Preparation of ¹⁸F-NaF radiopharmaceuticals using home-made automatic synthesis module at Hanoi Irradiation Center
Nuclear Science and Technology, Vol.9, No. 1 (2019), pp. 41-49
Preparation of 18F-NaF radiopharmaceuticals using home-made
automatic synthesis module at Hanoi Irradiation Center
Tran Manh Thang1, Mai Van Vinh1, Dam Thi Tam1, Nguyen Quang Anh1,
Le Thi Thu Hien1, Pham Minh Duc1, Nguyen Tuan Anh1, Nguyen Van Sy1,
Nguyen Thanh Hung1, Dang Quang Bao1, Nguyen Xuan Vinh1, Nguyen Thi Kim Dung2
1Hanoi Irradiation Center. Km12, Road 32, Minh Khai, Tu Liem North, Hanoi, Vietnam
2Nuclear Medicine Department, 108 Military Central Hospital,
No. 1, Tran Hung Dao, Hai Ba Trung, Hanoi, Vietmam
(Received 02 July 2019, accepted 23 September 2019)
Abstract: The aim of this study is to prepare 18F-NaF radiopharmaceutical using a home-made
automatic synthesis module consisting of hardware and software which was made by a researcher-
team of Hanoi Irradiation Center, HIC, Hanoi, Vietnam. Fluorine-18 isotopes produced in cyclotron
KOTRON13 were transferred to the module and radioactive cation impurities were first removed by
cation exchange on a carboxymethyl cation exchange (CM) cartridge, and then 18F- ion were trapped
by a quaternary methyl ammonium anion exchange (QMA) cartridge. Finally, 18F- was eluated from
the cartridge by isotonic saline water (NaCl 0,9% in water) in the form of 18F-NaF. Time of the
preparation process was about 13 minutes. Radiochemical yield of the preparation was as high as
95.5%, in average. The qualities of the product were satisfied the criteria of the United States
Pharmacopoeia (USP38). PET/CT bone scaner (skeletal scintigraphy) pre-clinical tests using of the
18F-NaF product showed good quality of imaging for the entire skeletal and distribution of the 18F-NaF
in the kidney and the bladder agreed with it’s natural distribution.
Keywords: Sodium [18F]-fluoride radiopharmaceutical, KOTRON13 cyclotron, Synthesis module,
bone scan.
reactors. Therefore until 2000, FDA approved
I. INTRODUCTION
18F-NaF as a radiopharmaceuticals for bone
scintigraphy as part of its modernization on
The
use
of
18F-NaF
the handling of new drug applications [1]. The
demand of 18F-NaF radiopharmaceutical is
expected to increase rapidly in the coming
years [5]. Nowadays, 99mTc-methylene
diphosphate (99mTc-MDP) and 18F-NaF have
been used in bone scintigraphy with SPECT
(gamma camera) and PET/CT, respectively.
However, comparing image using 18F-
NaF/PET-CT technique with those of using
99mTc-MDP/SPECT showed that the former
technique has a higher sensitivity in detecting
osteolytic lesions compared to the latter one.
The 18F-NaF/PET-CT shows high sensitivity
in both lytic and blastic lesions. Further, there
are many advantages of using 18F-NaF in
radiopharmaceuticals for bone scintigraphy
dates back to the early 1960s [1]. It was
introduced as a skeletal PET imaging agent by
18
Blau in 1962 [2,3]. The indication of F-NaF
as a bone scintigraphy agent to define areas of
altered osteogenic activity was approved by
the U.S. Food and Drug Administration
(FDA) in 1972 [2,4]. However, due to the
unavailability of cyclotron to produce 18F
preparation in many countries at that time,
that the bone scintigraphy has been
conveniently performed with phosphate
compounds labelled with technetium-99m.
The 99mTc obtained as a decay product from
molybdenum-99 [5,6] produced on nuclear
©2019 Vietnam Atomic Energy Society and Vietnam Atomic Energy Institute
PREPARATION OF 18F-NAF RADIOPHARMACEUTICALS USING HOME-MADE AUTOMATIC…
imaging such as sensitivity, specificity, high
spatial, contrast resolution compared to the
99mTc use in combination with CT or MRI
surgery information [7]. In recent years, some
of nuclear reactors around the world which
under installation in Kien Giang hospital, two
in Ho Chi Minh City). Therefore, the
development and application of 18F-NaF
radiopharmaceuticals are feasible. In the
future, it can be replaced a part of 99mTc-MDP
in the bone cancer diagnosis.
regularly
supply
molybdenum-99
(technetium-99m generators) are going to
shutdown [8]. This could be leading to a large
number of patients would be denied essential
imaging diagnosis and the nuclear medicine
community would fall into crisis by the lack
of 99mTc supply [5]. Moreover, fluorine-18
isotope that is produced by cyclotron has a
short half-life (109.83 minutes) so it can not
be imported from abroad. Up to present
(2019), Vietnam has seven cyclotrons (three
in Hanoi City, one in Da Nang hospital, one is
At present, many companies have
commercialized
18F-NaF
radiopharmaceuticals synthesis module with
the yield of over 90% such as Eckert &
Ziegler [9], GE, IBA [1,10], TRASIS [11],
KIRAMS, etc. Current process of preparation
of 18F-NaF radiopharmaceuticals worldwide
is based on the same principle according to
the flow chart shown below.
Fig. 1. Flow chart of 18F-NaF radiopharmaceuticals preparation
In Fig. 1 CM and QMC stand for
carboxymethyl cation ion exchange and
quaternary methyl ammonium anion exchange
radiochemical yields. The 18F-NaF product
produced was checked for its quality and pre-
clinical tests.
In this study, a procedure of 18F-NaF
radiopharmaceuticals preparation on a home-
made automatic synthesis module is presented.
The module was manufactured by a researcher-
team of Hanoi Irradiation Center (HIC) which
includes hardware and software to control
operation of the module (Fig. 2). The process
of preparation was evaluated for its chemical,
II. EXPERIMENT
A. Chemicals, materials and methods
Material for 18F-NaF module manufacture
The hardware of the module includes:
two stepper motor moving up and down, six
of 2/2 way valves type 0127 ID 120721 from
42
TRAN MANG THANG et al.
Burkert-Germany, six of 3/2 way valves type
and quick-connect Luer adapters from
Kinesis-UK, etc. The size of the module is
400(H) x 300(L) x 285(W) mm (Fig.2).
Software for operational control of the
0127 ID 120433 from Burkert-Germany, two
radioactivity monitoring detectors, Teflon
tube, PEEK and super flangeless fittings,
flangeless fittings, flangeless fitting for 1/16”
OD tubing, bulk head unions, Y connectors,
module
was
written
on
Labview
programming language.
Fig. 2. A view of the home-made automatic module used for preparation of 18F-NaF
Chemicals and materials for 18F-NaF
synthesis
pH of the preparation was measured
using indicator strips (Macherey-Nagel);
half-life of 18F isotope was determined by a
Dose calibrator (ISOMED2010-Germany);
Chemical purity of 18F-NaF preparation was
analyzed by Radio-TLC development
following by scanning using a Raytest
scanner from Germany and Radio-HPLC
Agilent 1260-Raytest; radionuclide purity of
18F-NaF preparation was identified by using
18
Enriched [18O]-water (H2 O) was
supplied from the Rotem/Israel (18O purity >
97%). Quaternary methyl ammonium Sep-Pak
Accell Plus Light (QMA) cartridges and
carboxymethyl Sep-Pak Accell Plus Short
(CM) Cartridges were purchased from the
Waters (USA). Ethyl alcohol (PA grade),
acetonitrile (PA grade), glass-based silica thin
layer chromatography (TLC) plates, Millex-
FG filters were from the Merck/Germany.
AEF filters 0,22µm pore size are from the
PALL (UK); sterile water for injection and
NaCl isotonic saline water (0,9 %) were from
the Fresenius Kabi Bidiphar/Vietnam.
Syringes of 20mL capacity were from the BD
(Belgium). Venting needles were from the
Millipore (USA) and sterile vacuum vials
were from Korea.
multi-channel
analyzer
(MCA/Raytest-
Germany); Residual solvent (ethyl alcohol)
was determined by Gas chromatography
(GC/Agilent 7890B); Bacterial Endotoxins
was tested by Endotoxin PTS-100 (Charles
River, USA); Sterility was examined in the
Dalat
Nuclear
Research
Institute’s
laboratory.
Quality of 18F-NaF radiopharmaceuticals
was evaluated at the HIC, Cyclotron Center of
the 108 Military Central Hospital, and Dalat
Nuclear Research Institute laboratories.
Materials and equipment for product’s
quality control
43
PREPARATION OF 18F-NAF RADIOPHARMACEUTICALS USING HOME-MADE AUTOMATIC…
Ossein scintigraphy was performed with
the use of 18F-NaF at a PET/CT Light Speed
device (GE, USA) at Nuclear Medicine
Department, 108 Military Central Hospital.
5 mL of enriched 18O-water as a liquid
target was cỉrculated through a Nb cavity
covered with Havar foil window. The target
was bombarded with proton beam of a current
of 30 µA for 60 minutes. Resulting solution
containing H18F was transferred into the
automatic synthesis module (Fig.2, 3). The
H18F solution first was allowed to pass through
the CM cation exchange cartridge that was
prepared previously to purify all cations
impurities generated from activation reactions
between protons and the metals made of the
Havar alloy, then the solution was passed
through QMA cartridge where 18F- anions were
trapped on the resin. Finally, 18F was eluted
from the QMA cartridge with 10 mL of 0,9%
NaCl isotonic saline solution. The solution of
18F-NaF was filtered through an AEF filter of
0.22 µm pore size into a sterile, pyrogen-free
vial. Progress of the synthetic processes will be
shown on screen by an animation scheme (Fig.
3).
Preparation of QMA, CM cartridges
before its use
Sep-park QMA and CM cartridges need
to be activated before its use. First, both of
them were preconditioned with 10 mL ethyl
alcohol then, they were washed by 12 mL
sterile water for injection. Finally, they were
dried by blowing a dry air flow.
Production
of
18F-NaF
radiopharmaceutical
Fluorine-18
was
produced
by
bombarment of protons particles accelerated to
energy 13 MeV on a KOTRON13 cyclotron
(Korea) located in the HIC. The reaction was
proceeded as follows.
188O11p198F01n
(1)
Fig. 3. Graphical screen showing progress of 18F-NaF preparation process
44
TRAN MANG THANG et al.
Operation of the module was programed with following menu:
Section
Image
Display
Operation
1
2
Value of measured radioactivity will be displayed as graphs
This menu is for input of necessary data
Set-up
3
Control mode
Process mode
Start
This menu is used for automatic control or manual control
This menu is used for synthesis or cleaning equipment
Start a process under the conditions which were input
Stop a process
4
5
6
Stop
7
Program running Show current status of the module
8
Elapsed time
The Yield
Display elapsed time since the moment of program started
9
Display the yield of a synthetic batch
Display status of process
10
Control status
(2)
IV. RESULTS AND DISCUSSIONS
Ten (10) batches of 18F-NaF were
prepared for evaluating performance of the
module, and for determining the quality of the
product and for pre-clinical test with PET/CT
technique.
Where Rp is the final product activity measured
in position of the product storing vial (Fig.3);
R0 is the initial activity measured in position of
the QMA cartridge (Fig. 3).
The yield of 18F-NaF preparation achieved
in average around 95.5% in 10 experimental
batches as shown in Fig. 4. The time of the
synthetic process is about 13 minutes.
The yield of synthetic process
The yield of synthetic process was
estimated by the formula:
Batch number
Fig. 4. The yield of 18F-NaF synthetic process determined by batch
contains no particulate matters. Other
Quality of the product
The quality of the product was
examined. Result of the examination showed
that 18F-NaF solution was clear, colorless,
parameters were also satisfied the criteria of
the United States Pharmacopoeia (USP38)
applied to 18F-NaF pharmaceuticals as shown
in Table I [12].
45
PREPARATION OF 18F-NAF RADIOPHARMACEUTICALS USING HOME-MADE AUTOMATIC…
Table I. Quality of 18F-NaF produced at HIC, Hanoi, Vietnam
Parameter
Appearance
Release Criteria (USP38)
Result
Clear, colorless, no contains
particulate matters
Pass
pH
4.5 - 8.0
> 95%
7.0
> 95%
Pass
Pass
Pass
Pass
Pass
Radiochemical purity
Radionuclidic purity
Half-life
> 99,5 % (511±15 keV)
105-115 min
< 5 mg/mL
Residual solvent
Endotoxin
< 175 EU/mL
Sterile
Sterility
pH value of the solution was around
7.0 that met the acceptance criteria of
between 4.5 to 8.0. Radiochemical purity of
the product was higher than 95 % of the
total radioactivity measured as it was
determined by TLC development. The
retention factor (Rf) of the product was
found to be from 0.0 to 0.01 (Fig.5). The
acceptance criteria for radiochemical purity
is not less than 95%.
C/mm *1000
TLC
14.0
12.0
10.0
8.0
6.0
4.0
2.0
0.0
0
20
40
60
80
mm
Fig. 5. The radio-TLC spectrum of 18F-NaF
Fig.6. The radio-HPLC spectrum of 18F-NaF
produced at the HIC
produced at the HIC
Radiochemical purity and identity of 18F-
Bacterial Endotoxin was not more than 175
EU/mL (USP Endotoxin Units per mL) of
injection that met the acceptance criteria of not
more than 175 EU/mL. The test for sterility is
carried out under aseptic conditions. Sterility was
tested in the fluid thioglycolate medium at 30-
35oC, the soya-bean casein medium and incubated
at 20-25oC, respectively. The samples were
counted 14 days after incubation. The produce was
sterile that met the acceptance criteria of sterile.
NaF product were higher than 95 % of the total
radioactivity measured at retention time around
4.5 minutes (Fig.6).
Radionuclidic purity was checked using a
multi-channel gamma spectrometer and it was
found that the purity of the product is not less
than 99.5 % at 511 keV peak (Fig.7) that met the
acceptance criteria of not less than 99.5%.
46
TRAN MANG THANG et al.
180
160
CPS/keV
Tr1
140
120
100
80
60
40
20
0
0
500
1000
1500
keV
Fig.7. A gamma spectrum of 18F-NaF showing a peak at 511 keV
Fig.8. A GC chromatogram of solution 18F-NaF produced at the HIC
showing no peak representing ethyl alcohol
Fig. 9. PET/CT images of rabbits administered with 18F-NaF preparation produced at the HIC
Imaging Study and biodistribution
47
PREPARATION OF 18F-NAF RADIOPHARMACEUTICALS USING HOME-MADE AUTOMATIC…
Pre-clinical study is carried out at
Nuclear Medicine Department, 108 Military
Central Hospital in Hanoi. Subject of the
test were rabbits to which were injected
about 0.3-0.4 mCi (about 0.14 mCi/kg) of
18F-NaF solution. The uptake time for
animals was 40 minutes. Afterwards,
animals were scaned with a low-dose CT,
full body PET scanner. PET attenuation
images were corrected by CT. Standardized
uptake values (SUV) are the maximum
values at the region of interest and
calculated in g/mL.
Institute is acknowledged. The authors would
like to thank Dr. Jung Young Kim, Korea
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In this study, it was proven that the Hanoi
Irradiation Center has successfully manufactured
automatic synthesis module for 18F-NaF
radiopharmaceuticals. The duration of the
synthetic process was about 13 mins.
Radiochemical yield was as high as 95.5%, in
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of the United States Pharmacopoeia (USP38). The
PET/CT imaging test on animals showed good
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ACKNOWLEDGMENTS
The financial support to conduct this
research was from Ministry of Science and
Technology of Vietnam under Project encoded
ĐTCB.07/16/TTCX. The authors are thankful
to Vietnam Atomic Energy Institute, and Hanoi
Irradiation Center for the administrative
assistances. The co-operation of 108 Military
Central Hospital and Dalat Nuclear Research
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