acquired. List mode with ECG gating, the scan time was
8 min. The images were reconstructed with a conventional fil-
tered-back projection method using a Butterworth-ramp filter with
a cutoff frequency of 1.25 cmÀ1. The matrix size was 2.0 Â 2.0 mm
with128 Â 128pixels, and theslice thicknesswas 3.125 mm. There-
gions of interest (ROI) were placed on the myocardium, liver and
lung. The standardized uptake value (SUV) was calculated as follow:
SUV = [mean ROI count (cps/pixel) Â body weight (kg)]/[injected
dose (mCi) Â calibration factor (cps/pixel)].
The in vivo biodistribution study of [18F]FP2OP was carried out
in normal Kunming mice (18–20 g) obtained from the Animal Cen-
ter of Peking University. About 185 kBq [18F]FP2OP in 0.1 mL 5%
ethanol solution was injected through the tail vein (5 animals
per group). The mice were sacrificed at 2, 15, 30 and 60 min
post-injection and the tissues and organs of interest were col-
lected, wet weighed and counted in a 1470 Wizard™ Automatic
Gamma Counter. The percentage of injected dose per gram (% ID/
g) for each sample was calculated by comparing its activity with
that of an appropriate aliquot of the injection solution, the values
expressed as mean 1 standard deviation (SD).
In order to compare this new PET tracer ([18F]FP2OP) with the
traditional SPECT myocardial perfusion imaging agent: 99mTc-MIBI,
the biodistribution study of 99mTc-MIBI was performed at the same
condition described as above.
2.16. Metabolic stability17,10,18
3. Results
Normal Kunming mice (18–20 g) were intravenously injected
with 3.7 MBq of the [18F]FP2OP injection solution. The animals
were sacrificed and dissected at 2, 30 and 60 min after tracer injec-
tion. Blood was sampled after decapitation, and immediately cen-
trifuged at 6000 rpm for 5 min. Urine was sampled from the
urinary bladder, and directly diluted with 1 mL of phosphate buf-
fered saline (PBS) (0.025 mol/L, pH 7.4) and then passed through
a Sep-Pak C18 cartridge. The cartridges were washed with 0.5 mL
water and 0.5 mL methanol. Both of them were collected, passed
3.1. Chemistry
The precursor OTs-P2OP was synthesized according to Figure 1
with good yield and characterized by 1H NMR, ESI-MS and IR. The
preparation procedure of nonradioactive [19F]FP2OP is also shown
in Figure 1. The structure of the desired nonradioactive compound
was confirmed by 1H NMR, 13C NMR, 19F NMR, ESI-MS, and IR anal-
ysis. The HPLC chromatogram shows that [19F]FP2OP has a very
good chemical purity (>98% at k = 254 nm), with a retention time
of 21.7 min (Fig. 2A). Based on these results mentioned above, this
through a 0.22 lm Millipore filter, and injected onto a semi-pre-
parative HPLC column using a flow rate of 5 mL/min and the gradi-
ent described above. The heart was homogenized using a Labgen 7
homogenizer, suspended in 1 mL methanol, and centrifuged for
5 min at 13,000 rpm. After removal of the supernatants, the pellets
were washed with 0.5 mL of methanol. All the methanol solution
was passed through a Sep-Pak C18 cartridge, and washed with
0.5 mL water and 0.5 mL methanol. Both of them were collected,
[
19F]FP2OP compound is considered to be an acceptable referenced
standard for the radioactive compound [18F]FP2OP.
3.2. Radiochemistry
Starting from [18F]FÀ in a Kryptofix 2.2.2./K2CO3 solution, the to-
tal reaction time, including final HPLC purification, is about 100 min.
The overall radiochemical yield, corrected for decay is 41 5.3%
(n = 7), the RCP of the purified [18F]FP2OP, >98%. The [18F]FP2OP is
well separated from the precursor OTs-P2OP (with a retention time
of 24.7 min, the HPLC profile was shown in Figure 2C). The specific
activity of [18F]FP2OP is estimated by radio-HPLC to be about
passed through a 0.22 lm Millipore filter, and injected onto a
semi-preparative HPLC column using a flow rate of 5 mL/min and
the gradient described above.
2.17. Ex vivo autoradiography
Heart from a normal SD rat was dehydrated with 30% sucrose
solution at 4 °C, sectioned (30 lm) with a cryostat and thaw-
180 GBq/lmol,with a retention time of 22.1 min (Fig. 2B).
mounted onto Superfrost microscope slides (LEICA, CM1900). Fro-
zen sections were fixed in acetone at room temperature for
30 min, and then stored at À20 °C. Frozen sections were removed
from the freezer and air-dried at room temperature, then incu-
3.3. Partition coefficient (log P) of [18F]FP2OP
The measured partition coefficient (log P) of [18F]FP2OP is
log P = 2.20 0.00 (n = 3), suggesting that the compound was
lipophilic.
bated in 100
L [19F]FP2OP solution at room temperature for 30 min, respec-
tively. After removing the above solution, 100
L [18F]FP2OP solu-
lL saline, 20 lmol/L rotenone solution or 20 lmol/
l
3.4. Stability of [18F]FP2OP
tion (about 14.1 kBq) was added to the sections and incubated at
room temperature for 30 min. After washing with water and 40%
ethanol solution, the sections were dried and subjected to autora-
diography for 10 min. Radioactive images were developed and
quantified in Cyclone Phosphoimager system (Perkin-Elmer Inc.,
Boston, MA).
Figure 3A indicates that about 78.3% of the total 18F was eluted
at 21.5 min, while Figure 3C indicates that about 66.6% of the total
18F was eluted at 20.5 min, suggesting that some decomposition of
[
18F]FP2OP occurred during the 1 h incubation period in water or in

T. Mou et al. / Bioorg. Med. Chem. 18 (2010) 1312–1320
1317
Figure 2. The HPLC chromatograms of [19F]FP2OP (A) and OTs-P2OP (C) as well as the radiochromatogram of [18F]FP2OP (B). The retention time of [19F]FP2OP (21.7 min) and
OTs-P2OP (24.7 min) were measured with a UV detector while the retention time of [18F]FP2OP (22.1 min) was measured radiometrically.
Figure 3. The radiochromatograms of [18F]FP2OP after storage in water at room temperature for 1 h (A), in 80% ethanol solution at room temperature for 4 h (B), and after
incubation in murine plasma at 37 °C for 1 h (C).
murine plasma. The stability of [18F]FP2OP in 80% ethanol solution
was also tested and the results showed that there have more than
95% of the total 18F was eluted at 22.7 min (Fig. 3B), suggesting that
it could be stable in 80% ethanol solution over 4 h. Accordingly, the
HPLC purified [18F]FP2OP was stocked in 80% ethanol solution and
diluted with saline to 5% ethanol solution for use.
As described in Table 1, [18F]FP2OP has a significant heart up-
take. The initial heart uptake is 41.90 4.52% ID/g at 2 min post-
injection (p.i.) time, which is much higher than that of 99mTc-MIBI
(15.61 1.50%ID/g at 2 min p.i.). Meanwhile, a low 18F uptake is
observed in most of the other tissues, especially in liver and kid-
ney. The liver uptake of [18F]FP2OP is 6.14 0.48% ID/g at 2 min
p.i., while for 99mTc-MIBI, 20.92 5.14% ID/g at 2 min p.i. The ratios
of heart/liver, heart/lung and heart/blood are 6.83, 9.49 and 35.74,
respectively at 2 min after injection, thus making the material suit-
able to be a new myocardial perfusion imaging agent.
3.5. Paper electrophoresis
In paper electrophoresis, more than 98% [18F]FP2OP did not
show any movement, indicating neutrality of this compound.
3.7. Metabolic stability
3.6. Biodistribution of [18F]FP2OP in mice
The metabolic stabilities of [18F]FP2OP were determined in the
heart, blood and urine of Kunming mice at 2, 30 and 60 min after
injection. The HPLC analysis results of the fractions are shown in
Figure 4. The heart radiochromatograms (Fig. 4A–C), indicates that
Biological distribution results in mice for [18F]FP2OP and 99mTc-
MIBI are shown in Table 1, as a percentage of the Injected Dose per
Gram of organ (%ID/g SD).
Table 1
The biodistribution of [18F]FP2OP and 99mTc-MIBI in normal mice. Expressed as% injected dose per gram (% ID/g SD), n = 5
[
18F]FP2OP
99mTc-MIBI
2 min
15 min
30 min
60 min
2 min
60 min
Heart
Liver
Spleen
Lung
Muscle
Bone
Kidney
Blood
Heart/liver
Heart/lung
Heart/blood
41.90 4.52
6.14 0.48
2.60 0.54
4.42 0.61
4.68 0.85
1.61 0.26
18.43 2.11
1.17 0.08
6.83
33.54 4.04
5.92 0.55
2.11 0.12
2.54 0.51
9.24 1.82
2.10 0.20
13.02 0.82
1.22 0.29
5.67
28.07 2.11
5.37 0.53
2.48 0.22
2.98 0.31
9.11 3.25
2.25 0.30
11.59 2.18
1.98 0.18
5.24
24.80 0.71
4.80 0.53
2.41 0.22
3.17 0.14
9.74 1.74
3.70 0.39
9.25 1.55
2.13 0.14
5.17
15.61 1.50
20.92 5.14
5.17 0.64
6.93 0.44
5.62 0.779
3.66 0.74
37.78 6.02
2.16 0.23
0.75
15.62 1.42
13.74 3.06
1.18 0.25
1.09 0.10
5.53 0.48
1.54 0.78
21.16 2.84
0.10 0.01
1.14
9.49
35.74
13.22
27.53
9.41
14.2
7.82
11.62
2.25
7.24
14.35
154.7

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T. Mou et al. / Bioorg. Med. Chem. 18 (2010) 1312–1320
Figure 4. The HPLC profiles of soluble fractions of [18F]FP2OP. Heart was collected at 2 min (A), 30 min (B) and 60 min (C) after injection; blood was collected at 2 min (D) and
60 min (E) after injection; and urine (F) was collected at 30 min after injection into a normal Kunming mouse.
more than 95% of the total 18F was eluted at 22 min, suggesting
that [18F]FP2OP could be stable in the myocardium over 60 min
after injection. At 2 min after injection, [18F]FP2OP was stable in
blood ( Fig. 4D). While at 60 min after injection, the peak at
22.0 min has almost disappeared and two new peaks have ap-
peared at 3.8 min and 10.9 min, suggesting that the compound
undergoes considerable degradation in blood (Fig. 4E). Similarly,
the urine radio chromatogram Figure 4F suggests that no intact
binding site and comparable affinity with rotenone (a known
MC-I inhibitor with high affinity). Based on autoradiography re-
sults, we believe that both of [19F]FP2OP and [18F]FP2OP com-
pounds are potent inhibitors of MC-I.
3.9. Cardiac PET/CT imaging
The PET/CT studies of [18F]FP2OP were performed in a healthy
Chinese mini-swine. The representative PET images were displayed
in Figure 6. High heart activity accumulation was observed. The
SUVs of heart were 10.15 (5 min p.i.), 9.39 (15 min p.i.), 8.42
(30 min p.i.) and 5.83 (60 min p.i.). The clearance tendency was
well agreed with that of biodistribution studies in mice. The out-
line of myocardium was clear and the uptakes in background or-
gans (liver and lung) were very low at all time points. The SUVs
of liver were 2.85, 2.69, 2.14 and 1.82 at 5, 15, 30 and 60 min
p.i., respectively. The SUVs of lung were 0.69, 0.71, 0.64 and 0.39
at 5, 15, 30 and 60 min p.i., respectively. The clearance rate of activ-
ity from these organs have no significant difference, while in mice
biodistribution studies the activity cleared from heart much faster
than that of liver and lung. The heart/liver and heart/lung ratios
were calculated as 3.56 and 14.71 (5 min p.i.), 3.49 and 13.23
[
18F]FP2OP was excreted in the urine and no defluorination of
the [18F]FP2OP appears to have occurred since increasing bone up-
take was not observed (Table 1).
3.8. Ex vivo autoradiography
Ex vivo autoradiography studies were performed on heart fro-
zen sections from a normal SD rat ( Fig. 5). The autoradiogram
shows that [18F]FP2OP had high uptake in myocardium (Fig. 5B),
and it could be blocked by both of pre-incubated with rotenone
(Fig. 5C) and [19F]FP2OP (Fig. 5D). The net intensity was calculated,
the ratios of control to rotenone inhibited section and control to
[
19F]FP2OP inhibited section were 4.0 and 2.6, respectively. The re-
sults of autoradiography suggesting that [19F]FP2OP has the same
Figure 5. The autoradiograms of heart sections from a normal SD rat. The sections were incubated with 100
temperature pre-treated with 100
autoradiography.
l
L [18F]FP2OP solution (about 14.1 kBq) for 30 min at room
lL saline (B), 20 lmol/L rotenone (C) or 20 l
mol/L [19F]FP2OP (D), respectively. A is the photo of a heart section before subjected to

T. Mou et al. / Bioorg. Med. Chem. 18 (2010) 1312–1320
1319
Figure 6. Cardiac PET images of a healthy Chinese mini-swine with 85 MBq [18F]FP2OP in 5% ethanol solution. The images were collected at 5, 15, 30, 60 min after injection,
respectively.
(15 min p.i.), 3.93 and 13.16 (30 min p.i.), 3.20 and 14.95 (60 min
p.i.), respectively.
ity images of myocardium were obtained in PET/CT study of
healthy Chinese mini-swine. The high initial heart uptake and
low background uptake at earlier time point make it possible for
performing imaging at earlier time with minimal injection dose.
It is also worth mentioning that the fast myocardium clearance
of [18F]FP2OP could lower the irradiation dose and make it a good
choice for stress and rest imaging in one-day protocol. All of the
properties of [18F]FP2OP reported here make it could be superior
to the other MPI agents.
4. Discussion
In the early 1990s, several novel 99mTc-labeled perfusion tracers
(
99mTc-MIBI, 99mTc-tetrofosmin and 99mTcN-NOEt) had been devel-
oped for SPECT myocardial perfusion imaging. Among those
agents, 99mTc-MIBI has been accepted worldwide for evaluation
of CAD with SPECT imaging. Thence forwards, several new MIBI
complexes (99mTcN-MIBI19 and 99mTc(CO)3(MIBI)320) with different
99mTc core have been reported for myocardial perfusion imaging.
All of them have improved biodistribution properties in the mouse
when compared with 99mTc-MIBI.
Very recently, there is increasing interest in and actual use of PET
for myocardial perfusion imaging21 and several new 18F-labeled
tracers have been reported as mitochondrial complex I (MC-I) inhib-
itors and evaluated for this purpose. In 2004, Marshall et al. reported
an 18F-labeled rotenone analogue(18F-FDHR) and it was evaluated in
the isolated rabbit heart as a new myocardial flow tracer.8 Unfortu-
nately, there are no further in vivo data of it being reported till now.
Studies by Yu et al.6,9,22 indicate that BMS-747158-02 is a novel 18F-
labeled pyridazinone derivative designed for cardiac imaging, and it
represents a new class of PET myocardial perfusion imaging agent.
Cardiac imaging with this agent shows clear myocardium and iden-
tificationoftheperfusiondeficitareainrats, rabbits, pigs, nonhuman
primates, and human subjects.
5. Conclusion
A novel 18F-labeled compound [18F]FP2OP has been successfully
prepared in high yield and high radiochemical purity (>98%). Based
on the results of the experiments reported here comes a conclusion
that [18F]FP2OP is a lipophilic and neutral complex. The biodistri-
bution studies in mice shows that this compound has a significant
high heart uptake, and good heart/liver, heart/lung, heart/blood ra-
tios. Cardiac PET imaging in a healthy Chinese mini-swine shows
clear outline of myocardium at all time points, suggesting the po-
tential usefulness of this compound as a myocardial perfusion
imaging agent.
Acknowledgments
This work was supported by the National Natural Science Foun-
dation of China (20871020) and Beijing Natural Science Foundation
(2092018). The authors wish to acknowledge the Beijing SHIHONG
Pharmaceutical Co, Ltd for the donation of MIBI Kits. Dr. Yuanqun
Jiang is acknowledged for her useful comments and suggestions on
the language of our manuscript.
In this study, we report the synthesis of a new 18F-labeled pyri-
daben analogue: [18F]FP2OP as a MPI agent. The physicochemical
properties, stabilities and biodistribution in mice of this compound
were evaluated. Compared with other MPI agents, [18F]FP2OP had
a much higher heart uptake. Even at 60 min after injection, the
heart uptake was 24.80 0.71% ID/g, which was still higher than
that of 99mTc-MIBI (15.62 1.42% ID/g at 60 min after injection)
and 18F-BMS-747158-02 (9.5% 0.5% ID/g at 60 min after injec-
tion).23 Furthermore, the heart/liver ratios of [18F]FP2OP were
6.83 and 5.17 at 2 min and 60 min, respectively after injection,
which were comparable with the other reported 18F-labeled mito-
chondrial complex I inhibitors.6,9,22 The results of the biodistribu-
tion in vivo indicated that the [18F]FP2OP had rapid and high
uptake in the heart and low background uptake in the blood, liver
and lung of the mouse. Compared with 99mTc-MIBI, the [18F]FP2OP
had much higher heart/liver ratios at all time points after injection
and higher heart/lung and heart/blood ratios at earlier time point
(2 min after injection) than that of 99mTc-MIBI (Table 1).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2009.12.022.
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