- Email: [email protected]
Simple and effective method for producing [11C]phosgene using an environmental CCl4 gas detection tube
Available online at www.sciencedirect.com
Nuclear Medicine and Biology 37 (2010) 73 – 76 www.elsevier.com/locate/nucmedbio
Simple and effective method for producing [11 C]phosgene using an environmental CCl4 gas detection tube☆ Masanao Ogawaa,b , Yuuki Takadaa,c , Hisashi Suzukia , Kazuyoshi Nemotoa , Toshimitsu Fukumuraa,⁎ a
Molecular Probe Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan b SHI Accelerator Service, Ltd., Tokyo 141-8686, Japan c Department of Radiology, School of Medicine, Yokohama City University, Yokohama 236-0004, Kanagawa, Japan Received 20 February 2009; received in revised form 7 July 2009; accepted 24 August 2009
Abstract Introduction: Carbon-11-labeled phosgene is an important labeling precursor for PET molecular probes. Despite the usefulness of [11C] phosgene, some difficulties, especially in the formation of [11C]phosgene process from [11C]CCl4, hamper its use. The present article shows a simple preparation method for [11C]phosgene. Method: [11C]CCl4 was obtained using the conventional method by passing a mixture of [11C]CH4 and Cl2 through a heated quartz tube. The [11C]CCl4 was transformed to [11C]phosgene simply by passing through a pretreatment tube of a Kitagawa gas detection system for the working-environmental CCl4 concentration measurement at room temperature with a flow rate of 50 ml/min. Result: This tube successfully transformed [11C]CCl4 to [11C]phosgene at room temperature. [11C]Phosgene was obtained at nearly 80% radiochemical yield (EOB) in a short synthesis time with high reproducibility. Conclusion: A high yield and reliable [11C]phosgene production method using a gas detector tube system for working-environmental CCl4 concentration measurement was developed. © 2010 Elsevier Inc. All rights reserved. Keywords: [11C]phosgene; Synthesis; Gas detector tube system; Carbon-11; PET
1. Introduction Carbon-11 is an important radionuclide giving a wide variety of PET tracers with unchanging parent structure. Carbon-11-labeled phosgene is an important, highly reactive labeling precursor for ureas, carbonate esters, etc.; thus, some useful PET tracers have been prepared using [11C] phosgene as a labeling precursor [1–7]. In most cases, [11C]phosgene has been prepared by the chlorination of [11C]methane to [11C]CCl4 and subsequent catalytic conversion to [11C]phosgene. Several conversion methods have been reported using Fe as a catalyst with/without added ☆ This study was partially supported by a consignment grant for the Molecular Imaging Program on Research Base for PET Diagnosis from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT). ⁎ Corresponding author. Tel.: +81 43 206 3261; fax: +81 43 206 3261. E-mail address: [email protected] (T. Fukumura).
0969-8051/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.nucmedbio.2009.08.008
oxygen gas [7,8]; however, these methods had some problem in the radiochemical yield and reproducibility. Nishijima et al. [10] reported the synthesis of [11C]phosgene by adding iron(III) oxide to an Fe catalysis column as an oxygen source. This method increased the radiochemical yield of [11C]phosgene with high reproducibility; however, this method uses a column oven for the formation of [11C] COCl2 and yield has been affected by [11C]CCl4 flow and the particle size of the metal catalyst. In the present article, we will report the highly reliable synthesis method from [11C]CCl4 to [11C]phosgene at room temperature. 2. Experimental 2.1. General CO2 was produced by the 14N(p, α)11C reaction using a National Institute of Radiological Sciences cyclotron. 11
74
M. Ogawa et al. / Nuclear Medicine and Biology 37 (2010) 73–76
Radioactivity was quantified with a dose calibrator (IGC-7, Aloka, Tokyo Japan). Reaction mixtures were analyzed by HPLC and GC equipped with NaI(Tl) scintillation detectors. The Kitagawa gas detector tube system (tube no. 147S) was purchased from Komyo Rikagaku Kogyo (Tokyo, Japan). Chlorine gas [20% Cl2 in He (V/V)] was purchased from Taiyo Nippon Sanso (Tokyo, Japan). 2.2. Synthesis apparatus Fig. 1 shows the synthesis apparatus for [11C]phosgene. This apparatus consists of parts that perform the condensation of [11C]CO2, conversion of [11C]CO2 into [11C]CH4 by a methanizer, condensation of [11C]CH4, production of [11C] CCl4 and subsequent conversion to [11C]phosgene, and a syringe for mixing Cl2 and [11C]CH4. Operations (switching of valves, control of furnace temperatures, gas flow rates, timing and duration of each step, etc.) are controlled remotely using a programmable
logic controller. Valves 1–8 are of the following types: 1–2 are stainless-steel solenoid valves (A2011-V, Gems Sensors & Controls); 3 is a PTFE two-way valve (EXV-2-1-1/4UG2, Takasago Electric); and 4–8 are PTFE three-way solenoid valves (STV-3-N1/4UG, Takasago Electric). A disposable plastic syringe for mixing Cl2 and [11C]CH4 is mounted on a custom-made syringe drive operated pneumatically. Coils 1 and 2 were prepared by filling Porapak Q (80–100 mesh) into stainless-steel tubes (Coil 1: 1/8 OD, 2.0 mm ID, 150 mm length; Coil 2: 1/16 OD, 1.0 mm ID, 300 mm length). All components were connected by Teflon tubing (1.6 mm OD, 0.75 mm ID). Coils 1 and 2 were cooled by liquid nitrogen blower (Nakazawa Seisakusyo, Chiba, Japan). 2.3. Production of [11C]carbon tetrachloride [11C]Carbon tetrachloride was prepared from [11C]CO2 produced by irradiation of the target gas (N2+0.01% O2) with an 18 MeV proton beam. Target gas containing [11C]CO2
Fig. 1. Apparatus for the synthesis of [11C]phosgene.
M. Ogawa et al. / Nuclear Medicine and Biology 37 (2010) 73–76
75
2.5. Analysis of the reaction mixture
Fig. 2. Influence of gas flow on the radiochemical yield of [11C]CCl4.
was passed by expansion through Coil 1 cooled at −100°C by cold nitrogen gas blow from liquid nitrogen to trap the [11C]CO2 with a flow rate of 500 ml/min. Coil 1 was heated with an air heater, and the released [11C]CO2 was introduced into a methanizer (211MT, GL Science) with target gas, which was used as vector gas in our synthesis apparatus, at a flow rate of 10 ml/min. The [11C]CO2 gas was mixed with H2 gas and subsequently passed through heated Ni catalyst column (400°C). [11C]CH4 generated by the methanizer was passed through a column (P2O5 and Ascarite II) and trapped in Coil 2 at −130°C. Coil 2 was purged with target gas at a flow rate of 10 ml/min for 15 s to remove H2 gas. Coil 2 was then warmed by an air heater and the released [11C]CH4 was transferred to a plastic disposal syringe (Terumo SS-10ESZ 10 ml) previously loaded with 20% Cl2/He (2 ml). The mixture of [11C]CH4/target gas and Cl2/He (ca. 7 ml) was introduced into a top of a vertical quartz tube (12 mm OD, 10 mm ID, 300 mm length) heated at 560°C by pushing the syringe. Immediately after injection, V8 was switched and the gas mixture was passed through the column from top to bottom at 50 ml/min. [11C]CCl4 was trapped in toluene (500 μl) cooled at 0°C for radio-HPLC analysis. 2.4. Production of [11C]phosgene The [11 C]CCl4 was sequentially passed through a horizontal pretreatment tube of the Kitagawa gas detection tube system for working-environmental CCl4 concentration at room temperature at a flow rate of 50 ml/min. The produced [11C]COCl2 was passed through a Teflon tube (6.0 mm OD, 4.0 mm ID, length 45 mm) filled with antimony/ glass beads (500 mg, Sb/glass beads=1:1) to remove chlorine and acidic gas from pretreatment tube. The yield of [11C] COCl2 was evaluated by the yield of [11C]N,N′-diphenylurea after reaction with an aniline/toluene solution (10 μl/500 μl) by bubbling through at room temperature.
Fig. 3. Conversion reaction of CCl4 to phosgene by the workingenvironment gas detection system.
The obtained reaction mixture was analyzed on a reversed-phase column (YMC-Pack Pro-C18, 4.6×150 mm; YMC, Kyoto, Japan) using CH3CN/H2O (60:40) as the mobile phase at a flow rate of 1.0 ml/min with a radioHPLC system. Under these conditions, [11C]CH2Cl2, [11C] N,N′-diphenylurea, [11C]CHCl3 and [11C]CCl4 were eluted at 3.2, 3.6, 4.3 and 7.0 min, respectively. Waste gases from the reaction mixture collected in Tedlar gas sampling bag were analyzed by the radio-GC system (column: Porapak Q; oven temperature: 50°C; carrier gas: He; flow rate: 36 ml/min). With these conditions, the retention times of [11C]CO, [11C]CH4 and [11C]CO2 were 2.1, 3.0 and 5.5 min, respectively.
3. Results and discussion 3.1. Synthesis of [11C]carbon tetrachloride Synthesis of [11C]CCl4 was carried out according to published methods [8–10]. Seven milliliters of [11C]CH4/ Cl2/N2 mixture was passed through a quartz tube at 560°C at various speeds. The effect of the flow rate on the yield of [11C]CCl4 is shown in Fig. 2. In the range of 10 to 50 ml/min, [11C]CCl4 was obtained at almost 90% radiochemical yield with high reproducibility. Byproducts such as [11C]CHCl3, [11C]CH2Cl2, etc., were not found by radio-HPLC analysis. A higher flow rate (70–90 ml/min) also gave [11C]CCl4 at more than 80% radiochemical yield; however, the dispersion of yield was larger than that of the lower flow rate. Low vector gas flow rate increased the yield of [11C]CCl4 by the longer reaction time [11]. In the present case, [11C]CCl4 was successfully obtained from [11C]CH4 in high yield and reproducibility at low gas flow rate (b50 ml/min). 3.2. Synthesis of [11C]phosgene [11C]Phosgene has been produced by the transformation of [11C]CCl4 on heated catalysts. Various methods have been reported using Fe, CuO, Fe+Fe2O3 as catalysts. These methods require a furnace to heat the catalysis column. Additionally, the automated synthesis apparatus for these methods requires a large space. In the present study, we Table 1 Influence of the gas flow on the radiochemical yield of [11C]phosgene⁎ Flow rate (ml/min)
10 30 50 70
Reaction mixture 11
11
[ C]N,N′-Diphenylurea (%)
[ C]CCl4 (%)
7.2 75.9 80.8±3.1⁎⁎ 66.6±14.1⁎⁎⁎
3.7 7.5 9.9±4.7⁎⁎ 14.6±11.5⁎⁎⁎
Waste gas (%)
89.1 16.6 8.3±3.1⁎⁎ 18.7±6.4⁎⁎⁎
⁎ Percentages of products were based on the recovered total activity. ⁎⁎ n=5. ⁎⁎⁎ n=3.
76
M. Ogawa et al. / Nuclear Medicine and Biology 37 (2010) 73–76
developed a simple method for the transformation of [11C] CCl4 into [11C]phosgene at room temperature using workingenvironmental gas detection tube (Kitagawa gas detector tube system). The Kitagawa gas detector tube system for measuring the CCl4 concentration in the working environment consists of two glass tubes (i.e., pretreatment tube and detector tube). The pretreatment tube is filled with supporting material which contains I2O5 and fuming H2SO4. The detector tube is filled with supporting material which contains 4-(p-nitrobenzyl)pyridine and benzylaniline. After connecting two glass tubes with a silicon tube, the system is used for measurement of working-environmental CCl4 concentration by passing sample air. The pretreatment tube converts CCl4 into phosgene by I2O5 and fuming H2SO 4 at room temperature (Fig. 3). Phosgene reacts with 4-(p-nitrobenzyl)pyridine and benzylaniline to form dyestuff in the detector tube. In the present study, we used the pretreatment tube for the transformation of [11C]CCl4 into [11C]COCl2. [11C]CCl4 produced in a previous chlorination step was subsequently passed through the pretreatment tube at room temperature. Table 1 shows the percentage of [11C]N,N′diphenylurea under various carrier gas flow rates. The yield of [11C]N,N′-diphenylurea depended on the stream velocity of carrier gas. At a low flow rate (10 ml/min), nearly 90% radioactivity was found in waste gas and gave [11C]N,N′diphenylurea in poor radiochemical yield. Radio-GC analysis of this waste gas revealed that the main radioactive product in waste gas was [11C]CO2, suggesting that [11C]CCl4 underwent excess reaction to [11C]CO2 by longer retention time in a pretreatment tube at a low flow rate. The radiochemical yield of [11C]N,N′-diphenylurea increased with the increase in the [11C]CCl4 gas flow rate. At a flow rate of 50 ml/min, approximately 80% [11C]N,N′-diphenylurea was found in the reaction mixture with high reproducibility and unreacted [11C]CCl4 was increased. Furthermore, at higher flow rate (70 ml/min), the percentage of [11C]N,N′-diphenylurea was decreased, with increasing unreacted [11C]CCl4 and waste gas component. These results show that the [11C]CCl4 flow rate is an important factor for the radiochemical yield of [11C] phosgene in this method. The suitable air flow rate of the Kitagawa gas detection system for working-environment measurement is around 60–70 ml/min. With the results of the high yield and reproducible conversion of [11C]CCl4 from [11C]CH4 at a flow rate of 50 ml/min, we concluded that around 50 ml/min is the most favorable gas flow rate for this [11C]phosgene production apparatus. The specific activity of [ 11 C]COCl 2 calculated from [ 11 C]N,N′-diphenylurea obtained from approximately 7.4 GBq of [11C]CO2 was 85.1±51.8 GBq/μmol (n=3, not corrected for decay) after 10 min of synthesis time.
4. Conclusion We developed a new preparation method of [11 C] phosgene and an automated synthesis apparatus for this
reaction. The pretreatment tube for the Kitagawa gas detection system yielded [11C]phosgene with high yield and reproducibility. Additionally, the transformation process was performed at room temperature without a furnace, thereby downsizing the automated syntheses apparatus. Furthermore, this gas detection system is cost effective, allowing the use of a new pretreatment tube each time. The present method will contribute to the development and routine production of PET molecular probes.
Acknowledgments The authors thank the staff of the Cyclotron Operation Section and the Department of Molecular Probes of the National Institute of Radiological Sciences (NIRS) for their support with the operation of the cyclotron and production of radioisotopes.
References [1] Roger G, Dollé F, De Bruin B, Liu X, Besret L, Bramoullé Y, et al. Radiosynthesis and pharmacological evaluation of [11C]EMD-95885: a high affinity ligand for NR2B-containing NMDA receptors. Bioorg Med Chem 2004;12:3229–37. [2] Steel CJ, Brady F, Luthra SK, Brown GD, Khan I, Poole KG, et al. An automated radiosynthesis of 2-[11C]thymidine using anhydrous [11C]urea derived from [11C]phosgene. Appl Radiat Isot 1999;51: 377–88. [3] Lidström P, Bonasera TA, Marquez MM, Nilsson S, Bergström M, Långström B. Synthesis and in vitro evaluation of [carbonyl-11C] estramustine and [carbonyl-11C]estramustine phosphate. Steroids 1998;63:228–34. [4] van Waarde A, Elsinga PH, Doze P, Heldoorn M, Jaeggi KA, Vaalburg W. A novel beta-adrenoceptor ligand for positron emission tomography: evaluation in experimental animals. Eur J Pharmacol 1998;343: 289–96. [5] Roeda D, Tavitian B, Coulon C, David F, Dollé F, Fuseau C, et al. Synthesis of [11C]RPR-72840A and its evaluation as a radioligand for the serotonin reuptake site in positron emission tomography. Bioorg Med Chem 1997;5:397–403. [6] Bernard S, Fuseau C, Schmid L, Milcent R, Crouzel C. Synthesis and in vivo studies of a specific monoamine oxidase B inhibitor: 5-[4(benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-[11C]-2(3H)one. Eur J Nucl Med 1996;23:150–6. [7] Brady F, Luthra SK, Tochon-Danguy HJ, Steel CJ, Waters SL, Kensett MJ, et al. Asymmetric synthesis of a precursor for the automated radiosynthesis of S-(3′-t-butylamino-2′-hydroxypropoxy)benzimidazol-2-[11C]one (S-[11C]CGP 12177) as a preferred radioligand for beta-adrenergic receptors. Int J Rad Appl Instrum [A] 1991;42:621–8. [8] Landais P, Crouzel C. A new synthesis of carbon-11 labeled phosgene. Appl Radiat Isot 1987;38:297–300. [9] Link JM, Krohn KA. A simplified production of high specific activity [11C] labeled phosgene, 11COCl2. J Labeled Compds Radiopharm 1997;40:306–8. [10] Nishijima K, Kuge Y, Seki K, Ohkura K, Motoki N, Nagatsu K, et al. A simplified and improved synthesis of [11C]phosgene with iron and iron (III) oxide. Nucl Med Biol 2002;29:345–50. [11] Solbach C, Machulla H-J. Production of [11C]chloroform by direct chlorination of [11C]methane without catalyst support for the synthesis of [11C]diazomethane. Appl Radiat Isot 2007;65:1345–9.
Nuclear Medicine and Biology 37 (2010) 73 – 76 www.elsevier.com/locate/nucmedbio
Simple and effective method for producing [11 C]phosgene using an environmental CCl4 gas detection tube☆ Masanao Ogawaa,b , Yuuki Takadaa,c , Hisashi Suzukia , Kazuyoshi Nemotoa , Toshimitsu Fukumuraa,⁎ a
Molecular Probe Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan b SHI Accelerator Service, Ltd., Tokyo 141-8686, Japan c Department of Radiology, School of Medicine, Yokohama City University, Yokohama 236-0004, Kanagawa, Japan Received 20 February 2009; received in revised form 7 July 2009; accepted 24 August 2009
Abstract Introduction: Carbon-11-labeled phosgene is an important labeling precursor for PET molecular probes. Despite the usefulness of [11C] phosgene, some difficulties, especially in the formation of [11C]phosgene process from [11C]CCl4, hamper its use. The present article shows a simple preparation method for [11C]phosgene. Method: [11C]CCl4 was obtained using the conventional method by passing a mixture of [11C]CH4 and Cl2 through a heated quartz tube. The [11C]CCl4 was transformed to [11C]phosgene simply by passing through a pretreatment tube of a Kitagawa gas detection system for the working-environmental CCl4 concentration measurement at room temperature with a flow rate of 50 ml/min. Result: This tube successfully transformed [11C]CCl4 to [11C]phosgene at room temperature. [11C]Phosgene was obtained at nearly 80% radiochemical yield (EOB) in a short synthesis time with high reproducibility. Conclusion: A high yield and reliable [11C]phosgene production method using a gas detector tube system for working-environmental CCl4 concentration measurement was developed. © 2010 Elsevier Inc. All rights reserved. Keywords: [11C]phosgene; Synthesis; Gas detector tube system; Carbon-11; PET
1. Introduction Carbon-11 is an important radionuclide giving a wide variety of PET tracers with unchanging parent structure. Carbon-11-labeled phosgene is an important, highly reactive labeling precursor for ureas, carbonate esters, etc.; thus, some useful PET tracers have been prepared using [11C] phosgene as a labeling precursor [1–7]. In most cases, [11C]phosgene has been prepared by the chlorination of [11C]methane to [11C]CCl4 and subsequent catalytic conversion to [11C]phosgene. Several conversion methods have been reported using Fe as a catalyst with/without added ☆ This study was partially supported by a consignment grant for the Molecular Imaging Program on Research Base for PET Diagnosis from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT). ⁎ Corresponding author. Tel.: +81 43 206 3261; fax: +81 43 206 3261. E-mail address: [email protected] (T. Fukumura).
0969-8051/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.nucmedbio.2009.08.008
oxygen gas [7,8]; however, these methods had some problem in the radiochemical yield and reproducibility. Nishijima et al. [10] reported the synthesis of [11C]phosgene by adding iron(III) oxide to an Fe catalysis column as an oxygen source. This method increased the radiochemical yield of [11C]phosgene with high reproducibility; however, this method uses a column oven for the formation of [11C] COCl2 and yield has been affected by [11C]CCl4 flow and the particle size of the metal catalyst. In the present article, we will report the highly reliable synthesis method from [11C]CCl4 to [11C]phosgene at room temperature. 2. Experimental 2.1. General CO2 was produced by the 14N(p, α)11C reaction using a National Institute of Radiological Sciences cyclotron. 11
74
M. Ogawa et al. / Nuclear Medicine and Biology 37 (2010) 73–76
Radioactivity was quantified with a dose calibrator (IGC-7, Aloka, Tokyo Japan). Reaction mixtures were analyzed by HPLC and GC equipped with NaI(Tl) scintillation detectors. The Kitagawa gas detector tube system (tube no. 147S) was purchased from Komyo Rikagaku Kogyo (Tokyo, Japan). Chlorine gas [20% Cl2 in He (V/V)] was purchased from Taiyo Nippon Sanso (Tokyo, Japan). 2.2. Synthesis apparatus Fig. 1 shows the synthesis apparatus for [11C]phosgene. This apparatus consists of parts that perform the condensation of [11C]CO2, conversion of [11C]CO2 into [11C]CH4 by a methanizer, condensation of [11C]CH4, production of [11C] CCl4 and subsequent conversion to [11C]phosgene, and a syringe for mixing Cl2 and [11C]CH4. Operations (switching of valves, control of furnace temperatures, gas flow rates, timing and duration of each step, etc.) are controlled remotely using a programmable
logic controller. Valves 1–8 are of the following types: 1–2 are stainless-steel solenoid valves (A2011-V, Gems Sensors & Controls); 3 is a PTFE two-way valve (EXV-2-1-1/4UG2, Takasago Electric); and 4–8 are PTFE three-way solenoid valves (STV-3-N1/4UG, Takasago Electric). A disposable plastic syringe for mixing Cl2 and [11C]CH4 is mounted on a custom-made syringe drive operated pneumatically. Coils 1 and 2 were prepared by filling Porapak Q (80–100 mesh) into stainless-steel tubes (Coil 1: 1/8 OD, 2.0 mm ID, 150 mm length; Coil 2: 1/16 OD, 1.0 mm ID, 300 mm length). All components were connected by Teflon tubing (1.6 mm OD, 0.75 mm ID). Coils 1 and 2 were cooled by liquid nitrogen blower (Nakazawa Seisakusyo, Chiba, Japan). 2.3. Production of [11C]carbon tetrachloride [11C]Carbon tetrachloride was prepared from [11C]CO2 produced by irradiation of the target gas (N2+0.01% O2) with an 18 MeV proton beam. Target gas containing [11C]CO2
Fig. 1. Apparatus for the synthesis of [11C]phosgene.
M. Ogawa et al. / Nuclear Medicine and Biology 37 (2010) 73–76
75
2.5. Analysis of the reaction mixture
Fig. 2. Influence of gas flow on the radiochemical yield of [11C]CCl4.
was passed by expansion through Coil 1 cooled at −100°C by cold nitrogen gas blow from liquid nitrogen to trap the [11C]CO2 with a flow rate of 500 ml/min. Coil 1 was heated with an air heater, and the released [11C]CO2 was introduced into a methanizer (211MT, GL Science) with target gas, which was used as vector gas in our synthesis apparatus, at a flow rate of 10 ml/min. The [11C]CO2 gas was mixed with H2 gas and subsequently passed through heated Ni catalyst column (400°C). [11C]CH4 generated by the methanizer was passed through a column (P2O5 and Ascarite II) and trapped in Coil 2 at −130°C. Coil 2 was purged with target gas at a flow rate of 10 ml/min for 15 s to remove H2 gas. Coil 2 was then warmed by an air heater and the released [11C]CH4 was transferred to a plastic disposal syringe (Terumo SS-10ESZ 10 ml) previously loaded with 20% Cl2/He (2 ml). The mixture of [11C]CH4/target gas and Cl2/He (ca. 7 ml) was introduced into a top of a vertical quartz tube (12 mm OD, 10 mm ID, 300 mm length) heated at 560°C by pushing the syringe. Immediately after injection, V8 was switched and the gas mixture was passed through the column from top to bottom at 50 ml/min. [11C]CCl4 was trapped in toluene (500 μl) cooled at 0°C for radio-HPLC analysis. 2.4. Production of [11C]phosgene The [11 C]CCl4 was sequentially passed through a horizontal pretreatment tube of the Kitagawa gas detection tube system for working-environmental CCl4 concentration at room temperature at a flow rate of 50 ml/min. The produced [11C]COCl2 was passed through a Teflon tube (6.0 mm OD, 4.0 mm ID, length 45 mm) filled with antimony/ glass beads (500 mg, Sb/glass beads=1:1) to remove chlorine and acidic gas from pretreatment tube. The yield of [11C] COCl2 was evaluated by the yield of [11C]N,N′-diphenylurea after reaction with an aniline/toluene solution (10 μl/500 μl) by bubbling through at room temperature.
Fig. 3. Conversion reaction of CCl4 to phosgene by the workingenvironment gas detection system.
The obtained reaction mixture was analyzed on a reversed-phase column (YMC-Pack Pro-C18, 4.6×150 mm; YMC, Kyoto, Japan) using CH3CN/H2O (60:40) as the mobile phase at a flow rate of 1.0 ml/min with a radioHPLC system. Under these conditions, [11C]CH2Cl2, [11C] N,N′-diphenylurea, [11C]CHCl3 and [11C]CCl4 were eluted at 3.2, 3.6, 4.3 and 7.0 min, respectively. Waste gases from the reaction mixture collected in Tedlar gas sampling bag were analyzed by the radio-GC system (column: Porapak Q; oven temperature: 50°C; carrier gas: He; flow rate: 36 ml/min). With these conditions, the retention times of [11C]CO, [11C]CH4 and [11C]CO2 were 2.1, 3.0 and 5.5 min, respectively.
3. Results and discussion 3.1. Synthesis of [11C]carbon tetrachloride Synthesis of [11C]CCl4 was carried out according to published methods [8–10]. Seven milliliters of [11C]CH4/ Cl2/N2 mixture was passed through a quartz tube at 560°C at various speeds. The effect of the flow rate on the yield of [11C]CCl4 is shown in Fig. 2. In the range of 10 to 50 ml/min, [11C]CCl4 was obtained at almost 90% radiochemical yield with high reproducibility. Byproducts such as [11C]CHCl3, [11C]CH2Cl2, etc., were not found by radio-HPLC analysis. A higher flow rate (70–90 ml/min) also gave [11C]CCl4 at more than 80% radiochemical yield; however, the dispersion of yield was larger than that of the lower flow rate. Low vector gas flow rate increased the yield of [11C]CCl4 by the longer reaction time [11]. In the present case, [11C]CCl4 was successfully obtained from [11C]CH4 in high yield and reproducibility at low gas flow rate (b50 ml/min). 3.2. Synthesis of [11C]phosgene [11C]Phosgene has been produced by the transformation of [11C]CCl4 on heated catalysts. Various methods have been reported using Fe, CuO, Fe+Fe2O3 as catalysts. These methods require a furnace to heat the catalysis column. Additionally, the automated synthesis apparatus for these methods requires a large space. In the present study, we Table 1 Influence of the gas flow on the radiochemical yield of [11C]phosgene⁎ Flow rate (ml/min)
10 30 50 70
Reaction mixture 11
11
[ C]N,N′-Diphenylurea (%)
[ C]CCl4 (%)
7.2 75.9 80.8±3.1⁎⁎ 66.6±14.1⁎⁎⁎
3.7 7.5 9.9±4.7⁎⁎ 14.6±11.5⁎⁎⁎
Waste gas (%)
89.1 16.6 8.3±3.1⁎⁎ 18.7±6.4⁎⁎⁎
⁎ Percentages of products were based on the recovered total activity. ⁎⁎ n=5. ⁎⁎⁎ n=3.
76
M. Ogawa et al. / Nuclear Medicine and Biology 37 (2010) 73–76
developed a simple method for the transformation of [11C] CCl4 into [11C]phosgene at room temperature using workingenvironmental gas detection tube (Kitagawa gas detector tube system). The Kitagawa gas detector tube system for measuring the CCl4 concentration in the working environment consists of two glass tubes (i.e., pretreatment tube and detector tube). The pretreatment tube is filled with supporting material which contains I2O5 and fuming H2SO4. The detector tube is filled with supporting material which contains 4-(p-nitrobenzyl)pyridine and benzylaniline. After connecting two glass tubes with a silicon tube, the system is used for measurement of working-environmental CCl4 concentration by passing sample air. The pretreatment tube converts CCl4 into phosgene by I2O5 and fuming H2SO 4 at room temperature (Fig. 3). Phosgene reacts with 4-(p-nitrobenzyl)pyridine and benzylaniline to form dyestuff in the detector tube. In the present study, we used the pretreatment tube for the transformation of [11C]CCl4 into [11C]COCl2. [11C]CCl4 produced in a previous chlorination step was subsequently passed through the pretreatment tube at room temperature. Table 1 shows the percentage of [11C]N,N′diphenylurea under various carrier gas flow rates. The yield of [11C]N,N′-diphenylurea depended on the stream velocity of carrier gas. At a low flow rate (10 ml/min), nearly 90% radioactivity was found in waste gas and gave [11C]N,N′diphenylurea in poor radiochemical yield. Radio-GC analysis of this waste gas revealed that the main radioactive product in waste gas was [11C]CO2, suggesting that [11C]CCl4 underwent excess reaction to [11C]CO2 by longer retention time in a pretreatment tube at a low flow rate. The radiochemical yield of [11C]N,N′-diphenylurea increased with the increase in the [11C]CCl4 gas flow rate. At a flow rate of 50 ml/min, approximately 80% [11C]N,N′-diphenylurea was found in the reaction mixture with high reproducibility and unreacted [11C]CCl4 was increased. Furthermore, at higher flow rate (70 ml/min), the percentage of [11C]N,N′-diphenylurea was decreased, with increasing unreacted [11C]CCl4 and waste gas component. These results show that the [11C]CCl4 flow rate is an important factor for the radiochemical yield of [11C] phosgene in this method. The suitable air flow rate of the Kitagawa gas detection system for working-environment measurement is around 60–70 ml/min. With the results of the high yield and reproducible conversion of [11C]CCl4 from [11C]CH4 at a flow rate of 50 ml/min, we concluded that around 50 ml/min is the most favorable gas flow rate for this [11C]phosgene production apparatus. The specific activity of [ 11 C]COCl 2 calculated from [ 11 C]N,N′-diphenylurea obtained from approximately 7.4 GBq of [11C]CO2 was 85.1±51.8 GBq/μmol (n=3, not corrected for decay) after 10 min of synthesis time.
4. Conclusion We developed a new preparation method of [11 C] phosgene and an automated synthesis apparatus for this
reaction. The pretreatment tube for the Kitagawa gas detection system yielded [11C]phosgene with high yield and reproducibility. Additionally, the transformation process was performed at room temperature without a furnace, thereby downsizing the automated syntheses apparatus. Furthermore, this gas detection system is cost effective, allowing the use of a new pretreatment tube each time. The present method will contribute to the development and routine production of PET molecular probes.
Acknowledgments The authors thank the staff of the Cyclotron Operation Section and the Department of Molecular Probes of the National Institute of Radiological Sciences (NIRS) for their support with the operation of the cyclotron and production of radioisotopes.
References [1] Roger G, Dollé F, De Bruin B, Liu X, Besret L, Bramoullé Y, et al. Radiosynthesis and pharmacological evaluation of [11C]EMD-95885: a high affinity ligand for NR2B-containing NMDA receptors. Bioorg Med Chem 2004;12:3229–37. [2] Steel CJ, Brady F, Luthra SK, Brown GD, Khan I, Poole KG, et al. An automated radiosynthesis of 2-[11C]thymidine using anhydrous [11C]urea derived from [11C]phosgene. Appl Radiat Isot 1999;51: 377–88. [3] Lidström P, Bonasera TA, Marquez MM, Nilsson S, Bergström M, Långström B. Synthesis and in vitro evaluation of [carbonyl-11C] estramustine and [carbonyl-11C]estramustine phosphate. Steroids 1998;63:228–34. [4] van Waarde A, Elsinga PH, Doze P, Heldoorn M, Jaeggi KA, Vaalburg W. A novel beta-adrenoceptor ligand for positron emission tomography: evaluation in experimental animals. Eur J Pharmacol 1998;343: 289–96. [5] Roeda D, Tavitian B, Coulon C, David F, Dollé F, Fuseau C, et al. Synthesis of [11C]RPR-72840A and its evaluation as a radioligand for the serotonin reuptake site in positron emission tomography. Bioorg Med Chem 1997;5:397–403. [6] Bernard S, Fuseau C, Schmid L, Milcent R, Crouzel C. Synthesis and in vivo studies of a specific monoamine oxidase B inhibitor: 5-[4(benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-[11C]-2(3H)one. Eur J Nucl Med 1996;23:150–6. [7] Brady F, Luthra SK, Tochon-Danguy HJ, Steel CJ, Waters SL, Kensett MJ, et al. Asymmetric synthesis of a precursor for the automated radiosynthesis of S-(3′-t-butylamino-2′-hydroxypropoxy)benzimidazol-2-[11C]one (S-[11C]CGP 12177) as a preferred radioligand for beta-adrenergic receptors. Int J Rad Appl Instrum [A] 1991;42:621–8. [8] Landais P, Crouzel C. A new synthesis of carbon-11 labeled phosgene. Appl Radiat Isot 1987;38:297–300. [9] Link JM, Krohn KA. A simplified production of high specific activity [11C] labeled phosgene, 11COCl2. J Labeled Compds Radiopharm 1997;40:306–8. [10] Nishijima K, Kuge Y, Seki K, Ohkura K, Motoki N, Nagatsu K, et al. A simplified and improved synthesis of [11C]phosgene with iron and iron (III) oxide. Nucl Med Biol 2002;29:345–50. [11] Solbach C, Machulla H-J. Production of [11C]chloroform by direct chlorination of [11C]methane without catalyst support for the synthesis of [11C]diazomethane. Appl Radiat Isot 2007;65:1345–9.