Preparation of ¹⁸F-NaF radiopharmaceuticals using home-made automatic synthesis module at Hanoi Irradiation Center

 [1,10], TRASIS [11], 
of 99mTc supply [5]. Moreover, fluorine-18 
isotope that is produced by cyclotron has a KIRAMS, etc. Current process of preparation 
 18
short half-life (109.83 minutes) so it can not of F-NaF radiopharmaceuticals worldwide 
be imported from abroad. Up to present is based on the same principle according to 
(2019), Vietnam has seven cyclotrons (three the flow chart shown below. 
in Hanoi City, one in Da Nang hospital, one is 
 Fig. 1. Flow chart of 18F-NaF radiopharmaceuticals preparation 
 In Fig. 1 CM and QMC stand for radiochemical yields. The 18F-NaF product 
carboxymethyl cation ion exchange and produced was checked for its quality and pre-
quaternary methyl ammonium anion exchange clinical tests. 
 In this study, a procedure of 18F-NaF 
 II. EXPERIMENT 
radiopharmaceuticals preparation on a home-
made automatic synthesis module is presented. A. Chemicals, materials and methods 
The module was manufactured by a researcher- 
 Material for 18F-NaF module manufacture 
team of Hanoi Irradiation Center (HIC) which 
includes hardware and software to control The hardware of the module includes: 
operation of the module (Fig. 2). The process two stepper motor moving up and down, six 
of preparation was evaluated for its chemical, 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 
0127 ID 120433 from Burkert-Germany, two Kinesis-UK, etc. The size of the module is 
radioactivity monitoring detectors, Teflon 400(H) x 300(L) x 285(W) mm (Fig.2). 
tube, PEEK and super flangeless fittings, Software for operational control of the 
flangeless fittings, flangeless fitting for 1/16” module was written on Labview 
OD tubing, bulk head unions, Y connectors, programming language. 
 Fig. 2. A view of the home-made automatic module used for preparation of 18F-NaF 
 Chemicals and materials for 18F-NaF pH of the preparation was measured 
synthesis using indicator strips (Macherey-Nagel); 
 18 18 18
 Enriched [ O]-water (H2 O) was half-life of F isotope was determined by a 
supplied from the Rotem/Israel (18O purity > Dose calibrator (ISOMED2010-Germany); 
 18
97%). Quaternary methyl ammonium Sep-Pak Chemical purity of F-NaF preparation was 
Accell Plus Light (QMA) cartridges and analyzed by Radio-TLC development 
carboxymethyl Sep-Pak Accell Plus Short following by scanning using a Raytest 
(CM) Cartridges were purchased from the scanner from Germany and Radio-HPLC 
Waters (USA). Ethyl alcohol (PA grade), Agilent 1260-Raytest; radionuclide purity of 
 18
acetonitrile (PA grade), glass-based silica thin F-NaF preparation was identified by using 
layer chromatography (TLC) plates, Millex- multi-channel analyzer (MCA/Raytest-
FG filters were from the Merck/Germany. Germany); Residual solvent (ethyl alcohol) 
AEF filters 0,22µm pore size are from the was determined by Gas chromatography 
PALL (UK); sterile water for injection and (GC/Agilent 7890B); Bacterial Endotoxins 
NaCl isotonic saline water (0,9 %) were from was tested by Endotoxin PTS-100 (Charles 
the Fresenius Kabi Bidiphar/Vietnam. River, USA); Sterility was examined in the 
Syringes of 20mL capacity were from the BD Dalat Nuclear Research Institute’s 
(Belgium). Venting needles were from the laboratory. 
Millipore (USA) and sterile vacuum vials Quality of 18F-NaF radiopharmaceuticals 
were from Korea. was evaluated at the HIC, Cyclotron Center of 
 Materials and equipment for product’s the 108 Military Central Hospital, and Dalat 
quality control Nuclear Research Institute laboratories. 
 43 
 PREPARATION OF 18F-NAF RADIOPHARMACEUTICALS USING HOME-MADE AUTOMATIC 
 Ossein scintigraphy was performed with 5 mL of enriched 18O-water as a liquid 
the use of 18F-NaF at a PET/CT Light Speed target was cỉrculated through a Nb cavity 
device (GE, USA) at Nuclear Medicine covered with Havar foil window. The target 
Department, 108 Military Central Hospital. was bombarded with proton beam of a current 
 of 30 µA for 60 minutes. Resulting solution 
 Preparation of QMA, CM cartridges 
 containing H18F was transferred into the 
before its use 
 automatic synthesis module (Fig.2, 3). The 
 Sep-park QMA and CM cartridges need H18F solution first was allowed to pass through 
to be activated before its use. First, both of the CM cation exchange cartridge that was 
them were preconditioned with 10 mL ethyl prepared previously to purify all cations 
alcohol then, they were washed by 12 mL impurities generated from activation reactions 
sterile water for injection. Finally, they were between protons and the metals made of the 
dried by blowing a dry air flow. Havar alloy, then the solution was passed 
 18 -
 Production of 18F-NaF through QMA cartridge where F anions were 
 18
radiopharmaceutical trapped on the resin. Finally, F was eluted 
 from the QMA cartridge with 10 mL of 0,9% 
 Fluorine-18 was produced by NaCl isotonic saline solution. The solution of 
bombarment of protons particles accelerated to 18F-NaF was filtered through an AEF filter of 
energy 13 MeV on a KOTRON13 cyclotron 0.22 µm pore size into a sterile, pyrogen-free 
(Korea) located in the HIC. The reaction was vial. Progress of the synthetic processes will be 
proceeded as follows. shown on screen by an animation scheme (Fig. 
 18 1 18 1 (1) 3). 
 8 O 1p 9 F 0 n 
 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 Operation 
 1 Display Value of measured radioactivity will be displayed as graphs 
 2 Set-up This menu is for input of necessary data 
 3 Control mode This menu is used for automatic control or manual control 
 4 Process mode This menu is used for synthesis or cleaning equipment 
 5 Start Start a process under the conditions which were input 
 6 Stop Stop a process 
 7 Program running Show current status of the module 
 8 Elapsed time Display elapsed time since the moment of program started 
 9 The Yield Display the yield of a synthetic batch 
 10 Control status Display status of process 
 (2) 
 IV. RESULTS AND DISCUSSIONS 
 Ten (10) batches of 18F-NaF were 
 Where R is the final product activity measured 
prepared for evaluating performance of the p 
 in position of the product storing vial (Fig.3); 
module, and for determining the quality of the 
 R is the initial activity measured in position of 
product and for pre-clinical test with PET/CT 0
 the QMA cartridge (Fig. 3). 
technique. 
 The yield of 18F-NaF preparation achieved 
The yield of synthetic process 
 in average around 95.5% in 10 experimental 
 The yield of synthetic process was batches as shown in Fig. 4. The time of the 
estimated by the formula: synthetic process is about 13 minutes. 
 Batch number 
 Fig. 4. The yield of 18F-NaF synthetic process determined by batch 
Quality of the product contains no particulate matters. Other 
 parameters were also satisfied the criteria of 
 The quality of the product was the United States Pharmacopoeia (USP38) 
examined. Result of the examination showed applied to 18F-NaF pharmaceuticals as shown 
that 18F-NaF solution was clear, colorless, 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 Release Criteria (USP38) Result 
 Appearance Clear, colorless, no contains Pass 
 particulate matters 
 pH 4.5 - 8.0 7.0 
 Radiochemical purity > 95% > 95% 
 Radionuclidic purity > 99,5 % (511±15 keV) Pass 
 Half-life 105-115 min Pass 
 Residual solvent < 5 mg/mL Pass 
 Endotoxin < 175 EU/mL Pass 
 Sterility Sterile Pass 
 pH value of the solution was around determined by TLC development. The 
7.0 that met the acceptance criteria of retention factor (Rf) of the product was 
between 4.5 to 8.0. Radiochemical purity of found to be from 0.0 to 0.01 (Fig.5). The 
the product was higher than 95 % of the acceptance criteria for radiochemical purity 
total radioactivity measured as it was is not less than 95%. 
 14.0 C/mm *1000 TLC
 NaF
 Front
 Origin
 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 
NaF product were higher than 95 % of the total EU/mL (USP Endotoxin Units per mL) of 
radioactivity measured at retention time around injection that met the acceptance criteria of not 
4.5 minutes (Fig.6). more than 175 EU/mL. The test for sterility is 
 carried out under aseptic conditions. Sterility was 
 Radionuclidic purity was checked using a tested in the fluid thioglycolate medium at 30-
multi-channel gamma spectrometer and it was 35oC, the soya-bean casein medium and incubated 
found that the purity of the product is not less at 20-25oC, respectively. The samples were 
than 99.5 % at 511 keV peak (Fig.7) that met the counted 14 days after incubation. The produce was 
acceptance criteria of not less than 99.5%. sterile that met the acceptance criteria of sterile. 
 46 
 TRAN MANG THANG et al. 
 180 CPS/keV Tr1
 NaF
 160
 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 Institute is acknowledged. The authors would 
Nuclear Medicine Department, 108 Military like to thank Dr. Jung Young Kim, Korea 
Central Hospital in Hanoi. Subject of the Institute of Radiological & Medical Sciences 
test were rabbits to which were injected for his valuable discussions during the study. 
about 0.3-0.4 mCi (about 0.14 mCi/kg) of 
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