Radiofluoridations of m-substituted nitrobenzenes

Article abstract of DOI:10.1002/jlcr.515

The fluoridation of a range of m-substituted nitrobenzenes with no-carrier-added [18F]fluoride was investigated. Electron-deficient m-substituted nitrobenzenes react with no-carrier-added [18F]fluoride to give 18F-labelled m-disubstituted benzenes in low

Full text of DOI:10.1002/jlcr.515

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Labelled Cpd Radiopharm 2001; 44: 889–898.
DOI: 10.1002/jlcr.515
Research Article
7
The sequential syntheses of [ Br]FBAU
6
0
0
76
,5 -dibenzoate and [ Br]FBAU
3
Chih-Hao K. Kao*, Mark B. Sassaman, Lawrence P. Szajek, Ying Ma,
y
Atsuo Waki and William C. Eckelman
Positron Emission Tomography Department, Warren Grant Magnuson Clinical
Center, National Institutes ofHealth, Buildin g 10, Room 1C/401, Bethesda,
MD 20892, USA
Summary
Thymidine analogs labeled with positron emitting radionuclides are potential
proliferation markers for positron emission tomography (PET). Bromine-76
(
T1/2=16.2 h) is ourchoice of ar dionuclide, because it allows formaximal
7
DNA incorporation of the tracer. Following the literature descriptions, Br
6
7
was produced using the As ( He, 2n) Br reaction. We then recovered Br
5
3
76
76
7
6
from the target in the form of [ Br]NH Brwith a yield of 60 Æ 12% (n ¼ 32).
4
Peracetic acid was used as the oxidant for electrophilic bromodestannylation to
6
7
0
0
prepare [ Br]FBAU 3 ,5 -dibenzoate (71.2 Æ 12.1%, RCY) and a basic
7
6
hydrolysis of the dibenzoate then yielded [ Br]FBAU. The yield of the
hydrolysis reaction was 53.1 Æ 9.2% when heated at 1008C for15 min or
quantitative (decay corrected) when left at room temperature overnight. The
7
6
0
0
76
sequential synthesis of [ Br]FBAU 3 ,5 -dibenzoate and [ Br]FBAU allowed
us to perform a side-by-side comparison of their metabolic stabilities. While
7
6
0
0
76
Br]FBAU 3 ,5 -dibenzoate was hydrolyzed to [ Br]FBAU within 10 minutes
[
7
6
76
ꢀ
by hepatocyte at 378C, [ Br]FBAU was stable and no [ Br]Br was released
from either radiopharmaceutical. Both compounds are potential proliferation
markers for PET. Copyright # 2001 John Wiley & Sons, Ltd.
Key Words: bromine-76; thymidine; proliferation marker; PET; FBAU
*Correspondence to: C-H. K. Kao, NIH/CC/PET 10/1C495, 10 Center Drive MSC 1180,
Bethesda, MD 20892, USA. E-mail: CK132j@nih.gov
y
Current address: Biomedical Imaging Research Center, Fukui Medical University, Matsuoka,
Fukui 910-1193, Japan.
Copyright # 2001 John Wiley & Sons, Ltd.
Received 9 March 2001
Revised 10 May 2001
Accepted 2 August 2001

8
90
C-H. K. KAO ET AL.
Introduction
Thymidine and its analogs have been labeled with various radioactive
nuclides to assess proliferation potential using positron emission
tomography (PET) or single photon emission computed tomography
(SPECT). Ideally, a close relationship between the tracer uptake and
rapidly proliferating cells would be established. The early attempts using
1
1
[
allow the observation of DNA incorporation and presented analytical
C]thymidine forPET studies lacked the long physical half-life to
1
–5
difficulties.
analogs, iodo- and bromo-deoxyuridine, were extensively used in the
Separately, the iodinated and brominated thymidine
6
,7
histological assessment of proliferation.
7
Forimaging p up roses,
7
123
Br]bromodeoxyuridine (BrdU), [ I]iododeoxyuridine, [ I]iodo-
131
[
deoxyuridine and, most recently, [ Br]BrdU have been developed as
76
8–11
potential tracers.
These nuclides all provide half-lives long enough
for extended observations. Unfortunately, these tracers suffer from
rapid metabolism and thus have a very short biological half-life. A study
8
using [ Br]BrdU showed that 90% of plasma radioactivity was
2
8
2
ꢀ
12
[
life of 12 days in humans.
Br]Br afteronly 10 min.
Bromide is poorly excreted with a half-
Once radioactive bromide is released, the
background radiation becomes too great to perform high contrast
1
3,14
76
imaging studies. In a study using [ Br]BrdU, attempts to force
excretion with diuretics and supplemental chloride replacement was
1
not entirely successful in reducing background activity. The rapid
5
76
dissociation of [ Br] as bromide in vivo not only impaired the imaging
7
possibility, but also defeated the purpose of choosing Bras the nuclide
6
7
6
of interest for labeling. The main advantage of using Brlabeled
compounds forPET imaging is to exploit its 16.2 h half-life for
applications with slow kinetics.
124
Meanwhile, [ I]5-iodo-1-(2-deoxy-2-fluoro-b-d-arabinofuranosyl)-
16
11
uracil (FIAU) and [ C]5-methyl-1-(2-deoxy-2-fluoro-b-d-arabinofur-
17
anosyl) uracil (FMAU) have been developed forimaging t ar nsgene
expression with PET. These tracers were shown to be good substrates
for the herpes simplex virus thymidine kinase gene (HSV1-tk) selected
as a marker gene. The 2-fluoro substitution greatly reduced the
metabolism of nucleosides compared to deoxyuridine-type analogs.
This attribute will, in principle, eliminate much of the background
radiation due to free 5-halouracil or dehalogenated uracil. Very
7
6
76
18
recently, [ Br]bromofluorodeoxyuridine ([ Br]BFU) was developed.
76
The study in rats showed [ Br]BFU was indeed much more stable than
Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 889–898

7
6
0
0
THE SEQUENTIAL SYNTHESES OF [ BR]FBAU 3 ,5 -DIBENZOATE
891
7
6
[
Br]BrdU in vivo and produced very limited amount of bromide.
However, the low metabolism of the tracer did not increase its
standardized uptake value, because 70% of injected activity was
eliminated as intact compound through urinary excretion. Nevertheless,
76
the study suggested that [ Br]BFU was incorporated into DNA, and
has potential as a proliferation marker for PET.
7
In this study, we report the sequential preparation of [ Br]1-(2-
6
7
6
fluoro-2-deoxy-3,5-O-dibenzoyl-b-d-arabanofuranosyl)-5-bromouracil([ Br]-
0
0
76
FBAU3 ,5 -dibenzoate) and [ Br]1-(2-fluoro-2-deoxy-b-d-arabanofur-
anosyl)-5-bromouracil ([ Br]FBAU). We also show the results of the
76
7
hepatocyte metabolism studies of these two Brcompounds.
6
Results and discussion
7
6
76
Production of Br and preparation of[ Br]NH Br
4
Bromine-76 is routinely produced on-site at the NIH Clinical Center
utilizing the helium-3 capacity of the Cyclotron Corporation CS30
cyclotron. We use low cost natural arsenic metal as target to prepare
7
6
75
3
76
19,20
76
Brin the As ( He, 2n) Brnuclear re action.
A
Brp ro duction
rate of 0.39 Æ 0.09 mCi/mA h (n ¼ 32) was obtained. Using 17 MeV
3
75
77
incident He particles, 0.4 Æ 0.1% Br(1.61 h) and 1.4 Æ 0.3% Br
(
57 h) were observed as radionuclidic impurities at 18 h post-EOB.
To isolate bromine activity from the target, we encountered problems
7
obtaining [ Br]NH Brusing established methods.
6
21–23
Specifically,
4
there was a substantial amount of ammonium sulfate contamination in
the products, and when these products were used for labeling,
radiochemical yields were usually very low. We then modified the
76
distillation method of [ Br]NH Br preparation, so that the ammonium
4
sulfate contamination was negligible. The modified procedure also
shortened the time of preparation to less than 1 h and the bromine
activity was recovered from the target in 60 Æ 12% (n ¼ 32) decay
corrected yield.
7
6
0
0
76
Syntheses of[ Br]FBAU 3 ,5 -dibenzoate and [ Br]FBAU and
the metabolic study
7
6
0
In this study, we synthesized [ Br]FBAU 3 ,5-dibenzoate and
7
6
[
Br]FBAU in sequence (Scheme 1) for the purpose of side-by-side
Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 889–898

8
92
C-H. K. KAO ET AL.
7
Scheme 1. Preparation of [ Br]FBAU via its ester intermediate
6
FSAU 3’,5’-dibenzoate
1
Purification
Rad
UV
[Br-76]FBAU 3’,5’-dibenzoate
2
Quality Control
Rad
UV
0
10
20
30
40
Retention Time (min)
7
Figure 1. [ Br]FBAU 3 ,5 -dibenzoate (71.2%, RCY) was separated from the
6
0
0
trimethylstannyl precursor easily. Quality control revealed good chemical and
0
0
radiochemical purities, but a measurable amount of FBAU 3 ,5 -dibenzoate
30 ng) lowered the specific activity
(
7
6
0
0
comparison in the subsequent metabolic study. [ Br]FBAU 3 ,5 -
dibenzoate was prepared using an electrophilic substitution reaction
from 1-(2-fluoro-2-deoxy-3,5-O-dibenzoyl-b-d-arabanofuranosyl)-5-tri-
0
0
24
76
methylstannyluracil (FSAU 3 ,5 -dibenzoate) and [ Br]FBAU was
0
7
6
0
prepared by basic hydrolysis of [ Br]FBAU 3 ,5 -dibenzoate.
0
0
The trimethylstannyl moiety of FSAU 3 ,5 -dibenzoate is more
0
76
0
lipophilic than the bromide of [ Br]FBAU 3 ,5 -dibenzoate and thus,
the excess precursor is easily separated from the product by HPLC
7
6
ꢀ
(
Figure 1). The oxidation of [ Br]Br was carried out by dilute
peracetic acid (0.3%) and the electrophilic substitution was completed
in acetic acid at room temperature in 20 min. We also found that when
higher amounts of peracetic acid and hydrogen peroxide were used as
oxidants in the presence of chloride, a large amount of chlorinated
Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 889–898

7
6
0
0
THE SEQUENTIAL SYNTHESES OF [ BR]FBAU 3 ,5 -DIBENZOATE
893
0
0
analog was produced. The bromo and chloro analogs of the 3 ,5 -
dibenzoate compounds have nearly the same polarity and cannot be
adequately separated by our HPLC system (experimental details not
shown). Thus, the chloro analog could dilute the effective specific
76
0
0
activity of [ Br]FBAU 3 ,5 -dibenzoate. We also avoided using
chloramine-T and N-chlorosuccinamide as oxidants for the same
reason.
0
0
When using FSAU 3 ,5 -dibenzoate, one needs to be careful about the
reaction conditions chosen, due to the propensity towards protodes-
tannylation in the presence of strong acids. Once destannylated, there
can be no regioselective radiobromination. It was determined
0
0
that FSAU 3 ,5 -dibenzoate was stable in acetic acid forat least
0 min but destannylated instantaneously if a trace of HCl was added.
Both the destannylated product (retention time (RT): 14.7 min)
3
and the trimethylstannyl precursor (RT: 35.0 min) can be easily
0
76
0
separated from [ Br]FBAU 3 ,5 -dibenzoate (RT: 25.0 min) (Figure 1,
chromatogram 1).
The reaction produced one major radioactive species, which was
7
6
0
0
identified to be [ Br]FBAU 3 ,5 -dibenzoate by a co-injection with the
0
0
authentic FBAU 3 ,5 -dibenzoate (synthesized according to Refer-
2
4,25
ences.
). The rest of the activity eluted out at the polar region and
there was also activity still retained on the HPLC column. The
radiochemical yield based on the final purified product was
7
1.2 Æ 12.1% (n ¼ 7). Quality control showed that the product was
radiochemically pure and had good chemical purity. (Figure 1,
chromatogram 2) The specific activity was determined to be
0
.6 Ci/mmol.
7
6
[
Br]FBAU was prepared by hydrolysis of the benzoyl groups of
0
7
6
0
[
Br]FBAU 3 ,5 -dibenzoate in base. After15 min at 100 8C, the
hydrolysis was complete. However, only 53.1 Æ 9.2% (n ¼ 5) of the
activity eluted as [ Br]FBAU. (Figure 2, chromatogram 1) The
76
7
6
ꢀ
remainder eluted earlier and was later determined to be [ Br]Br by
TLC. The hydrolysis was also performed at room temperature, and
after an overnight reaction, a quantitative yield was afforded with decay
correction. (Figure 2, chromatogram 2) The radiochemical purity was
>
was a hydrolyzed product of the purified [ Br]FBAU 3 ,5 -dibenzoate,
97% after purification and was chemically pure. As this compound
7
6
0
0
76
76
the specific activity of [ Br]FBAU differed from that of the [ Br]FBAU
0
0
76
,5 -dibenzoate only by the Brdecay overthe time lapsed between the
3
two preparations.
Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 889–898

8
94
C-H. K. KAO ET AL.
1
{
Br-76]bromide
1
00 C, 15 min
RAD
UV
[
Br-76]FBAU
2
RT, overnight
2
RAD
UV
0
4
6
8
10
12
14
Retention Time (min)
7
6
Figure 2. Hydrolysis of [ Br]FBAU 3 ,5 -dibenzoate under two different
0
0
7
conditions produced [ Br]FBAU with different yield
6
Our sequential syntheses produced
0
a
Br]FBAU 3 ,5 -dibenzoate, which can be used as a lipophilic prodrug
diester intermediate,
7
6
0
[
of [ Br]FBAU for certain applications. In fact, incubation of
7
6
7
6
0
0
[
produced complete deesterification to [ Br]FBAU in less than 10 min.
Br]FBAU 3 ,5 -dibenzoate with eitherhuman o rar t hepatocytes
76
7
6
Furthermore, [ Br]FBAU remained intact, with no further degradation
by hepatocytes forat least 4 h.
Experimental
7
6
76
Cyclotron production of Br and preparation of[ Br]NH Br
4
76
The cyclotron production of Brwas based on the established
1
9,20
procedure.
a single-use aluminum external target cup equipped with a 0.38 mm
In short, natural arsenic metal (200 mg) was pressed in
3
aluminum degrader that reduced the He incident beam energy to
1
7 MeV.Targets were irradiated at 20 mA for1 to 3 h and p ro cessed after
75
sufficient decay of Br( T1=2 ¼1.61 h).
To obtain [ Br]NH Br for labeling, the arsenic target and
76
4
Na Cr O ꢁ H O (1.5 g) were mixed in a distillation flask before the
2
2
7
2
aqueous sulfuric acid (50% v/v, 10 ml) was added. The mixture was
heated at 1258C for 30 min. The activity carried over by nitrogen was
trapped in 2 N NH OH. The NH OH solution containing [ Br]NH Br
7
6
4
4
4
was then evaporated to dryness before being reconstituted by water for
labeling applications.
Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 889–898

7
6
0
0
THE SEQUENTIAL SYNTHESES OF [ BR]FBAU 3 ,5 -DIBENZOATE
895
76
Synthesis of[ Br] 1-(2-fluoro-2-deoxy-3,5-O-dibenzoyl-b-d-arabanofur-
anosyl)-5-bromouracil ([ Br]FBAU 3 ,5 -dibenzoate)
76
0
0
1
-(2-Fluoro-2-deoxy-3,5-O-dibenzoyl-b-d-arabanofuranosyl)-5-trimethyl-
24
stannylsuracil (synthesized based on ) (0.12 mg,. 0.20 mmol) was
dissolved in peracetic acid (80 ml, 0.3% v/v in acetic acid). To this
solution was added [ Br]NH Brsolution in water(10 ml, 1.86 mCi or
76
4
6
8 MBq). The mixture was allowed to stand at the room temperature for
0 min.Without quenching the reaction, the entire volume of the
3
reaction was injected onto a HPLC for purification. The HPLC system
used for purification comprised Gilson gradient HPLC pumps (model
3
05 and 306), adjustable wavelength UV detector(model 151), f ra ction
collector(model 203b), and a Beckman ar diation detectorequipped
with a NaI probe. Gilson UniPoint software controlled the system. The
system was equipped with a Phenomenex, Luna 5m C18(2) column
(4.6 mm ꢂ 250 mm). An isocratic mobile phase of acetonitrile/water (50/
5
2
0) running at 1 ml/min then eluted out the product at 25.0 min. At
6 min, the mobile phase was changed to 90% acetonitrile to elute out
the remaining stannous precursor. The collected product (1.25 mCi or
6 MBq) was passed through a SepPak C18 Light cartridge and
collected in 0.3 ml of EtOH. Without further formulation, the EtOH
4
7
6
0
0
solution of [ Br]FBAU 3 ,5 -dibenzoate was used for the preparation of
7
6
[
Br]FBAU or for the in vitro metabolism study.
Quality control and specific activity determination were performed by the
following procedures. The ethanol solution (15 ml) of the product (typically
0–80 mCi) was injected into the same HPLC system used forpu ir fication.
Wavelength forUV detection was set at 276 nm, an abso rp tion peak forthe
3
0
0
authentic FBAU 3 ,5 -dibenzoate, and the sensitivity was set so that 0.01 mg
gave rise to a distinguishable peak. The integration under the UV peak was
0
0
compared to the standard curve of the absorption generated by FBAU 3 ,5 -
).
24,25
dibenzoate (synthesized based on
76
Synthesis of[ Br] 1-(2-fluoro-2-deoxy-b-d-arabanofuranosyl)-5-bro-
mouracil ([ Br]FBAU)
7
6
76
0
0
To the ethanol solution of [ Br]FBAU 3 ,5 -dibenzoate (20 ml, 2.0 mCi.
or74 MBq) was added a solution of 3 N NaOH (20 ml). The reaction
mixture was sealed in a 1 ml v-vial and heated at 1008C for15 min.After
cooling down, the solution was neutralized by 3 N HCl (20 ml).
Alternatively, the reaction mixture was kept at room temperature
overnight before being neutralized.
Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 889–898

8
96
C-H. K. KAO ET AL.
The entire solution was then injected into HPLC for purification. The
7
HPLC system was the same one used in the preparation of [ Br]FBAU
6
0
0
3
,5 -dibenzoate. The column used was a Supelco Supelcosil LC18S
column (4.6 mm ꢂ 250 mm). Phosphate buffer(pH 5, 0.05 M) with 9%
EtOH running at 1 ml/min eluted the product, and the fractions
collected between 9.0 and 10.0 min were combined to give the product.
The authentic FBAU used forco-injection was synthesized acco rd ing to
2
6,27
established methods.
reconstituted in EtOH for the in vitro metabolism studies. Quality
The HPLC solvent was evaporated and
7
control was performed by a procedure similar to that of the [ Br]FBAU
6
0
0
3
,5 -dibenzoate.
7
6
0
0
76
Incubation of[ Br]FBAU 3 ,5 -dibenzoate and [ Br]FBAU with
hepatocytes
The cryo-preserved hepatocytes from both male Sprague–Dawley rats
and male human livertissue we re thawed at 37 8C in a waterbath and
gradually diluted with cell culture medium (RPMI Medium 164O
media, Life Technologies, Rockville, MD). Afterwashing the cells with
the medium, the viable cell concentration was adjusted to 1.0 million/ml.
The resulting cell suspension was then incubated at 378C for15 min
76
0
0
before 20 ml EtOH solution of [ Br]FBAU 3 ,5 -dibenzoate (100 mCi, or
.7 MBq) was added to the suspension. The suspension was maintained
3
at 378C, and at 10, 30, 60, 120 and 240 min, 100 ml of cell suspension was
removed and mixed with 100 ml of EtOH. The mixture was centrifuged
at 5000 rpm for 5 min, and the supernatant (20 ml) was injected onto an
HPLC for analysis. The entire procedure was repeated for the
76
incubation of [ Br]FBAU.
Conclusion
7
Bromine-76 was produced on site based on the As ( He, 2n) Br
5
3
76
7
6
76
Br generated was recovered as [ Br]NH Br
4
nuclear re action and the
76
0
0
76
Br]FBAU 3 ,5 -dibenzoate and [ Br]FBAU were
forlabeling. [
successfully synthesized in sequence to provide both Brcompounds
forside-by-side compa ri son of theirmetabolic stabilities. Incubations of
7
6
7
both compounds with hepatocytes showed that [ Br]FBAU 3 ,5 -
76
dibenzoate was quickly metabolized to [ Br]FBAU, while [ Br]FBAU
6
0
0
76
76
ꢀ
was stable forup to 4 h. No [ Br]Br was released from either
Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 889–898

7
6
0
0
THE SEQUENTIAL SYNTHESES OF [ BR]FBAU 3 ,5 -DIBENZOATE
897
compound. Both compounds are good candidates for further studies to
establish their potential as proliferation markers for PET.
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Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 889–898