Radiosynthesis of 13N-labeled thalidomide using no-carrier-added [13N]NH3

Article abstract of DOI:10.1002/jlcr.1699

Recent studies revealed that thalidomide (1) has unique and broad pharmacological effects on multi-targets although the application of 1 in therapy is still controversial. In this study, we synthesized nitrogen-13-labeled thalidomide ([¹³N]1) as a potential positron emission tomography (PET) probe using no-carrier-added [¹³N]NH ₃ as a labeling agent. By use of an automated system, [ ¹³N]1 was prepared by reacting N-phthaloylglutamic anhydride (2) with [¹³N]NH₃, following by cyclization with carbonyldiimidazole in a radiochemical yield of 56±12% (based on [ ¹¹N]NH₃, corrected for decay) and specific activity of 49±24GBq/μmol at the end of synthesis (EOS). At EOS, 570-780MBq (n=7) of [¹³N]1 was obtained at a beam current of 15 μA after 15 min proton bombardment with a synthesis time of 14 min from the end of bombardment. Using a small animal PET scanner, preliminary biodistribution of [ ¹³N]1 in mice was examined. Copyright

Full text of DOI:10.1002/jlcr.1699

Research Article
Received 26 January 2009,
Revised 16 October 2009,
Accepted 21 October 2009
Published online 14 January 2010 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1699
13
Radiosynthesis of N-labeled thalidomide
using no-carrier-added [13N]NH3
Katsushi Kumata,a Makoto Takei,a,b Masanao Ogawa,a,c Joji Yui,a
Ã
Akiko Hatori,a Kazutoshi Suzuki,a and Ming-Rong Zhanga
Recent studies revealed that thalidomide (1) has unique and broad pharmacological effects on multi-targets although the
application of 1 in therapy is still controversial. In this study, we synthesized nitrogen-13-labeled thalidomide ([13N]1) as a
potential positron emission tomography (PET) probe using no-carrier-added [13N]NH3 as a labeling agent. By use of an
automated system, [13N]1 was prepared by reacting N-phthaloylglutamic anhydride (2) with [13N]NH3, following by
cyclization with carbonyldiimidazole in a radiochemical yield of 56712% (based on [11N]NH3, corrected for decay) and
specific activity of 49724 GBq/mmol at the end of synthesis (EOS). At EOS, 570–780 MBq (n = 7) of [13N]1 was obtained at a
beam current of 15 mA after 15 min proton bombardment with a synthesis time of 14 min from the end of bombardment.
Using a small animal PET scanner, preliminary biodistribution of [13N]1 in mice was examined.
Keywords: nitrogen-13; positron emission tomography; [13N]thalidomide; automated synthesis
action mechanism and to image new targets through in vivo
evaluation in animals. So far, 18F-labeled 1 has been synthesized;
however, the introduction of 18F into the small molecule changed
Introduction
Thalidomide (2-(2,6-dioxo-3-piperidyl)isoindoline-2,3-dione, 1;
Scheme 1) was first developed in 1956 as a drug with sedative
and hypnotic effects. However, due to its catastrophic effects on
fetal malformations, this drug was withdrawn from the market in
the 1960s. In recent years, interest in 1 has been increasing for
the treatment of several diseases: rheumatoid arthritis,1 AIDS,2
leprosy,3 Crohns disease,4 cancer related to pathologic angio-
genesis.5,6 The unique and broad pharmacological effects of this
agent have been approved in the USA for the treatment of
erythema nodosum leprosum. Recent studies revealed that this
drug is an agent acting on multi-targets and is still under study
for other diseases.7,8 However, because the precious mechan-
isms of the therapeutic and side effects are unknown, the
application of 1 in therapy is still controversial.9
Positron emission tomography (PET) is a useful medical
imaging method using radioactive probes labeled with positron
emitting radioactive isotopes, such as 11C, 18F, and 13N. PET can
be used to provide pharmacokinetic and pharmacodynamic
information about a drug in living bodies to determine the drug
efficacy and potential biochemical mechanisms of drug action,
including the side and toxic effects.10 The effectiveness of PET
prompted us to label 1 using a positron emitter to elucidate its
the structure of 1, which may also change its pharmacological
profile, such as binding affinity, bioavailability and pharmacoki-
netics etc.11 Labeling 1 with 11C was also performed; however, no
in vitro and in vivo evaluation in animals was reported.12
Herein, we labeled 1 with 13N and determined the biodis-
tribution of [13N]1 in mice as a novel PET probe (Scheme 1). The
short half-life (9.965 min; 100% b1 decay) of 13N has the
advantage that repeated studies can be performed on the same
individual. Compared with other positron emitters such as 11C
and 18F, PET scans using a [13N]ligand cause relatively low
radiation damage on the subject. [13N]1 does not change the
pharmacological profiles of 1, which could provide real and
accurate information. On the other hand, in PET study with high
specific activity, generally about 10 nmol of labeled compound
is introduced into the living body, so the pharmacological effect
induced by the amount of molecules on the subject is usually
negligible. However, although there were a number of reports
about the syntheses of [13N]ligands using low specific activity
[13N]NH3 or carrier-added [13N]NH3,13–17 no [13N]ligands with
high specific activity except [13N]NH3 have been used for
aDepartment of Molecular Probes, Molecular Imaging Center, National Institute
of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
bTokyo Nuclear Service Co. Ltd., 7-2-7 Ueno, Taito-ku, Tokyo 110-0005, Japan
cSHI Accelerator Service Co. Ltd., 5-9-11 Kitashinagawa, Shinagawa-ku, Tokyo
141-8686, Japan
*Correspondence to: Ming-Rong Zhang, Department of Molecular Probes,
Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1
Anagawa, Inage-Ku, Chiba 263-8555, Japan.
Scheme 1. Chemical structures of thalidomide1 and [13N]thalidomide ([13N]1).
E-mail: zhang@nirs.go.jp
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Kumata et al.
biological evaluation. Owing to the short half-life of 13N and
easy contamination by the nitrogen carrier, practical labeling
technique using no-carrier-added [13N]NH3 has not been
established well except our recent result.18 About 10 years
ago, Suzuki et al. developed an automated synthetic system to
produce [13N]NH3 with ultra-high specific activity (1850 GBq/
mmol).19 Using this system, they have prepared p-nitrophenyl
[13N]carbamate by reacting the corresponding chloroformate
with nca [13N]NH3.20
In this study, by use of an automated synthesis system, we
synthesized [13N]1 using anhydrous [13N]NH3 gas as a labeling
agent. Then, we performed a preliminary biodistribution study
of [13N]1 on mice using a small animal PET scanner. This is the
first report about the synthesis and preliminary distribution of a
promising PET probe labeled with no-carrier-added [13N]NH3.
Radiosynthesis
Anhydrous [13N]NH3 gas for labeling was produced according to
the procedures reported previously with some modifications.19
The nuclear 16O(p, a)13N reaction in the target generated an
aqueous [13N]NH3 solution that was quickly passed through a
pre-conditioned cation exchange column to concentrate
[13N]NH3 onto the column. Then, [13N]NH3 was released with
aqueous KOH solution and passed through a hot column filled
with CaO to give anhydrous [13N]NH3 gas, which was introduced
into a cooled vessel containing 2. From the end of bombard-
ment (EOB), the preparation of anhydrous NH3 took about 4 min.
The specific activity of [13N]NH3 used for the experiment was
50–80 GBq/mmol at the end of [13N]NH3 synthesis.
Radiosynthesis of [13N]1 was performed according to
Scheme 3. After [13N]NH3 (about 0.1 mmol) trapping into a
solution of 2, the reaction mixture was heated at 1301C for
2 min. The reaction of 2 with [13N]NH3 gave [13N]3 only with a
radiochemical yield of 20% (corrected for decay). We assumed
that trace mass of [13N]NH3 was trapped by the carboxylic acid
moiety of [13N]3. This was supported by the result that the
addition of unlabeled NH3 (100 mmol) improved [13N]ammono-
lysis efficiency to 68%. However, the addition of NH3 resulted in
a marked decrease of specific activity (o10 MBq/mmol) of [13N]3.
A PET probe with too low specific activity could not give high-
quality images of specific binding.20 To liberate [13N]NH3 from
[13N]3, in place of unlabeled NH3, i-Pr2NEt was added to the
reaction mixture before the [13N]NH3 trapping. This treatment
increased [13N]ammonolysis efficiency to 76%.
Following [13N]ammonolysis, CDI was added to the mixture,
which was continuously heated for 2 min to accomplish cyclization
to form [13N]1. The radioactive mixture was loaded onto a normal
phase semi-preparative HPLC system. After HPLC purification,
[13N]1 was obtained with a radiochemical purity of 98% and a
specific activity of 49724 GBq/mmol (n = 7). Starting from
3–4.4 GBq (15 mA, 15 min proton bombardment) of [13N]NH3,
Results and discussion
Chemical synthesis simulating radiosynthesis
Prior to radiosynthesis, we determined a route for synthesizing 1
using unlabeled NH3 (Scheme 2). In the previous synthesis of
unlabeled 1, urea, glutarimide or glutamine was used to
introduce N into the final product, which required relatively
long reaction times.21–24 Obviously, the routes were not suitable
for radiosynthesis with [13N]NH3, because common radiosynth-
esis must be accomplished within a short time, compatible with
the half-life of 13N, using only limited step sequences. In the
present route, a solution of anhydrous NH3 in DMF was reacted
with N-phthaloylglutamic anhydride (2) to yield the amide
intermediate 3, which was cyclized with carbonyldiimidazole
(CDI) to form 1 with a total chemical yield of 68%. To shorten the
synthesis time while guaranteeing the reaction efficiency, two
treatments were administered here: (1) heating the two-step
reaction mixtures at 1301C for 2 min twice; (2) achieving one-pot
synthesis without purifying 3.
Scheme 2. Chemical synthesis of 1.
Scheme 3. Radiosyntheis of [13N]1.
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Kumata et al.
570–780 MBq (n= 7) of [13N]1 was obtained at the end of synthesis to a minimal extent. After the probe injection, radioactivity
(EOS) as an injectable solution. This amount of radioactivity was immediately appeared in the lung and heart but decreased
enough for animal experiments. The radiochemical yield and rapidly. High reactivity in the liver, gall bladder and small
purity of [13N]1 was 56712% based on [13N]NH3 (corrected intestine from the early time period suggested biliary excretion
for decay) and 497%. The average production time from the of this probe. In the blood, the radioactivity displayed a rapid
recovery of [13N]NH3 to the formulation of [13N]1 was about initial decline and then remained at a steady level. In the brain, a
14 min. The synthesis time was thus only slightly longer than the high initial uptake was observed and radioactivity decreased
half life of 13N. In the final product solution, no significant peak slowly over time, suggesting that [13N]1 could pass through
relative to CDI, 2 and their decomposition products was detected. blood–brain barrier, a prerequisite as a promising PET probe for
Moreover, the radiochemical purity of [13N]1 remained \gt 95% brain imaging. Now, we are evaluating [13N]1 using several
after maintaining the preparation at room temperature for 60 min, animal models, including neuroinflammation and tumor. The
indicating that this PET probe was radiochemically stable for the data will be reported elsewhere.
time compatible with that of a PET scan.
Experimental
Biodistribution
Materials and general methods
The preliminary biodistribution of [13N]1 in mice (n = 3) was
determined using a small animal scanner (Figure 1). Owing to Melting points were uncorrected. Nuclear magnetic resonance
the relatively high specific activity of [13N]1, the mass of [13N]1 (1H-NMR) spectra were recorded on a JNM-GX-270 spectrometer
injected into the living body of mice was less than 200 ng. Thus, (JEOL, Tokyo) with tetramethylsilane as an internal standard. All
the pharmacological effects of 1 on the mice may be decreased chemical shifts (d) were reported in parts per million downfield
0-1 min
4-6 min
14-16 min
25-30 min
55-60 min
Brain
Gall bladder
Liver
Heart
Intestines
(a)
8.0
1.6
1.2
0.8
0.4
0.0
Blood
Brain
6.0
4.0
2.0
0.0
0
10 20 30 40 50 60
0
10 20 30 40 50 60
Time (min)
4.0
3.0
2.0
1.0
0.0
2.0
1.6
1.2
0.8
0.4
0.0
Liver
Kidney
(b)
0
10 20 30 40 50 60
0
10 20 30 40 50 60
Figure 1. Biodistribution of [13N]1 in mice (n = 3). A: Typical static micro PET images at different time points after tracer injection. B: Time–activity curves of [13N]1 in
mouse brain, blood, liver and kidneys. Radioactivity was detected and expressed as SUV. The SUV value (mean7SD, n = 3) was calculated according to the following
formula: measured activity concentration (Bq/mL) Â body weight (g)/injected activity (Bq).
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Kumata et al.
from the standard. Fast atom bombardment mass spectra (FAB- Preparation of [13N]thalidomide ([13N]1)
MS) were obtained on a JEOL NMS-SX102 spectrometer (JEOL,
Anhydrous [13N]NH3 gas was bubbled into a reaction vessel
containing 2 (2.0 mg), i-Pr2NEt (5 mL) and anhydrous DMF (1 mL)
cooled to À151C. After radioactivity reached a plateau, the
reaction vessel was warmed to 1301C and maintained for 2 min.
A solution of CDI (10 mg) in DMF (300 mL) was added to the
mixture, which was heated for another 2 min. The radioactive
mixture was loaded to the semi-preparative HPLC system. HPLC
purification was completed on a Capcell Pak column (normal
phase, AG-80; 10 mm f  250 mm; SHISEIDO, Tokyo) using a
mobile phase of AcOEt at a flow rate of 5.0 mL/min. The
retention time for [13N]1 was 4.1 min. The radioactive fraction
corresponding to the desire product was collected in a sterile
flask, evaporated to dryness, and re-dissolved in 2 mL of sterile
normal saline for analysis and animal experiments. Total
synthesis time was about 14 min from the EOB. At EOS,
570–780 MBq (n = 7) of [13N]1 was obtained as an i.v. injectable
solution using a beam current of 15 mA and 15 min proton
bombardment.
Tokyo). Column chromatography was performed on Merck
Kieselgel gel 60 F254 (70–230 mesh). Nitrogen-13 (13N) was
produced by the 15O(p, a)13N nuclear reaction using a CYPRIS
HM-18 cyclotron (Sumitomo Heavy Industry, Tokyo). Radio-
activity was measured with a dose calibrator (IGC-3R Curiemeter,
Aloka, Tokyo). HPLC was performed using a JASCO HPLC system
(JASCO, Tokyo): effluent radioactivity was monitored using a NaI
(Tl) scintillation detector system. If not otherwise stated,
chemicals were purchased from Aldrich Chemical (Milwaukee,
WI) and Wako Pure Industries (Osaka) with the highest grade
commercially available.
Chemical synthesis of thalidomide (1)
A mixture of N-phthaloylglutamic anhydride (2; 258 mg, 1 mmol)
and anhydrous NH3 in DMF (10%, 5 mL) was stirred on room
temperature for 14 h. After removal of unreacted NH3 by
evaporation, a solution of carbonyldiimidazole (CDI; 486 mg,
3 mmol) was added and the reaction mixture was heated at
1001C for 1 h. The mixture was quenched with CH2Cl2 and water
and the organic layer was washed with water and a saturated
NaCl solution. The CH2Cl2 layer was dried over Na2SO4 and was
removed to give a residue, which after recrystallization with
ethanol gave pure 1 (177 mg, 68.3%) as a white solid; mp: 2701C
(269–2711C).25 1H-NMR (300 MHz, DMSO–d6): 2.04–2.12 (1H, m),
2.49–2.63 (2H, m), 2.84–2.96 (1H, m), 5.17 (1H, dd, J = 5.4,
12.8 Hz), 7.87–7.97 (4H, m), 11.14 (1H, s). FAB-MS (m/z): 259.1
(M111)
Radiochemical purity and specific activity determinations
Radiochemical purity of [11N]1 was assayed by analytical HPLC
(Capcell Pak C18, 4.6 mm f  150 mm; SHISEIDO, Tokyo).
The retention time of [13N]1 was 5.2 min with a mobile phase
of H2O/CH3CN (7/3) at a flow rate of 2.0 mL/min. Confirmation of
the identity of [13N]1 was achieved by co-injection with authentic
non-radioactive 1. The same analytical HPLC system was used for
the determination of specific activity of [13N]1. The mass (mmol) of
1 with a known radioactivity (GBq) was determined by HPLC
comparison of UV absorbance at 254 nm of [13N]1 with those of
known concentrations of non-radioactive 1.
Radiosynthesis of [13N]thalidomide ([13N]1)
Animal experiment
Production System
The animal experimental procedures were approved by the
Animal Ethics Committee of the National Institute of Radi-
ological Sciences. Male ddY mice (7 weeks old) were purchased
from Japan SLC (Shizuoka, Japan). Before experiments, animals
were housed under a 12 h dark–light cycle and were allowed
free access to food pellets and water. PET scans were performed
using small animal PET scanner InveonTM (Siemens Medical
Solutions USA; Knoxville, TN), which provides 159 transaxial
slices 0.796 mm (center-to-center) apart, a 10 cm transaxial FOV,
and a 12.7 cm axial FOV.26 Combing the high light output of LSO
with 1.6 mm  1.6 mm detector pixel spacing, the Inveon
delivers less than 1.4 mm FWHM spatial resolution in images
reconstructed using the filtered back projection algorithm.27
Prior to the scans, the rats were anesthetized with 5% (v/v)
isoflurane, and maintained thereafter by 1–2% (v/v) isoflurane.
After transmission scans for attenuation using a 57Co point
source, emission scans were acquired for 60 min after the
intravenous injection of [13N]1 (average 40 MBq). During these
PET scans, ten arterial blood samples (15–30 mL each) were
drawn into heparin-treated syringes at 15 s intervals until 2 min,
followed by 30 mL aliquots at 3, 5, 10, 20, 15, 30, 45, 60 min.
Samples were measured for radioactivity and metabolite
analysis was not performed.
Radiosynthesis was performed using an automated system for
rapid production of 13N-labeled compounds with high specific
activity using anhydrous [13N]NH3.19 This system was designed
to minimize the inner volume of the production line and the
required amount of reagent, which decreased the radioactivity
loss in the line to a low level. The system enables one to carry
out all the procedures from production of [13N]NH3 to
formulation of [13N]1. The target chamber (21 mm f  6 mm)
was made of SUS316 and two SUS316 foils (100 mm thick)
were welded on both sides of the chamber by an electron beam
in vacuo.
Production of anhydrous [13N]NH3 gas
Before irradiation, a solution of 10 mM ethanol in water was
loaded into the target chamber. The target was irradiated at
15 mA for 15 min with 18 MeV protons (15.7 MeV on target) from
the cyclotron. A small column (1 mm f  40 mm, Teflon) filled
with 25 mg of cation exchange resin AG50W-X8 (100–200 mesh,
Bio-Rad, CA) was preconditioned by successive washing with 2 N
HCl, water, 2 N KOH and water. The irradiated solution was
quickly passed through this exchange column and [13N]NH3 in
the irradiated water was concentrated on this column. Then,
[13N]NH3 was eluted with aqueous KOH (2 N) under a He gas
flow and desiccated through a small column filled with 250 mg
of CaO (3 mm f  30 mm, kept at 1501C), and introduced into a
cooled solution containing a precursor for radiosynthesis.
All list-mode acquisition data were sorted into three-dimen-
sional sinograms, which were then Fourier rebinned into two-
dimensional sinograms (frames  min; 4  1, 8  2, 14  5).
Dynamic images were reconstructed with filtered back-projection
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Kumata et al.
using a ramp’s filter, a Nyquist cutoff of 0.5 cycle/pixel. Regions of
interest were placed on the whole brain, lung, heart, kidney by
using ASIPro VMTM (Analysis Tools and System Setup/Diagnostics
Tool; Siemens Medical Solutions USA) with reference to the MRI
template. Regional uptake of radioactivity was decay corrected to
injection time and expressed as the standardized uptake value
(SUV), normalized for injected radioactivity and body weight.
SUV= (radioactivity per cubic centimeter tissue/injected radio-
activity) Â gram body weight. Data are expressed as mean7SD.
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Conclusion
We synthesized [13N]1 for the first time as a promising PET
probe. At the EOS, 570–780 MBq of [13N]1 was obtained at a
specific activity of 49724 GBq/mmol using a beam current of
15 mA for 15 min. [13N]1 was obtained with a reproducible
radiochemical yield of 56% (based on [13N]NH3, corrected for
decay) and a radiochemical purity of 98%. [13N]1 may be a tool
for elucidating the action mechanism, binding site and adverse
effects of 1. We also believe that the rapid radiosynthesis using
no-carrier-added [13N]NH3 will contribute to the development of
more 13N-labeled probes for PET imaging.
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Acknowledgement
The authors are grateful to the crew of the Cyclotron Operation
Section and Department of Molecular Probes, Molecular Imaging
Center of National Institute of Radiological Sciences for their
support in the operation of the cyclotron and production of
radioisotopes. This study was supported in part by Grant-in-Aid for
the Molecular Imaging Program from the Ministry of Education,
Culture, Sports, Science and Technology, Japanese Government.
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