Synthesis and evaluation of novel F-18 labeled 4-aminoquinazoline derivatives: Potential PET imaging agents for tumor detection

Article abstract of DOI:10.1016/j.bmcl.2012.05.069

Three novel ¹⁸F-labeled 4-aminoquinazoline derivatives, N-(3-chloro-4-fluorophenyl)-6-(2-[¹⁸F]fluoroethoxy)-7- methoxyquinazolin-4-amine([¹⁸F]1), N-(3-ethynylphenyl)-6-(2-[ ¹⁸F]fluoroethoxy)-7-methoxyquinazolin-4-amine([¹⁸F]2), and N-(3-bromophenyl)-6-(2-[¹⁸F]fluoroethoxy)-7-methoxyquinazolin-4- amine([¹⁸F]3) were synthesized and radiolabeled by two-step reaction with overall radiochemical yield of 21-24% (without decay corrected). Then we carried out their biodistribution experiments in S180 tumor-bearing mice. Results showed that they had certain concentration accumulation in tumor and fast clearance from muscle and blood. It was encouraging that [¹⁸F]3 was competitive among three ¹⁸F-labeled 4-aminoquinazoline derivatives in some aspects such as tumor/muscle uptake ratio reaching 7.70 at 60 min post-injection, tumor/blood uptake ratio reaching 6.61 at 120 min post-injection. So we compared radioactivity characteristics of [ ¹⁸F]3 with those of [¹⁸F]-FDG and L-[¹⁸F]-FET in the same animal model. The absolute radioactivity uptake of [¹⁸F]3 in tumor reached 3.31 at 60 min p.i., which was slightly higher than [ ¹⁸F]-FDG (2.16) and L-[¹⁸F]-FET (2.75) at the same time phase. For [¹⁸F]3, tumor/muscle uptake ratio peaked 7.70 at 60 min, which was obviously superior to those of [¹⁸F]-FDG and L-[ ¹⁸F]-FET at all time points. The tumor/brain uptake ratios of [ ¹⁸F]3 were 10.36, 17.42, 41.11 at 30 min, 60 min and 120 min post-injection, respectively, and are much higher than those of L-[ ¹⁸F] FET (2.54, 2.92 and 2.95) and [¹⁸F]-FDG (0.61, 1.02 and 1.33) at the same time points. All these results indicate that [ ¹⁸F]3 is promising to become a potential PET tumor imaging agent.

Full text of DOI:10.1016/j.bmcl.2012.05.069

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4745–4749
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of novel F-18 labeled 4-aminoquinazoline derivatives:
Potential PET imaging agents for tumor detection
⇑
Yurong Chen, Man Feng, Shilei Li, Jingli Xu, Hongyu Ning, Yong He, Xiao Wang, Rui Ding, Chuanmin Qi
Key laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Three novel 18F-labeled 4-aminoquinazoline derivatives, N-(3-chloro-4-fluorophenyl)-6-(2-[18F]
fluoroethoxy)-7-methoxyquinazolin-4-amine([18F]1), N-(3-ethynylphenyl)-6-(2-[18F]fluoroethoxy)-7-
methoxyquinazolin-4-amine([18F]2), and N-(3-bromophenyl)-6-(2-[18F]fluoroethoxy)-7-methoxyquinaz-
olin-4-amine([18F]3) were synthesized and radiolabeled by two-step reaction with overall radiochemical
yield of 21–24% (without decay corrected). Then we carried out their biodistribution experiments in S180
tumor-bearing mice. Results showed that they had certain concentration accumulation in tumor and fast
clearance from muscle and blood. It was encouraging that [18F]3 was competitive among three 18F-labeled
4-aminoquinazoline derivatives in some aspects such as tumor/muscle uptake ratio reaching 7.70 at
60 min post-injection, tumor/blood uptake ratio reaching 6.61 at 120 min post-injection. So we compared
radioactivity characteristics of [18F]3 with those of [18F]-FDG and L-[18F]-FET in the same animal model.
The absolute radioactivity uptake of [18F]3 in tumor reached 3.31 at 60 min p.i., which was slightly higher
than [18F]-FDG (2.16) and L-[18F]-FET (2.75) at the same time phase. For [18F]3, tumor/muscle uptake ratio
peaked 7.70 at 60 min, which was obviously superior to those of [18F]-FDG and L-[18F]-FET at all time
points. The tumor/brain uptake ratios of [18F]3 were 10.36, 17.42, 41.11 at 30 min, 60 min and 120 min
post-injection, respectively, and are much higher than those of L-[18F] FET (2.54, 2.92 and 2.95) and
Article history:
Received 14 February 2012
Revised 9 May 2012
Accepted 18 May 2012
Available online 24 May 2012
Keywords:
18F-labeled
4-Aminoquinazoline derivatives
Tumor detection
PET imaging agent
[
18F]-FDG (0.61, 1.02 and 1.33) at the same time points. All these results indicate that [18F]3 is promising
to become a potential PET tumor imaging agent.
Ó 2012 Elsevier Ltd. All rights reserved.
As a class of heterocyclic compounds, aminoquinazolines and
their derivatives have many biological activities, such as anti-
inflammatory,1 antibacterial,2 antiviral3 and most importantly,
anticancer activity.4,5 And it is the anticancer activity that makes
aminoquinazolines derivatives as one important pharmacophore
widely used in the developing novel anticancer drugs. Representa-
tive drugs, like gefitinib, erlotinib, and lapatinib, have been
approved by the FDA and were successfully applied in clinic for
the treatment of multiple cancers, such as non-small cell lung can-
cer,6,7 pancreatic cancer,7 breast cancer,8 etc.
PET is a functional imaging technology which allows the three-
dimensional, quantitative determination of the distribution of
radioactivity within the human body at a molecular level, both in
healthy and pathological states.9 Of all commonly used positron
radionuclides in PET, 18F is often referred to as the ‘radionuclide
of choice’ due to its favorable physical half-life (t1/2 = 110 min).10
It is well known that [18F]-FDG has been the most widely used in
clinical diagnoses as PET radiopharmaceutical. However, some
drawbacks are found in [18F]-FDG: high uptake in nonmalignant,
inflammatory tissues causes false-positive results and high
background uptake in normal brain tissues limits its application
in brain tumor PET imaging.11,12 Therefore, there has been a lot
of research on the development of novel PET radiotracers,13,14 for
example, L-[18F]-FET,15 as alternate radiotracer.
Aminoquinazolines and their derivatives are also used for the
potential tumor imaging tracers due to inhibiting proliferation of
tumor cells.16–18 So there has been a growing interest in the study
of 4-aminoquinazoline drugs in clinical and preclinical trials as tu-
mor imaging tracers via nuclear medicine modality positron emis-
sion tomography (PET). The first drug candidates, PD 153035 and
its analogues were radiolabeled with [11C]/[125I] and evaluated.17,18
But the research is still not sufficient.19,20 Subsequently, several
4-anilinoquinazoline drugs are radiolabeled for PET imaging
tracers.21–23 They include [18F]gefitinib,24,25
[ [
11C]erlotinib,26 11C]-
ML03,27 11C]/[18F]-ML04.28,29 4-aminoquinazoline derivatives as
[
PET imaging tracers have already been developed, but these exist-
ing tracers present some drawbacks: low tumor uptake, low solu-
bility and poor stability in vivo.23,27
Consequently, we are interested in 4-aminoquinazoline deriva-
tives as PET tracers for tumor diagnose, and we also have been try-
ing to design and develop novel 18F labeled radiotracers for PET
imaging. It is reported that the 6- and 7-positions of 4-aminoqui-
nazolinos are very tolerant of substitution, which are preferably
⇑
Corresponding author.
E-mail address: qicmin@sohu.com (C. Qi).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.069

4746
Y. Chen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4745–4749
electron-donating ethers, and introducing substituent in these
positions will enhance their bioactivities.30 In order to find more
appropriate imaging agents overcoming shortcomings mentioned,
we designed and synthesized three novel 18F labeled 4-aminoqui-
nazoline derivatives modified by ethylene glycol-1, 2-ditosylate. In
this Letter, we described radiosynthesis and preliminarily biological
evaluation of three new 18F-labeled radiotracers, N-(3-chloro-4-
fluorophenyl)-6-(2-[18F]fluoroethoxy)-7-methoxyquinazolin-4-ami-
Partition coefficient was measured using the method which was
reported by our team previously.35 The partition coefficient (logP)
values of these compounds, [18F]1, [18F]2 and [18F]3, were 0.39,
1.64 and 0.89, respectively.
To evaluate stability in plasma of each 18F-labeled radiotracer,
0.1 mL PBS (pH 7.4) solution as described above was added in
2 mL mouse plasma and incubated 2 h at 37 °C. Then acetonitrile
was added to plasma solution, and centrifuged to discard plasma
proteins. The supernatant part was injected into HPLC to deter-
mine the stability of each compound. The results of radio-HPLC
analysis suggested that three 18F-labled radiotracers were stable
in plasma. In addition, radio-HPLC analysis proved that three
18F-labled radiotracers in saline remained stable in rt and 60 °C
for 2 h.
ne([18F]1),
N-(3-ethynylphenyl)-6-(2-[18F]fluoroethoxy)-7-meth-
oxyquinazolin-4-amine([18F]2) and N-(3-bromophenyl)-6-(2-[18F]
fluoroethoxy)-7-methoxyquinazolin-4-amine([18F]3) (Fig. 1). More-
over, biological activities of these new compounds were made fur-
ther evaluation in comparison with [18F]-FDG and L-[18F]-FET.
Compound 11 was synthesized from 3,4-dimethoxybenzoic as
shown in Scheme 1 according to procedure in the literature, with
slight modification.31,32 The synthesis routes of compounds
12–17 were a slight modification of the procedures described liter-
ature.32–34 Briefly, Compounds 12, 13 and 14 were prepared
through coupling of intermediate 11 with 3-chloro-4-fluoroaniline,
3-bromoaniline and 3-aminophenylacetylene in isopropanol with
85%–96% yield. Hydrolysis of the acetyl group on compounds 12,
13 and 14 was performed using sodium hydroxide in methanol
to give 4-anilino-6-hydroxy-7-methoxyquinazoline derivatives
15, 16 and 17 in 65%–75% yield. Fluorine-19 substituted com-
pounds [19F]1, [19F]2 and [19F]3 were synthesized by, respectively,
reacting 15, 16, and 17 with 1-bromo-2-fluoroethane using potas-
sium carbonate as a base in N,N-dimethylformamide with 60%–75%
yields based on the following procedure in Scheme 1. 2-fluoroeth-
yltosylate (19) was synthesized by reacting 1,2-bistosyloxyethane
(18) with tetrabutylammonium fluoride in acetonitrile in 80%
yield. (Scheme 1)
All animal experiments were carried out under humane condi-
tions and in compliance with the national laws related to the con-
duct of animal experimentation. The biological evaluation studies
were investigated in S180 tumor-bearing mice. S180 tumor model
was established by injecting 5 Â 106 S180 tumor cells into left
forelimb of female mice without anesthesia. The experimental
procedure was performed after inoculating the tumor cells for
14–18 days when the tumors were about 0.5 cm in diameter. A vol-
ume of 0.1 mL 18F labeled radiotracer (8–10
lCi) in a solution of
PBS (pH 7.4) purified by radio-HPLC as mentioned above was in-
jected into each mouse through tail vein (4 animals in per time
phase). Then the mice were sacrificed at 5, 30, 60 and 120 min
post-injection. Tumor, brain, blood, and other organs of interest
were collected, wet-weighed, and measured for radioactivity in
gamma counter. The biodistribution results of 18F labeled com-
pounds [18F]1, [18F]2 and [18F]3 were shown in Tables 2–4, respec-
tively. The data in tables was expressed as percentage of injected
dose per gram of tissue weight (%ID/g). Values were expressed as
mean SD (n = 4).
All 18F labeled compounds, [18F]1, [18F]2 and [18F]3 were pre-
pared with [18F]KF-K2.2.2 complex via a prosthetic group in two-
step reaction that consisted of l8F-fluorination of ethylene glycol-
1, 2-ditosylate and subsequent I8F-fluoroethylation of precursors
(Scheme 2). Firstly, 2-[18F]fluoroethyl tosylate (20) was prepared
by nucleophilic fluorination substitution of compound 18 with
anhydrous [18F]KF-cryptate ([K2.2.2]/18F) in the presence of acetoni-
trile at 100 °C for 15 min. Secondly, after acetonitrile was removed
at 100 °C under a flow of nitrogen, intermediate 20 without isola-
tion was added to a solution of potassium salt of precursors in
DMSO, heating up 100 °C for 15 min, producing 18F-labeled prod-
uct [18F]1, [18F]2 and [18F]3, respectively. The resulting mixture
was highly diluted with water, concentrated on a C18 Sep-Pak car-
tridge and almost quantitatively desorbed with acetonitrile. Fol-
lowing purification was executed by semi-preparative HPLC with
reversed-phase Grace Alltima™ C18 Column (250 Â 10 mm, parti-
Table 2 presented a rapid distribution of [18F]1 in all organs and
tissues. Initial radioactivity uptakes in liver and kidney were high,
however, declined rapidly as time lapsed, showed that the sys-
temic metabolism was governed by liver and kidney. Although
the radioactivity uptake of [18F]1 in tumor was comparably low
at initial time, it had a significant increasing accumulation in
tumor from 5 to 120 min post-injection. And maximum of radioac-
tivity uptake in tumor was 5.80 0.72%ID/g at 30 min post-injec-
tion, and only decreased to 4.71 0.27%ID/g at 120 min p.i., still
81% radioactivity retained, which demonstrated good retention in
tumor throughout the process of investigation. The radioactivity
of [18F]1 in blood peaked at 7.00 3.61%ID/g immediately at
5 min post-injection, and decreased to 3.61 0.10% ID/g at
120 min post-injection. The tumor/blood uptake ratios were 0.99
at 30 min, 1.09 at 60 min and 1.3 at 120 min post-injection, and
this indicated the blood clearance was not satisfactory.
cle size: 10 lm). The column was eluted using isocratic solvent as
followed Table 1. The eluent was collected, solvent was evaporated
and then the products were dissolved in phosphate-buffered saline
solution (pH 7.4) for further use. The radiochemical purity and
chemical purity were above 99%. The total reaction time for each
For [18F]2 (Table 3), a fast clearance in liver and kidney could be
observed after rapid distribution and accumulation in all organs
and tissues. Radioactivity of [18F]2 in tumor was 1.40 0.06,
3.32 0.44, 2.98 0.17 and 1.81 0.13%ID/g at 5, 30, 60, and
120 min post-injection respectively, a relatively smooth trend in
tumor. Surprisingly, the blood uptake reached its maximum
[
18F]-labeled product was about 60 min including purification with
radio-HPLC. The overall radiochemical yield without decay correc-
tion and retention time were summarized in Table 1.
F
Br
Cl
HN
N
HN
HN
O
O
18F
N
18F
N
O
18F
N
MeO
[
MeO
N
MeO
N
18F]1
18F]3
[
18F]2
[
Figure 1. Structure of three 18F-labeled 4-aminoquinazoline derivatives.

Y. Chen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4745–4749
4747
O
N
O
N
COOH
MeO
MeO
COOEt
HO
MeO
MeO
COOEt
NO2
MeO
MeO
COOEt MeO
d
MeO
MeO
e
NH
b
NH
F
c
a
MeO
NH2
MeO
4
5
9
6
7
8
R
R
N
R
N
Cl
O
N
HN
HN
HN
O
AcO
AcO
HO
MeO
AcO
N
g
h
NH
N
i
j
i
MeO
N
MeO
MeO
N
N
MeO
N
11
10
[
19F]1, [19F]2, [19F]3
12-14
15-17
F
F
F
12:
13:
R=
[
19F]1:
15:
Cl
R=
k
Cl
R=
F
Cl
OTs
TsO
TsO
16:
17:
[
19F]2:
R=
R=
R=
R=
R=
R=
18
19
14:
[
19F]3:
Br
Br
Br
Scheme 1. Synthesis of [19F]1, [19F]2 and [19F]3. Experiment reagents and conditions: (a) CH3CH2OH, H2SO4, refluxing; (b) AcOH, HNO3,0–5 °C; (c) Pd/C,H2; (d) formamide,
160–170 °C; (e) methansulfonic acid, -methionine, 120 °C; (f) Ac2O, pyridine, DMAP, 100 °C; (g) POCl3, toluene, refluxing; (h) R–Ar–NH2, pyridine, i-PrOH, refluxing; (i)
NaOH, MeOH, H2O; (j) BrCH2CH2F, K2CO3, DMF. (k) TBAF, CH3CN, 90 °C.
L
R
N
R
N
HN
N
HN
O
18F
HO
b
OTs
a
OTs
18F
TsO
MeO
MeO
N
20
18
18F]1, [18F]2, [18F]3
15, 16, 17
[
F
F
15:
16:
17:
R=
[
18F]1
R=
Cl
Cl
[
18F]2
R=
R=
R=
R=
[
18F]3
Br
Br
Scheme 2. Radiochemical synthesis of [18F]1, [18F]2 and [18F]3. Experiment reagents and conditions: (a) K18F, Kryptofix 2.2.2., CH3CN, 100 °C, 15 min; (b) intermediate 20,
KOH, DMSO, 100 °C, 15 min.
Table 1
Compounds
RCY (no decay correction)
Radio-HPLC conditions (eluent, flow rate)
Retention time
[
[
[
18F]1
18F]2
18F]3
21%
22%
24%
CH3OH/H2O = 80:20, 5 mL/min
CH3OH/H2O = 80:20, 3 mL/min
CH3OH/H2O = 80:20, 3 mL/min
8.2 min
9.1 min
7.3 min
Table 2
Biodistribution data of [18F]1 in mice bearing S180 tumor (%ID/g; mean SD; n = 4)
Table 3
Biodistribution data of [18F]2 in mice bearing S180 tumor (%ID/g; mean SD; n = 4)
Organs
%ID/g SD
Organs
%ID/g SD
5 min
30 min
60 min
120 min
5 min
30 min
60 min
120 min
Heart
Liver
Spleen
Lung
Kidney
Stomach
Muscle
Brain
Tumor
4.40 0.02
11.34 0.79
4.50 0.59
4.60 0.0.13
14.25 0.98
5.35 0.35
5.12 0.92
1.97 0.58
1.87 0.04
7.00 0.66
0.37
5.02 0.69
5.38 0.82
3.67 0.55
4.57 0.59
5.20 0.32
11.87 0.49
4.18 0.83
3.15 0.47
5.80 0.72
5.85 0.59
1.39
4.26 0.41
4.22 0.24
3.23 0.62
3.75 0.65
3.99 0.42
4.44 0.09
3.35 0.73
2.94 0.14
5.51 0.58
5.07 0.27
1.64
2.52 0.36
2.58 0.05
2.39 0.15
2.57 0.21
2.23 0.25
3.64 0.21
1.74 0.30
1.98 0.23
4.71 0.27
3.61 0.10
2.71
Heart
Liver
Spleen
Lung
Kidney
Stomach
Muscle
Brain
Tumor
8.68 0.23
8.75 0.31
0.98 0.15
3.60 0.14
6.35 0.35
8.56 0.33
0.74 0.13
5.51 0.23
1.40 0.06
7.56 0.36
1.89
2.85 0.12
7.63 0.32
1.93 0.26
2.99 0.24
4.16 0.31
5.94 0.71
1.74 0.06
2.59 0.03
3.32 0.44
3.06 0.43
1.91
1.99 0.13
4.07 0.17
0.77 0.08
1.88 0.07
2.53 0.18
4.14 0.38
0.82 0.18
0.3 0.05
2.98 0.17
1.19 0.05
3.63
1.03 0.08
3.40 0.09
1.04 0.08
1.62 0.06
1.27 0.05
1.07 0.05
1.36 0.12
1.50 0.04
1.81 0.13
0.77 0.05
1.33
Blood
Blood
Tumor/muscle
Tumor/blood
Tumor/brain
Tumor/muscle
Tumor/blood
Tumor/brain
0.27
0.95
0.99
1.84
1.09
1.87
1.3
2.38
0.19
0.25
1.08
1.28
2.50
9.93
2.35
1.21
7.56 0.36%ID/g at 5 min, and it sharply declined to 0.77 0.05%ID/
g at 120 min, almost 90% radioactivity cleared from the blood.
Although radioactivity in other organs and tissues presented
certain uptake, it dropped faster than that in tumor as time elapsed.
Therefore [18F]2 had good tumor/muscle, tumor/blood, and tumor/
brain ratios at 60 min post-injection: 3.63, 2.50 and 9.93.

4748
Y. Chen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4745–4749
Table 4
agents: high uptake in tumor and the fastest clearance from blood
and muscle. Thus, we concluded that [18F]3 was much more suit-
able for PET tumor imaging.
Biodistribution data of [18F]3 in mice bearing S180 tumor (%ID/g; mean SD; n = 4)
Organs
%ID/g SD
In order to determine this, we compared biodistribution data of
5 min
30 min
60 min
120 min
[
18F]3 with those of [18F]-FDG and L-[18F]-FET in the same animal
Heart
Liver
Spleen
Lung
Kidney
Stomach
Muscle
Brain
Tumor
4.79 0.02
9.67 0.89
2.84 0.52
12.21 0.52
10.85 0.25
8.52 0.33
1.87 0.2
0.78 0.45
0.38 0.02
4.43 0.46
0.20
1.12 0.20
7.96 0.50
1.25 0.58
5.12 0.50
2.83 0.14
7.03 0.17
2.46 0.46
0.39 0.23
4.04 0.62
1.58 0.11
1.64
0.98 0.50
1.87 0.26
0.8 0.55
5.6 0.05
0.90 0.04
4.05 0.06
0.43 0.02
0.19 0.07
3.31 0.04
1.11 0.35
7.70
1.87 0.59
1.78 0.34
1.05 0.28
3.60 0.15
1.07 0.01
4.10 0.03
1.31 0.12
0.09 0.01
3.70 0.44
0.56 0.006
2.82
model as shown in Table 5. For [18F]-FDG, extremely rapid blood
clearance (tumor/blood ratio was 19.47 at 60 min p.i.) and moder-
ate clearance from muscle (tumor/muscle ratio was 2.23 at 60 min
p.i.) made it widely applied in clinical as PET radiopharmaceuticals.
However, its high background uptake in brain during the study
period limited its application as brain tumor imaging agent. The tu-
mor/brain uptake ratios of [18F]-FDG were 0.53, 0.61, 1.02, 1.33 at
5 min, 30 min, 60 min, 120 min post-injection. For L-[18F]-FET,
although its tumor/blood ratios remained in a low level (1.02, 1.1
and 1.92 at 30, 60 and 120 min post-injection), higher tumor/brain
ratios (2.54, 2.92 and 2.95 at 30, 60 and 120 min post-injection) en-
abled it to a supplement to [18F]-FDG as brain imaging agents.
Compared with [18F]-FDG and L-[18F]-FET, [18F]3 has several
distinct advantages. As shown in Table 5, absolute radioactivity
uptakes of [18F]3 in tumor were higher than those of [18F]-FDG
and L-[18F]-FET at 30, 60, 120 min post-injection. At 60 min post-
injection, uptakes of [18F]3 in tumor was 3.31, which was slightly
higher than those of [18F]-FDG (2.16) and L-[18F]-FET (2.75);
Blood
Tumor/muscle
Tumor/blood
Tumor/brain
0.09
0.49
2.56
10.36
2.98
17.42
6.61
41.11
As can be seen from Table 4 given below, the radioactivity accu-
mulation of [18F]3 reached the highest level in all other organs and
tissues except for muscle and tumor at 5 min post-injection. After
that the radioactivity in other organs or tissues except tumor de-
creased, and the compound was excreted from body via kidney
and liver. Maximum of radioactivity uptake in tumor was
4.04 0.62%ID/g at 30 min post-injection, and decreased a little
to 3.70 0.44%ID/g at 120 min post-injection, still 91% radioactiv-
ity retained throughout the time course. It was obvious that
[
[
18F]3 had higher tumor/muscle uptake ratio (7.7) than those of
18F]-FDG (2.3) and L-[18F]-FET (1.23), which made it possible to
get a clear tumor imaging for [18F]3; It was worth mentioning that
[
18F]3 has a low brain uptake (0.19 0.07%ID/g at 60 min p.i.) and
that resulted in high tumor/brain ratio (17.42) which was ten
[
18F]3 remained a high tumor uptake level in a long period. In addi-
times more than [18F]-FDG (1.02) and five times more than L-
tion, initial radioactivity uptake in blood was 4.43 0.46%ID/g, and
reduced rapidly to 0.56 0.006%ID/g at 120 min p.i., approximately
88% radioactivity cleared from blood. So a fast blood clearance
could be seen. Since the elimination rate in tumor was much
slower than that in other organs or tissues, [18F]3 had high tu-
mor/muscle, tumor/blood, and tumor/brain ratios at 60 min post-
injection: 7.70, 2.98 and 17.42.
[
18F]-FET (2.92) at 60 min post-injection; Tumor/blood uptake ratio
of [18F]3 (2.98) was higher than that of L-[18F]-FET (1.1), but was
lower than that of [18F]-FDG (19.47) at 60 min post-injection. Con-
sequently, the described results reflected that [18F]3 could be ap-
plied in PET tumor imaging as potential tracer .
In summary, we successfully prepared three [18F]-labeled 4-
aminoquinazoline derivatives by two-step reaction with high
yields. Biodistribution experiments of [18F]1, [18F]2 and [18F]3 were
performed in S180 tumor-bearing mice. Results indicated that
As shown in Tables 2–4, there were some significant differences
in biodistribution data of these three 18F-labeled radiotracers. On
the one hand, the clearance rate of [18F]3 in muscle, blood and
brain was much higher than those of [18F]1 and [18F]2. Tumor/mus-
cle, tumor/blood, and tumor/brain ratios of [18F]3 were 7.70, 2.98
and 17.42 at 60 min post-injection, respectively. They were much
higher than those of [18F]1 (1.64, 1.09 and 1.87) and [18F]2 (3.63,
2.50 and 9.93) at the same time point. On the other hand, at
60 min p.i., radioactivity uptake value of [18F]3 in tumor was
3.31, slightly higher than that of [18F]2 (2.98), less than that of
[
18F]3 had higher tumor/muscle uptake ratio and tumor/blood ra-
tio than those of [18F]1 and [18F]2. Furthermore, based upon the
comparison of [18F]3 with [18F]-FDG and L-[18F]-FET, we found that
[
18F]3 had a relatively high tumor accumulation, high tumor/brain
and tumor/muscle uptake ratios from 30 min onward. So [18F]3 can
serve as a potential tumor imaging agent. Further research and
more experiments are needed to evaluate the potential of [18F]3
and other [18F]-labeled 4-aminoquinazoline derivatives to be suit-
able for promising PET tumor imaging radiotracers.
[
18F]1 (5.51) at the same time phase. Overall, [18F]3 among them
showed the most favorable characteristics as PET tumor imaging
Table 5
Biodistribution data comparison of [18F]3, [18F]-FDG and L-[18F] FET in mice bearing S180 tumor (%ID/g; mean SD; n = 4)a
Organs
Radioactive tracer
Time(min)
5
30
60
120
Tumor
[
[
18F]3
0.38 0.02
1.27 0.54
2.08 0.49
0.2
0.81
0.72
0.09
1.17
0.31
0.49
4.04 0.62
1.86 0.18
3.28 0.69
1.64
1.75
0.62
2.56
11.38
1.02
10.36
3.31 0.04
2.16 0.34
2.75 0.36
7.7
2.23
1.23
2.98
19.47
1.1
17.42
1.02
2.92
3.70 0.44
1.7 0.06
2.15 1.36
2.82
2.2
1.4
6.61
15.85
1.92
41.11
1.33
2.95
18F]-FDG
L-[18F]-FET
Tumor/muscle
Tumor/blood
Tumor/brain
[
[
18F]3
18F]-FDG
L-[18F]-FET
[
[
18F]3
18F]-FDG
L-[18F]-FET
[
[
18F]3
18F]-FDG
0.53
2.1
0.61
2.54
L-[18F]-FET
a
The data of [18F]-FDG and L-[18F]-FET was from literature.36

Y. Chen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4745–4749
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Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.
2012.05.069.
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