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

Article abstract of DOI:10.1016/j.bmcl.2009.03.027

Two F-18 labeled fluoroarylvaline derivatives, methyl 2-(2-[¹⁸F]fluoro-4-nitrobenzamido)-3-methylbutanoate ([¹⁸F]1, [¹⁸F]MFNBMB) and its corresponding acid 2-(2-[¹⁸F]fluoro-4-nitrobenzamido)-3-methylbutanoic aci

Full text of DOI:10.1016/j.bmcl.2009.03.027

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4873–4877
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of novel F-18 labeled fluoroarylvaline derivatives:
Potential PET imaging agents for tumor detection
Yali Qiao a, Yong He a, Shuting Zhang a, Guixia Li a, Hang Liu a, Jingli Xu a, Xiao Wang a, Chuanmin Qi a,
,
*
Cheng Peng b
a Key laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University, Beijing 100875, People’s Republic of China
b Center of PET, Xuan Wu Hospital, Beijing 100053, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Two F-18 labeled fluoroarylvaline derivatives, methyl 2-(2-[18F]fluoro-4-nitrobenzamido)-3-methylbut-
anoate ([18F]1, [18F]MFNBMB) and its corresponding acid 2-(2-[18F]fluoro-4-nitrobenzamido)-3-methylb-
utanoic acid ([18F]2, [18F]FNBMBA), have been designed and synthesized, respectively, by our team.
Meanwhile, we research on their biodistributions in mice model bearing S 180 tumor. Furthermore,
we also carried out the biological evaluations of 2-[18F]fluorodeoxyglucose ([18F]FDG) and O-2-[18F]flu-
Article history:
Received 12 November 2008
Revised 15 February 2009
Accepted 6 March 2009
Available online 14 March 2009
oroethyl-L-tyrosine (L
-[18F]FET) in the same model for comparison with our targeting molecules [18F]1
Keywords:
Amino acids
F-18 labeled
Fluoroarylvaline derivatives
PET imaging agents
Tumor detection
and [18F]2. Excitingly, the tumor/blood (T/Bl) and tumor/brain (T/Br) ratios were 2.91, 7.06 at 30 min,
3.44, 5.61 at 60 min post injection for [18F]1, 2.32, 13.30 for [18F]2 at 30 min post injection, which were
obviously superior to [18F]FDG and -[18F]FET in the same model and demonstrated that [18F]1 and
L
[
18F]2, especially [18F]2, were potential PET imaging agents for tumor detection.
Ó 2009 Elsevier Ltd. All rights reserved.
As one of the nuclear medicine imaging modalities, positron
emission tomography (PET) possesses the highest resolution and
makes tracer concentration in tissues quantified.1 As we all know,
diagnosis of tumors with a high specificity, particularly for brain
tumors.6
Mainly due to the longer half-time of 18F (110 min) compared
with 11C (20 min), fluorine-18 becomes a widely used PET radionu-
clide in radiopharmacy.5a Thus, fluorine-18 labeled radiopharma-
ceuticals, particularly various 18F-labeled amino acids, have been
designed and synthesized to evaluate their potential use as PET
imaging agents for tumors. From a radiochemosynthesis perspec-
tive, however, to label amino acids with 18F is no easy work, espe-
cially for some aromatic substrates.7–9 Initially, tyrosine, for
example, was directly labeled with 18F on its aromatic positions7
by electrophilic substitution reaction with [18F]AcOF or [18F]F2,
which usually has low radiochemical yield. Whereafter, Wester’s
team indirectly labeled tyrosine by introduction of a fluoroalkyl
group to the aromatic position, successfully getting O-2-[18F]flu-
[
18F]FDG has been extensively applied for diagnosing brain and
systemic tumors as an efficient PET radiotracer.2 When it comes
to brain tumors, however, [18F]FDG has high background uptake
in normal brain tissues which can reduce tumor-to-brain ratios;
on the other hand, it represents substantive uptake in inflamma-
tory tissues.3 Consequently, [18F]FDG always demonstrates low T/
Br ratios and cannot well distinguish tumors from inflammation,
both of which limit its application in the field of brain tumor PET
imaging. Hence, plentiful research on the development of novel
PET radiotracers has been carried out aiming at supplementing
[
18F]FDG.4 Fortunately, researchers have discovered that multifari-
ous radiolabeled amino acids generally have huge potential value
in oncology, especially for brain tumors with PET imaging modality
which may be better tumor-imaging agents than [18F]FDG.5 So far,
efforts primarily have focused on radiolabeled nonnatural amino
acids considering their improved metabolic stability over radiola-
beled natural amino acids and comparatively simple interpretation
oroethyl-L-tyrosine (L
-[18F]FET), which prolonged the labeling time,
though improved its radiochemical yield to some degree.6a,b There-
fore, considering radiochemosynthetic factors, we designed and
synthesized novel F-18 labeled fluoroarylvaline derivatives based
on natural amino acid L-valine modified by 2,4-dinitrobenzoic acid.
of tracer kinetics. O-2-[18F]fluoroethyl-
L
-tyrosine (
L
-[18F]FET), as an
The primary reason for adopting 2,4-dinitrobenzoic acid to modify
the natural amino acid is owning to the synthetically easy intro-
duction of fluorine-18 at ortho-position of the 2,4-dinitrobenzam-
ide precursor. In addition, on account of the influence of
molecular structure on its lipophilic property, we respectively
produced methyl 2-(2-[18F]fluoro-4-nitrobenzamido)-3-methyl-
analogue of tyrosine, has been developed and evaluated which
proved to be a useful nonnatural amino acid PET radiotracer for
* Corresponding author. Tel.: +086 13681380097; fax: +086 010 58802075.
E-mail address: qicmin@sohu.com (C. Qi).
butanoate ([18F]1,
[
18F]MFNBMB) and its corresponding acid
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.027

4874
Y. Qiao et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4873–4877
2-(2-[18F]fluoro-4-nitrobenzamido)-3-methylbutanoic acid ([18F]2,
18F]FNBMBA) to evaluate their potential use as PET tumor tracers.
In this Letter, we report the synthesis and biological evaluation of
quent acidification with 1 N HCl and purification by recrystaliza-
tion afforded its acid F-19 substituted compound 2-(2-fluoro-4-
nitrobenzamido)-L-valine (2) in 85% yield (structure analysis data
[
two novel non-natural fluorine-substituted
L
-valine derivatives for
for 1 and 2 can be found in a Ref. 10).
tumor imaging, ester [18F]1 and its corresponding acid [18F]2. The
biological properties of these new radiotracers were evaluated
using in vivo uptake assays in mice bearing S 180 tumor. Moreover,
we also carried out the biological evaluation experiments of 2-
The radiosynthesis of [18F]MFNBMB and [18F]FNBMBA were
performed beginning with the 2,4-dinitrobenzoic acid modified
precursor by the nucleophilic substitution denitrofluorination
reaction as shown in see Scheme 2. Fixation of K [18F] F on Krypto-
fix2.2.2. was used in the synthetic process. Optimal reaction condi-
tions were obtained with a mixture of the precursor and the
fluoride-Kryptofix2.2.2. complex in 0.5 ml DMF at 115 °C for
20 min in sealed conditions. The mixed product was highly diluted
with water, adsorbed on a Sep-Pak Plus C18 cartridge and almost
quantitatively desorbed with acetonitrile. Purification of the sepa-
rated product was immediately executed by semi-preparative
HPLC: Grace C18 column (250 Â 4 mm i.d.); eluent: MeCN/
H2O = 70:30; flow rate: 3 ml/min; tR (ester [18F]1) = 7–10 min.
After the separation and purification obtaining ester [18F]1, hydro-
lysis using LiOH in MeOH at rt for only 10 min in open conditions
and immediate acidification with 1 N HCl afforded [18F]2 (tR for
acid [18F]2 = 3–5 min). The pure compounds [18F]1 and [18F]2 were
collected using physiological saline prepared for use in the biolog-
ical evaluation experiment. The radiochemical yield is approxi-
mately 30–40% without decay correction. The radiochemical
purity and chemical purity were >99%. Total labeling synthesis of
[
18F]fluorodeoxyglucose ([18F]FDG) and O-2-[18F]fluoroethyl-
L-
tyrosine (
targeting molecules [18F]1 and [18F]2 (Fig. 1).
The precursor 2-(2,4-dinitrobenzamido)-
(5) used in this study was easily prepared in only two steps from
natural amino acid -valine (3) as shown in Scheme 1. -valine
methyl ester hydrochloride (4) was produced by the reaction of
-valine with slightly more SOCl2 in MeOH at 0 °C for 30 min, then
L
-[18F]FET) in the same model for comparison with our
L
-valine methyl ester
L
L
L
at rt for 12 h, followed by removal of SOCl2 and MeOH by evapora-
tion and further purified by recrystalization in 80% yield. The pre-
cursor was synthesized using 1.5 equiv
hydrochloride (4) and 1.5 equiv triethylamine (TEA) dissolved in
CH2Cl2, mixed for 5 min, then added 1.0 equiv 2,4-dinitrobenzoic
acid, 1.1 equiv N-hydroxybenzotriazole (HOBt) and 1.1 equiv N,N-
dicyclohexylcarbodiimide (DCC) at 0 °C for 30 min, raised to room
temperature for 12 h, the mixture was filtrated, washed and iso-
lated by flash column chromatography in 38% yield. F-19 substi-
L-valine methyl ester
tuted compound 2-(2-fluoro-4-nitrobenzamido)-
L
-valine methyl
[
18F]1 and [18F]2 needed approximately100 min.
On account of usage of natural amino acid -valine as the initial
material in the preparation of the precursor, we obtained two F-18
labeled
-[18F]fluoroarylvaline derivatives in this study which were
ester (1) was synthesized directly from the 2,4-dinitrobenzoic acid
modified precursor using TBAFÁ3H2O in DMF at 115 °C for 20 min
in 66% yield. Hydrolysis of compound 1 with LiOH in MeOH, subse-
L
L
further confirmed by Radio-HPLC. After separation and purifica-
tion, [18F]MFNBMB ([18F]1) was measured by Radio-HPLC showing
a single peak at 7.3 min which matched well with its correspond-
ing F-19 substituted MFNBMB (1, tR = 7.0 min) within admissible
error. As for [18F]FNBMBA ([18F]2), single peak presented at
3.0 min, also matched well with FNBMBA (2, tR = 2.4 min).
Partition coefficients of the [18F]MFNBMB and [18F]FNBMBA
were determined by using 2.5 ml n-octanol as the organic phase
and 2.5 ml 0.01 M PBS (pH 7.4) as water phase. After HPLC purifi-
cation, 0.01 ml of [18F]1 or [18F]2 was added, mixed for 5 min
and centrifuged for 5 min at room temperature. The radioactivity
of equal volume of each phase was measured, respectively. The
lgP of ester [18F]1 was 0.58 and that of its corresponding acid
Figure 1. Structure of the F-18 labeled fluoroarylvaline derivatives used in this
study.
[
18F]2 was À0.25.
The in vitro stability of [18F]1 and [18F]2 were tested by incuba-
tion of certain amounts of them in 0.9% NaCl, 0.01 M phosphate
buffered saline (PBS) or 96% ethanol at room temperature up to
6 h and in organic solvents such as ethanol, DMF and MeCN at
60 °C up to 30 min. According to TLC and HPLC, the compounds
proved to be stable. No degradation or defluorination of them were
observed.
The blood stability of [18F]1 and [18F]2 was evaluated in a tu-
mor-bearing KM mouse, respectively. Thirty minutes after intrave-
nous injection of 4 MBq of [18F]1 and [18F]2, the mouse was
sacrificed. The blood was collected and immediately centrifuged
for 5 min at 13,200 rpm. The supernatants of both centrifugation
steps of blood were combined and passed through a C18 Sep-Pak
cartridge. The cartridge was washed with 2 ml of water and eluted
Scheme 1. Synthesis of MFNBMB (1) and FNBMBA (2). Experimental reagents and
conditions: (a) SOCl2, MeOH, 0 °C, 0.5 h, then rt, 12 h, 80%; (b) 2,4-dinitrobenzoic
acid, TEA, HOBt, DCC, CH2Cl2, 0 °C, 0.5 h, then rt, 12 h, 38%; (c) TBAFÁ3H2O, DMF,
115 °C, 20 min, 66%; (d) (1) LiOH, MeOH, 0 °C, 0.5 h, then rt, overnight, (2) 1 N HCl,
85%.
Scheme 2. Radiosynthesis of [18F]MFNBMB ([18F]1) and [18F]FNBMBA ([18F]2). Experimental reagents and conditions: (a) K [18F] F, Kryptofix 2.2.2., DMF, 115 °C, 20 min, 30–
40%; (b) (1) LiOH, MeOH, rt, 10 min, 2) 1 N HCl, >95%.

Y. Qiao et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4873–4877
4875
with 2 ml of MeCN containing 0.1% TFA. After evaporation of the
solvent, the residue was redissolved in 1 ml PBS and was injected
onto the analytical HPLC. The compounds were stable in blood
according to the analysis of HPLC.
tion. Obviously, uptakes in all the tissues and organs except for
that in femur decreased as time elapsed. Uptake in femur peaked
at 15 min post-injection and then reduced slightly with the lapse
of time indicating the stabilization of [18F]1 in vivo. Tumor had a
relatively high initial radioactivity uptake representing approxi-
mately 2.78 0.50 %ID/g, and decreased to 1.97 0.47 %ID/g, still
71% radioactivity retained, showing certain retention in tumor.
The blood uptake peaked immediately after injection, however, it
decreased rapidly to only 22%, 9% radioactivity retained at
30 min, 60 min, respectively. The tumor-to-blood (T/Bl) uptake ra-
tio was 2.91 at 30 min and 3.44 at 60 min post-injection, mean-
while, the tumor-to-brain (T/Br) uptake ratio was 7.06 at 30 min
and 5.61 at 60 min post-injection.
The in vivo biological evaluation of [18F]MFNBMB ([18F]1) and
[
18F]FNBMBA ([18F]2) were executed in female KM mice with S
180 tumor (animal experimental center, Peking University) weigh-
ing 20 2 g on average. The experimental processed were per-
formed 14–18 days after inoculating the mouse with 5 Â 106
tumor cells. The radiopharmaceuticals [18F]1 or [18F]2 radiosynthe-
sized as mentioned above was solved in 100 ll saline solution and
injected into the tail vein of awake mice subsequently placed into a
small cage. The injected activities per animal ranged from 240 to
370 kBq. These injected doses of [18F]1 or [18F]2 were tracer doses
without obvious pharmacological effects. The animals were sacri-
ficed at 5 min, 15 min, 30 min, 60 min or 120 min after radiotracer
injection, respectively. The tumor, brain and other organs to be
examined were immediately removed, weighed and measured
Compared with [18F]1, its corresponding F-18 labeled acid
[
18F]2 had significantly reduced uptakes in all tissues and organs,
nevertheless, uptake of [18F]2 still varied in the same way, that is
to decrease in a time-dependent pattern. The difference of absolute
radioactivity uptakes between the two F-18 labeled radiopharma-
ceuticals was mainly due to the discrepancy in their lipophilic
properties. Initial tumor absolute uptake was 1.37 0.68 %ID/g
which minished approximately 50% compared with ester [18F]1
in the same time point. Initial activity uptake in blood was
2.43 0.53 %ID/g which was decreased by more than 20% based
on [18F]1 and reduced rapidly to only 10%, 6% radioactivity retained
at 30 min, 60 min, respectively, which demonstrated a much faster
and thorough clearance than ester [18F]1. To our surprise, the tu-
mor-to-brain (T/Br) uptake ratio reached a maximum 13.30 (much
higher than [18F]1) at 30 min post-injection, meanwhile, the tu-
mor-to-blood (T/Bl) uptake ratio was 2.32 at the same time point.
for F-18 radioactivity in a
c counter. The uptake of F-18 radioactiv-
ity in tissues and organs was expressed as percentage of injected
dose per gram of tissue weight (%ID/g). The mean values were cal-
culated from the individual measurements taking into account the
background from the counter measurements and expressed at a
precision of standard deviation (mean SD, n = 4). The biological
evaluation data of [18F]MFNBMB and [18F]FNBMBA in mice bearing
S 180 tumor were summarized in Tables 1 and 2, respectively.
In the distribution data of [18F]1 shown as in Table 1, the radio-
activity uptakes demonstrated an extremely rapid distribution and
accumulation in all the tissues and organs at only 5 min after injec-
Table 1
Biodistribution data of [18F]MFNBMB ([18F]1) in mice bearing S 180 tumora
Organ
Time point (min)
5
15
30
60
120
Blood
Heart
Liver
Lung
Kidney
Femur
Muscle
Spleen
Brain
3.09 0.38
1.35 0.57
15.90 0.66
5 49 0.17
17.90 0.88
1.60 0.03
1.43 0.34
1.48 0.22
0.99 0.12
2.78 0.50
0.90
2.18 0.12
0.60 0.22
8.60 0.34
2.57 0.34
11.28 0.49
2.23 0.38
1.39 0.23
1.13 0.18
0.60 0.10
2.06 0.84
0.94
0.68 0.04
0.40 0.28
3.66 0.23
1.31 0.25
3.80 0.42
2.11 0.36
0.82 0.06
0.51 0.01
0.28 0.00
1.97 0.47
2.91
0.28 0.06
0.19 0.01
0.27 0.03
0.31 0.01
0.35 0.00
2.09 0.26
0.69 0.13
0.31 0.20
0.17 0.04
0.95 0.07
3.44
0.19 0.02
0.08 0.02
0.14 0.02
0.25 0.11
0.29 0.12
2.01 0.03
0.58 0.00
0.05 0.00
0.12 0.01
0.31 0.11
1.67
Tumor
Tumor/blood
Tumor/brain
Tumor/muscle
2.79
1.94
342
1.48
7 06
2.41
5 61
1 39
2 61
0.54
a
Values reported as means SD (n = 4 at each time point).
Table 2
Biodistribution data of [18F]FNBMBA ([18F]2) in mice bearing S 180 tumora
Organ
Time point (min)
30
5
15
60
120
Blood
Heart
Liver
Lung
Kidney
Femur
Muscle
Spleen
Brain
2.43 0.53
1.07 0.89
6.54 0.03
5.04 0.66
11.90 0.38
3.61 0.67
0.99 0.19
1.04 0.03
0.15 0.02
1.37 0.68
0.56
1.27 0.19
0.72 0.84
3.35 0.42
2.01 0.07
5.19 0.06
4.02 0.67
0.47 0.20
0.60 40.09
0.09 0.07
0.91 0.12
0.72
0.24 0.01
0.29 0.02
1.59 0.78
1.38 0.03
1.36 0.00
3.38 0.71
0.21 0.02
0.31 40.00
0.04 0.12
0.56 0.01
2.32
0.15 0.03
0.11 0.08
0.77 0.06
1.14 0.06
0.45 0.06
2.47 0.01
0.15 0.02
0.24 0.04
0.03 0.03
0.27 0.14
1.83
0.06 0.00
0.05 0.07
0.50 0.01
0.57 0.01
0.30 0.00
2.15 0.00
0.12 0.04
0.16 0.04
0.01 0.00
0.08 0.07
1.30
Tumor
Tumor/blood
Tumor/brain
Tumor/muscle
9.38
1.38
10 40
1.95
13.30
2.62
9 99
1.74
6.90
0.66
a
Values reported as means SD (n = 4 at each time point).

4876
Y. Qiao et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4873–4877
For the purpose of better evaluating their potential use as PET
tumor imaging agents, we executed the parallel biodistribution
experiments of [18F]FDG and -[18F]FET in the same animal model,
L
data of which were displayed in Tables 3 and 4.
In biodistribution data of [18F]FDG in Table 3, all tissues and or-
gans demonstrated substantially lower radioactivity uptakes ex-
cept for brain and tumor. For brain uptake, it achieved the
maximum at 30 min, then continuously decreased till 120 min
after injection. Evidently, uptake in brain had high values during
all the experimental period. To certain degree, however, its
[
18F]FDG’s high background uptake in normal brain that resulted
in the limitation of its application as a tumor imaging tracer, par-
ticularly for brain tumor. Tumor-to-brain uptake ratio was only
Figure 2. Comparison of blood clearance rates of [18F]1 and [18F]2 with those of
18F]FDG and -[18F]FET together in the same animal model bearing S 180 tumor.
[
L
1.33 at 120 min post-injection. Besides, for biological data of
[
30 min and subsequently decreased with time elapsed. While, tu-
mor-to-brain ratios varied from 2.10 to 2.95 and tumor-to-blood
ratios was only slightly more than 1.00 at 30 min and still less than
2.00 at 120 min.
L-
18F]FET in Table 4, both brain and tumor uptakes maximized at
shown in Tables 1–4, the radioactivity uptake in tumor and brain
peaked immediately at 5 min post-injection and continuously de-
creased till minimum for both [18F]1 and [18F]2 during all the exper-
imental period. Dissimilarly, tumor and brain uptake of [18F]FDG
and
Based on all these results, we summed up and compared tumor-to-
brain uptake ratios of [18F]1 and [18F]2 with those of [18F]FDG and
L
-[18F]FET first increased then decreased with the lapse of time.
From the comparison of blood clearance rates as summarized in
Figure 2, we can easily discover that radioactivity uptakes in blood
L-
[
[
18F]FET together in Figure 3. Patently, the T/Br ratios of compounds
of all F-18 labeled tracers ([18F]1, [18F]2, [18F]FDG and -[18F]FET)
L
18F]1 (2.61min–7.06max) reached 7.06 as the maximum at 30 min
were immediately peaked at 5 min post-injection and continuously
decreased till 120 min post-injection. Obviously, both [18F]1 and
post-injection which was much higher than the maximum
(0.53min–1.33max) of [18F]FDG (2.10min–2.95max) and that of
L
-
[
18F]2 had much lower absolute uptake values than -[18F]FET in
L
[
18F]FET showing much potential value as one of PET tumor radio-
blood from 5 min to 120 min post-injection. Moreover, compared
tracers. As for [18F]2, tumor-to-brain ratios excitingly achieved
13.30 at 30 min after injection with 6.90 as the minimum at
120 min, which demonstrated excellent properties to be an efficient
PET tumor imaging agent. In addition, maximums of T/Bl (2.32), T/Br
with [18F]FDG and -[18F]FET, the two radiotracers possessed much
L
faster blood clearance velocity in which the blood uptake dimin-
ished to only 22% uptake retained for [18F]1 and 10% for [18F]2 at
30 min after injection. Furthermore, in the biodistribution data as
Table 3
Biodistribution data of [18F]FDG in mice bearing S 180 tumora
Organ
Time point (min)
5
15
30
60
120
Blood
Heart
Liver
Lung
Kidney
Muscle
Spleen
Brain
Tumor
1.09 0.74
2.60 0.06
1.35 0.42
1.52 0 66
2.16 0.35
1.56 0.13
1.31 0.40
2.40 0.28
1.27 0.54
1.17
0.46 0.14
2.50 0.06
0.47 0.17
0.77 0.13
1.04 0.21
1.14 0.23
0 95 0.01
2.63 0.10
1.56 0.23
3.42
0.16 0.01
2.69 0.14
0.23 0.00
0.64 0.05
0.61 0.23
1.07 0.86
0.90 0.19
3.07 0.11
1.86 0.18
11.38
0.11 0.05
3.24 0.20
0.22 0.04
0.57 0.06
0.54 0.15
0.97 0.66
0.83 0.04
2.11 0.17
2.16 0.34
19.47
0.11 0.13
6.27 0.30
0.20 0.03
0.52 0.11
0.25 0.06
0.78 0.06
0.78 0.18
1.28 0.08
1.70 0.06
15.85
Tumor/blood
Tumor/brain
Tumor/muscle
0.53
0.81
0.59
1.37
0.61
1.75
1.02
2.23
1.33
2.20
a
Values reported as means SD (n = 4 at each time point).
Table 4
Biodistribution data of L-[18F]FET in mice bearing S 180 tumora
Organ
Time point (min)
30
5
15
60
120
Blood
Heart
Liver
Lung
Kidney
Muscle
Spleen
Brain
Tumor
6.81 0.95
5.89 1.23
7.67 1.34
16.80 2.98
6.58 0.84
2.88 1.33
3.34 0.51
0.99 0.24
2.08 0.49
0.31
3.30 0.25
3.41 0.31
5.60 0.30
9 82 0.45
6.79 0.23
3.34 0.41
5.42 0.31
1.03 0.12
2.50 0.23
0.76
3.23 0.33
3.27 0.37
4.23 0.28
8.57 0.63
2.38 0.43
2.69 0.96
1.16 0.61
1.29 0.09
3.28 0.69
1.02
2 51 0.36
3.14 0.26
3.56 0.29
4.70 0.41
3 75 0.49
2.37 0.38
3 37 0.34
0.94 0.23
2.75 0.36
1.10
1.12 0.21
0.94 0.36
1.22 0.51
1.55 0.73
1.25 0.21
2.10 1.33
1.22 0.37
0.73 0.21
2.15 1.36
1.92
Tumor/blood
Tumor/brain
Tumor/muscle
2.10
0.72
2.43
0.75
2.54
0.62
2.93
1.23
2.95
1.40
a
Values reported as means SD (n = 4 at each time point).

Y. Qiao et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4873–4877
4877
the cyclotron operator team of the PET Centre of Xuan Wu hospital,
for providing [18F]fluoride activity and technical assistance.
References and notes
1. Gibson, R. E.; Burns, H. D.; Hamill, T. G.; Eng, W.-S.; Francis, B. E.; Ryan, C. Curr.
Pharm. Des. 2000, 6, 973.
2. (a) Weber, W. A.; Avril, N.; Schwaiger, M. Strahlenther. Onkol. 1999, 175, 356;
(b) Delbeke, D. J. Nucl. Med. 1999, 40, 591; (c) Hoh, C. K.; Seltzer, M. A.; Franklin,
J.; deKernion, J. B.; Phelps, M. E.; Belldegrun, A. J. Urol. 1998, 159, 347; (d) Tang,
G. H. Acta Pharm. Sin. 2001, 36, 470.
3. (a) Conti, P. S.; Lilien, D. L.; Hawley, K.; Keppler, J.; Grafton, S. T.; Bading, J. R.
Nucl. Med. Biol. 1996, 23, 717; (b) Engel, H.; Steinert, H.; Buck, A.; Berthold, T.;
Huch-Boni, R. A.; von Schulthess, G. K. J. Nucl. Med. 1996, 37, 441; (c) Strauss, L.
G. Eur. J. Nucl. Med. 1996, 23, 1409.
4. Varagnolo, L.; Stokkel, M. P. M.; Mazzi, U.; Pauwels, E. K. Nucl. Med. Biol. 2000,
27, 103.
Figure 3. Comparison of tumor-to-brain uptake ratios of [18F]1 and [18F]2 with
those of [18F]FDG and
tumor.
L
-[18F]FET together in the same animal model bearing S 180
5. (a) Moon, B. S.; Lee, T. S.; Lee, K. C.; An, G. I.; Cheon, G. J.; Lim, S. M.; Choi, C. W.;
Chic, D. Y.; Chuna, K. S. Bioorg. Med. Chem. Lett. 2007, 17, 200; (b) Martarello, L.;
McConathy, J.; Camp, V. M.; Malveaux, E. J.; Simpson, N. E.; Simpson, C. P.;
Olson, J. J.; Bowers, G. D.; Goodman, M. M. J. Med. Chem. 2002, 45, 2250; (c)
Jager, P. L.; Vaalburg, W.; Pruim, J.; de Vries, E. G.; Langen, K. J.; Piers, D. A. J.
Nucl. Med. 2001, 42, 432.
6. (a) Wester, H. J.; Herz, M.; Weber, W.; Heiss, P.; Senekowitsch-Schmidtke, R.;
Schwaiger, M., et al J. Nucl. Med. 1999, 40, 205; (b) Heiss, P.; Mayer, S.; Herz, M.;
Wester, H. J.; Schwaiger, M.; Senekowitsch-Schmidtke, R. J. Nucl. Med. 1999, 40,
1367; (c) Weber, W. A.; Wester, H. J.; Grosu, A. L.; Herz, M.; Dzewas, B.;
Feldmann, H. J., et al Eur. J. Nucl. Med. 2000, 27, 542.
and T/M (tumor-to-muscle = 2.62) ratios appeared at the same time
point (30 min post-injection) and consequently acid [18F]1 can be
better than ester [18F]2 as the imaging agent. On one hand, [18F]1
and [18F]2 showed obvious advantages of biological properties in
biodistribution data when compared with [18F]FDG and -[18F]FET.
L
7. Wienhard, K.; Herholz, K.; Coenen, H. H.; Rudolf, J.; Kling, P.; Stocklin, G.; Heiss,
Besides, the two F-18 labeled fluoroarylvaline derivatives can be
easily and efficiently labeled with fluorine-18.Therefore, we expect
that the two tracers, especially the acid compound [18F]2, can have
potential application in tumor detection, particularly for brain tu-
W. D. J. Nucl. Med. 1991, 32, 1338.
8. Miura, S.; Murakami, M.; Kanno, I.; Iida, H.; Uemura, K. Nippon. Rinsho. 1992, 50,
1457.
9. Ito, H.; Hatazawa, J.; Murakami, M.; Miura, S., et al J. Nucl. Med. 1995, 36, 1232.
10. Structure analysis data. F-19 substituted ester 1: 1H NMR (500 MHz, CDCl3): d
8.28 (m, 1H, Ar-H), 8.15 (dd, J = 8.6, 1.8 Hz, 1H, Ar-H), 8.06 (dd, J = 11.0, 1.8 Hz,
1H, Ar-H), 7.22–7.19 (m, 1H, NH), 4.82–4.80 (m, 1H, CHCH(CH3)2), 3.82 (s, 1H,
OCH3), 2.35–2.33 (m, 1H, CH(CH3)2), 1.06–1.02 (s, 6H, CH(CH3)2); 13C NMR
(125 MHz, CDCl3): d 171.87, 161.15, 159.90 (d, 1C, JCF = 250.5 Hz), 150.31,
133.42, 126.58, 119.57, 112.26 (d, 1C, JCF = 30.0 Hz), 57.98, 52.45, 31.46, 19.01,
17.86; 19F NMR (400 MHz, CDCl3): d À109.37, À109.40, À109.42, À109.45; MS
(EI) m/z: 298.27, found: 299.13; Anal. Calcd for C13H15FN2O5: C, 52.35; H, 5.07;
N, 9.39. Found: C, 52.73; H, 4.79; N, 9.68. F-19 substituted acid 2: 1H NMR
(500 MHz, CDCl3): d 8.31 (m, 1H, Ar-H), 8.17 (dd, J = 8.5, 2.0 Hz, 1H, Ar-H), 8.07
(dd, J = 11.5, 2.0 Hz, 1H, Ar-H), 7.22–7.18 (m, 1H, NH), 4.87–4.84 (m, 1H,
CHCH(CH3)2), 2.46–2.39 (m, 1H, CH(CH3)2), 1.11–1.07 (m, 6H, CH(CH3)2); 13C
NMR (100 MHz, CDCl3): d 172.91, 163.42, 158.95 (d, 1C, JCF = 251.1 Hz), 149.49
(d, 1C, JCF = 9.0 Hz), 131.52 (d, 1C, JCF = 3.6 Hz), 131.07 (d, 1C, JCF = 16.6 Hz),
119.99 (d, 1C, JCF = 3.3 Hz), 112.38 (d, 1C, JCF = 27.5 Hz), 58.44, 30.18, 19.61,
18.49; 19F NMR (400 MHz, CDCl3): d À109.39, À109.42, À109.44, À109.47; MS
(EI) m/z: 284.24, found: 284.19; Anal. Calcd for C12H13FN2O: C, 50.71; H, 4.61;
N, 9.86. Found: C, 51.05; H, 4.34; N, 10.13.
mor imaging. In conclusion,
[
18F]FNBMBA ([18F]1) and
[
18F]MFNBMB ([18F]2) designed and synthesized in this study, par-
ticularly the acidic F-18 labeled product ([18F]2), demonstrate po-
tential value as more useful PET radiotracers for tumor imaging
than [18F]FDG and -[18F]FET. As an elementary study of [18F]1 and
L
[
18F]2 to be the potential PET radiotracers, however, our research
on such [18F]fluoroarylvaline derivatives still needs more investiga-
tion and further evaluation of them with PET to be better.
Acknowledgments
We acknowledged with thanks for financial supports from the
National Natural Science foundation of China (No. 20371009 and
20671014) and Beijing Key Subject Program. We also wish to thank