Determination of radionuclides and radiochemical impurities produced by in-house cyclotron irradiation and subsequent radiosynthesis of PET tracers

Objective To elucidate the radionuclides and radiochemical impurities included in radiosynthesis processes of positron emission tomography (PET) tracers. Methods Target materials and PET tracers were produced using a cyclotron/synthesis system from Sumitomo Heavy Industry. Positron and γ-ray emitting radionuclides were quantified by measuring radioactivity decay and using the high-purity Ge detector, respectively. Radiochemical species in gaseous and aqueous target materials were analyzed by gas and ion chromatography, respectively. Results Target materials had considerable levels of several positron emitters in addition to the positron of interest, and in the case of aqueous target materials extremely low levels of many γ-emitters. Five 11C-, 15O-, or 18F-labeled tracers produced from gaseous materials via chemical reactions had no radionuclidic impurities, whereas 18F-FDG, 18F-NaF, and 13N-NH3 produced from aqueous materials had several γ-emitters as well as impure positron emitters. 15O-Labeled CO2, O2, and CO had a radionuclidic impurity 13N-N2 (0.5–0.7 %). Conclusions Target materials had several positron emitters other than the positron of interest, and extremely low level γ-emitters in the case of aqueous materials. PET tracers produced from gaseous materials except for 15O-labeled gases had no impure radionuclides, whereas those derived from aqueous materials contained acceptable levels of impure positron emitters and extremely low levels of several γ-emitters. Electronic supplementary material The online version of this article (doi:10.1007/s12149-016-1134-3) contains supplementary material, which is available to authorized users.


Introduction
The quality assurance of positron-emitting tracers used in positron emission tomography (PET) is performed in accordance with guidance documents such as United States Pharmacopeia/National Formulary (USP/NF) and European Pharmacopeia (EP). Although slight differences among the documents were discussed previously [1], basic requirements include characters, radionuclidic identity, radionuclidic purity, radiochemical purity, chemical purity, pH, residual solvents, bacterial endotoxin, and sterility. Most tests can be finished before the release of PET tracers; however, tests such as those for sterility and endotoxins, especially in the case of 11 C-tracers, and radionuclidic purity depending on the measurement methods are completed after the release.
Regarding to radionuclidic purity, c-ray spectrometry is required for the detection and quantification of impurities. For the preparation of fludeoxyglucose ( 18 F) injection ( 18 F-FDG), sodium fluoride ( 18 F) injection ( 18 F-NaF), and ammonia ( 13 N) injection ( 13 N-NH 3 ), the radionuclides 18 F Electronic supplementary material The online version of this article (doi:10.1007/s12149-016-1134-3) contains supplementary material, which is available to authorized users. and 13 N are usually produced by proton irradiation of 18 O-H 2 O and 16 O-H 2 O, respectively, and it is well known that these aqueous target solutions contain very small amounts of c-emitters with a longer half-life than 18 F (109.8 min) [2 and references therein]. Most of these impurities are excluded from the final injections, but some impurities potentially remained in the preparation processes without purification using distillation or high-performance liquid chromatography (HPLC). Their levels may be much lower than that of 18 F or 13 N of interest, and the criteria for radionuclidic purity of PET tracers such as 18 F-FDG and 18 F-NaF required by the USP/NF (no less than 99.5 %) [3,4] and EP (minimum 99.9 %) [5,6]. Radionuclidic purity is also required for 11 C-labeled compounds such as 11 C-flumazenil and 11 C-raclopride; however, it is hardly considered that these tracers derived from 11 C-CO 2 via the chemical reactions and HPLC purification may contain radionuclides other than 11 C. The requirement for radionuclidic identity and purity for PET tracers synthesized chemically from gaseous materials seems to be substantially meaningless from a scientific point of view. However, systematic studies on what kinds of radionuclides and radiochemical species are included in the radiosynthesis processes of many PET tracers have not been reported.
The aim of this study was to clarify the radionuclides included in the radiosynthesis processes from target materials into final products. We focused on PET tracers labeled with four conventional radionuclides, 11 C, 13 N, 15 O, and 18 F, and investigated radionuclides and radiochemical species in the target materials, positron-labeled precursors, and five PET tracers. The target materials included 11 C-, 15 O-, and 18 F-labeled gases and 13 N-and 18 F-target solutions. The radionuclides investigated were short half-life positron emitters and longer half-life c-emitters. We discuss the significance of examinations of radionuclidic identity and purity in the quality control of PET tracers.

General
We used a 20 MeV cyclotron (CYPRIS HM-20), target and synthesis system developed by Sumitomo Heavy Industry (Tokyo, Japan). Target folders and materials used and the expected nuclear reactions are summarized in Supplementary Tables 1 and 2, respectively. The production of positron emitters and their labeled compounds were according to the standard specifications of Sumitomo Heavy Industry. Because the radionuclidic identity and purity could be changed depending on several parameters such as irradiation time, beam current, and target materials, we set the integrated beam currents to be suitable for routine production of each PET tracers in clinical use, and changed depending on the analyses to accurately evaluate or to avoid unnecessary radiation dose. The detailed information is summarized in Supplementary tables.
Production of 11 C-CO 2 , 11 C-methyl iodide, and 11 C-methylated compounds 11 C-CO 2 was produced by proton irradiation of N 2 containing 0.5 % O 2 at a pressure of 0.8 MPa.

C-CO 2 gas preparation
After 15-min irradiation with 10-50 lA, 11 C-CO 2 target gas was passed through a coiled stainless steel tube [0.5 mm inner diameter (i.d.) 9 90 cm length] immersed in liquid Ar (boiling point -186°C) to trap 11 C-CO 2 (boiling point -196°C). After returning the stainless steel tube to room atmosphere, the 11 C-CO 2 gas was recovered in a Tedlar Ò bag for about 60 s with a 30 ml/min N 2 flow to measure radioactivity decay.
Syntheses of 11 C-methyl iodide and three 11 C-methylated tracers After 15-min irradiation with 5-50 lA, 11 C-CH 3 I and 11 Cmethylated compounds were prepared using a multipurpose synthesizer CFN-MPS100 (Sumitomo Heavy Industries). 11 C-CO 2 gas was purged with a 30 ml/min N 2 flow into 0.1 ml of 0.1 M LiAlH 4 in tetrahydrofuran (ABX, Radeberg, Germany). After removal of tetrahydrofuran using a 200 ml/min N 2 flow heated to 180°C, 0.5 ml of HI was added and the solution was heated for 45 s. The 11 C-CH 3 I produced was recovered in a Tedlar Ò bag for about 60 s with a 30 ml/min N 2 flow to measure radioactivity decay. Radiosyntheses of 11 C-methionine, 11 C-ITMM, and 11 C-CB184 are described in the Supplementary material.

Production of 15 O-labeled gases and H 2 O
15 O-Gas was produced by deuteron irradiation of N 2 containing 0.5 % CO 2 or 2 % O 2 at a pressure of 0.29 MPa. After 10-min irradiation with 10-30 lA, 15 O-gas under continuous irradiation was transferred to a 15 O-gas/water synthesis system CYPRIS-G (Sumitomo Heavy Industries) with a 300 ml/min flow to produce the three 15 O-gases described below.

O-CO 2 production
Target 15 O-gas containing 0.5 % CO 2 was passed through a crushed carbon granules (size, between 1.0 and 3.35 mm) column (9.8 mm i.d. 9 150 mm length) at 400°C to convert traces of 15 O-CO to 15 O-CO 2 .

O-O 2 production
Target 15 O-gas containing 2 % O 2 was passed through three columns of crushed carbon granules (size, between 1.0 and 3.35 mm, 9.8 mm i.d. 9 150 mm length), soda lime (9.0 mm i.d. 9 150 mm length) and molecular sieve 5A 1/16 (Wako Pure Chemical Industries, Tokyo, Japan; 9.8 mm i.d. 9 150 mm length) at room temperature. Traces of 15 O-CO and 13 N-N 2 O were removed by these columns. 15 O-CO production Target 15 O-gas containing 2 % O 2 was passed through two columns of charcoal (9.8 mm i.d. 9 150 mm length) heated at 1000°C and soda lime (9 mm i.d. 9 150 mm length) at room temperature. Traces of 15 O-CO 2 are removed using the soda lime. 15 O-H 2 O synthesis 15 O-O 2 gas produced above was passed through a palladium black (about 20 mg, Wako Pure Chemical Industries) column (9.0 mm i.d. 9 2 mm length) heated at 130°C and a molecular sieve 5A 1/16 column (9.0 mm i.d. 9 70 mm length) at room temperature. This gas at a flow rate of 500 ml/min is mixed with H 2 at a flow rate of 7 ml/min and passed over a Pd wire (Aldrich 267163, Atlanta, GA) column (9.0 mm i.d. 9 15 mm length) heated at 180°C, and then bubbled into a sterile vial containing physiological saline.
Production of 18 F-F 2 and 4-10 B-borono-2-18 F-fluoro-L-phenylalanine ( 18 F-FBPA) with 10-50 lA, 13 N-ammonium solution was passed through a Sep-Pak Accel Plus CM Plus Short cartridge (Waters, Milford, MA). The cartridge was washed with 10 ml water for injection twice, and the 13 N-ammonium was eluted with 12 ml physiological saline for injection.
18 F-NaF production 18 F-NaF was prepared using a CFN multipurpose synthesizer CFN-MPS100 (Sumitomo Heavy Industries). After 3-45 min irradiation with 5-20 lA, 18 F-fluoride solution was passed through a Sep-Pak Accel Plus QMA Plus Light cartridge (Waters). The cartridge was washed with 10 ml water for injection, and 18 F-fluoride was eluted with 1 ml physiological saline for injection and diluted with 14 ml physiological saline.

Determination of positron emitters in target materials and radiolabeled compounds
Immediately after the end of bombardment (EOB), gaseous and aqueous target materials were recovered in a Tedlar Ò bag for gases and in a small glass vial for liquids, respectively, and the radioactivity decay was successively measured at first short intervals (15,20,30, and 60 s), then intermediate intervals (2,5,10, and 20 min) and finally long intervals (0.5, 1, and 2 h) using a radioisotope calibrator CRC Ò -712 (Capintec, Ramsey, NJ). Immediately after the recovery of 11 C-CO 2 and 11 C-methyl iodide gases and synthesis of radiolabeled compounds, the radioactivity decay was also successively measured, and percentages of radionuclides were decay-corrected at the EOB, at the time of recovery, or the end of synthesis (EOS).

Gas chromatography
Radiolabeled gases were analyzed using a gas chromatography (GC) system mounted in a 15 O-gas/water synthesis system CYPRIS-G (Sumitomo Heavy Industries). Radiolabeled gases were analyzed on a Porapak Q column (50/80 mesh, 3 mm i.d. 9 4 m length, Shimadzu, Kyoto, Japan) and a molecular sieves 13X column (30/60 mesh, 3 mm i.d. 9 4 m length, Shimadzu) at 55°C with a He flow at 55 kPa pressure (about 110 ml/min). CO 2 and N 2 O were absorbed using the molecular sieves 13X.
Ion chromatography 13 N-ammonium and 18 F-fluoride target solutions, 13 N-NH 3 , 18 F-NaF, and 18 F-FDG were successively analyzed 3-5 times using an ion chromatography (IC) system (Prominence HIC-SP, Shimadzu) immediately after EOS (2-8 min) up to 73 min to assign radionuclides of radioactive peaks. For analysis of anion a Shim-pack IC-SA2 (4.6 mm i.d. 9 250 mm length, Shimadzu) was used at 30°C by elution with of 12 mM NaHCO 3 /0.6 mM Na 2 CO 3 = 1/1 at a flow rate of 1.0 ml/min using an electric conductivity detector (suppressor method) and radioactivity monitor. For analysis of cations a Shim-pack IC-C4 (4.6 mm i.d. 9 150 mm length, Shimadzu) was used at 40°C by elution with of 3.5 mM oxalic acid/1 mM 18-Crown-6 ether = 1/1 at a flow rate of 1.0 ml/min by a non-suppressor method.

Detection of long half-lived gamma emitters in positron emitting compounds
For analyses of c-emitters of PET tracers we set the integrated beam currents to be suitable for routine clinical use: 13 N-NH 3 , 10-min irradiation with 20 lA; 18 F-FDG, 45-min irradiation with 50 lA; 11 C-methionine, 15-min irradiation with 10 lA; 18 F-FBPA, 120-min irradiation with 25 lA. The irradiation condition of 18 F-fluoride target solution and 18 F-NaF was same as that of 18 F-FDG. 13 N-ammonium target solution was produced by 30-min irradiation with 50 lA. Target materials and radiolabeled compounds were diluted with H 2 O to a 100 ml total volume, and the presence of impure metal ions emitting c-rays was measured using a high-purity Ge detector at FUJIFILM RI Pharma (GMX20190-P, SEIKO EG&G, Tokyo, Japan) for 18 F-target materials and 18 F-labeled compounds and at Tokyo Nuclear Services (GEM20200, SEIKO EG&G) for others. The radionuclides evaluated included 15 c-emitters: 22 Na, 48 V, 51 Cr, 52 Mn, 54 Mn, 55 Co, 56 Co, 57 Co, 58 Co, 57 Ni, 67 Ga, 93m Mo, 95 Tc, 96 Tc, and 181 Re. Each sample was measured twice for 1 and 10 h at 2-3 and 3-11 days, respectively, after EOB.

Results and discussion
Positron-emitting radionuclides and radiochemicals in 11 C-CO 2 target gas and 11 C-labeled compounds The total radioactivity decay curve of 11 C-CO 2 target gas (n = 3) is plotted in Fig. 1. There were three phases on a log scale. The decay line between 30 and 400 min (Fig. 1b) was well fitted to the decay of 11 C (t 1/2 = 20.4 min). After subtracting 11 C-radioactivity extrapolated to time zero at EOB from total radioactivity, the residual radioactivity decay line between 10 and 40 min fitted well to the decay of 13 N (t 1/2 = 9.97 min) (Fig. 1c). When further subtracting 13 N-radioactivity as above, the decay line between 1 and 4 min was slightly lower than the decay line of 14 O (t 1/2 = 70.6 s) (Fig. 1d). However, when considering the ratios of isotope: 14 N vs 15 N vs 16 O in the target material and the cross section of each isotope: 14 N(p, n) 14 Table 3). Radioactivity decay curves plotted on a log scale for 11 C-CO 2 gas, 11 C-CH 3 I, 11 C-methionine, 11 C-ITMM, and 11 C-CB184, showed only one component 11 C (Supplementary Table 3). 11 C-CO 2 target gas was analyzed by GC (n = 4). Radioactive peaks were detected in the retention times of O 2 /N 2 /CO, (2.4 min), CO 2 , (5.4 min) and N 2 O (6.5 min) on Porapak Q and those of O 2 , (1.5 min), N 2 , (2.2 min), and CO (5.3 min) on Molecular Sieve 13X (Fig. 2). When considering radionuclides detected by measurement of radioactivity decay, we assigned that CO 2 (average 60.4 %) and CO (1.0 %) were labeled with 11 C, N 2 (33.6 %) and N 2 O (0.1 %) were with 13 Table 4).
We did not analyze 11 C-CO 2 gas condensed in a stainless steel tube in liquid Ar by GC. However, the radioactivity decay of the 11 C-CO 2 gas showed a single component. 13  ) might lower than the detection limit during the condensation process of the 11 C-CO 2 target gas. Thus, we concluded that radionuclidic pure 11 C-CO 2 was used for the 11 C-labeling of PET tracers after the condensation process of the 11 C-CO 2 target gas at liquid Ar temperature.
Positron-emitting radionuclides and radiochemicals in 15 Table 5). 15 O-H 2 O decayed away with t 1/2 = 2 min. 15 O-Gases were analyzed using GC ( Supplementary  Fig. 2). 15 O-CO 2 (n = 6), 15 Fig. 2 Gas chromatograms of 11 C-CO 2 target gas. 11 C-CO 2 target gas was directly applied to a gas chromatography system mounted in a 15 O-gas/water synthesis system CYPRIS-G (Sumitomo Heavy Industries). Left side analysis using a Porapak Q column; right side analysis using a Molecular Sieve 13X column. Upper row thermal conductivity; lower row radioactivity Detection of a radionuclidic impurity 13 N 2 in a range of 0.5-0.8 % of total radioactivity in all three 15 O-gases indicates that criteria are necessary for both radionuclidic and radiochemical impurities in quality assurance of 15

Ogases.
Positron-emitting radionuclides and radiochemicals in 18 F-F 2 target gas and 18 F-FBPA Radioactivity decay of 18 F-F 2 target gas (n = 3) showed a biphasic decay curve (Supplementary Fig. 3). The decay line up to 1300 min fitted well to the decay of 18 F, and that between 1.5 and 4 min fitted well to the decay of 23 Ne (37.2 s). The amount of 23 Ne (83.2 %) was much larger than that of 18 F-F 2 (16.8 %) at EOB (Supplementary Table 7). 23 Ne is inert for chemical reactions. Radioactivity decay of 18 F-FBPA showed only a component of 18 F. In the present study, we added F 2 at 0.6 % in Ne which was sufficient to prevent adsorption of 18 F-F 2 on the inner surface of the target and tubing for transfer to the synthesis system. We consider that examination of radionuclidic impurity could be omitted in the quality assurance of 18 Flabeled PET tracers derived from 18 F-F 2 .

Positron-emitting radionuclides and radiochemicals in 13 N-ammonium target solution and 13 N-NH 3
Radioactivity decay of an 13 N-ammonium target solution (n = 3) showed a three-phase curve ( Supplementary  Fig. 4). The decay line between 100 and 1200 min fitted well to the decay of 18 F, and those between 10 and 70 min and between 3 and 8 min fitted well to the decay of 13 N and 15 O, respectively, and the ratios of 13 N, 15 O, and 18 F were 58.3, 41.1, and 0.6 %, respectively, at EOB (Supplementary Fig. 4; Table 8). It should be noted that during the recovery of 13 N-ammonium target solution in a glass vial by He pressure, radioactive gases such as 13 N-N 2 [7] could be removed, if they were present in the target solution. We detected 15 O and 18 F as contaminants in the 13 N-ammonium target solution as reported previously [9][10][11]. On the other hand, Tornai et al. found 17 F (t 1/2 = 64.5 s) in addition to 15 O in an 13 N-ammonium target solution produced by proton irradiation with an incident energy of 21 MeV, but not with an incident energy of 10.7 MeV [12]. 13 N-NH 3 (n = 3) showed a biphasic decay curve with t 1/2 = 10 and 110 min, and the ratio of 18 F was 0.005 % of total radioactivity at EOS (Supplementary Fig. 5; Table 8). It was pointed out that the elapsed time when the ratio of 18 F in each of three 13 N-NH 3 preparations exceeded 0.1 % of 13 N was 41-51 min after EOS. 13 N-Ammonium target solution and 13 N-NH 3 were analyzed using IC (n = 3). In the first of successive analyses of the 13 N-ammonium target solution on an anionexchange column, more than four minor radioactive peaks, in addition to a main radioactive peak in the void volume, were detected (Fig. 3a). The retention times of the three peaks were consistent with those of fluoride (3.9 min), nitrite (4.3 min), and nitrate (8.9 min). Based on previous studies [7,11,13,14], the nitrite and nitrate were probably labeled with 13 N. Candidate compounds for other minor radioactive compounds (void-1 and unknown-2) may be 13 N-NH 2 OH [14] and 15 O-H 2 O [12]. We detected 15 O in the 13 N-ammonium target solution by measuring radioactivity decay (Supplementary Table 8); however, we could not assign 15 O-labeled components in successive analyses. IC may barely detect low levels of 15 O-labeled components. The percentage of the main peak in the void volume containing 13 N-ammonium was 96.5 % at EOS, when the contribution of 15 O as a radioactive contaminant was ignored (Supplementary Table 9). 13 N-NH 3 showed a radioactive peak on an anion-exchange column.
In successive analyses of the 13 N-ammonium target solution on a cation-exchange column, three radioactive peaks were detected for these periods (Fig. 3a). The peak area corresponding to the retention time of ammonium (5.6 min) decreased in accordance with a half-life of 13 Table 9).
In 13 N-NH 3 , only one radioactive peak was detected in the void volume and at the retention time of ammonium on anion-and cation-exchange columns, respectively (Fig. 3b). The contaminant 18 F, probably 18 F-fluoride, detected by measuring radioactivity decay (0.005 % of total radioactivity), could not be monitored using a radioactivity detector even in the last of successive analyses (60-65 min at EOB) probably because of the very low level available to detect.
In quality assurance of 13 N-NH 3 , 18 F-fluoride is noticed as a radionuclidic impurity but not radiochemical impurity. A limited time of 13 N-NH 3 for clinical use may be at longest a three half-life period (30 min) after the EOS. Up to that time the ratio of 18 F increases, but is a very low level (about 0.05 % of total radioactivity) that is acceptable for clinical use.  Table 10). Radioactivity decay of 18 F-NaF (n = 4) showed two components 18 F (99.5 %) and 13 N (0.5 %) ( Supplementary Fig. 7), and 18 F-FDG (n = 3) had a component of 18 F (Supplementary Table 10). Contamination with 17 F probably disappeared during the preparation periods of 18 F-NaF (8-11 min) and 18 F-FDG (about 30 min). The elapsed times when the ratio of 13 N in each of the four 18 F-NaF preparations became less than 0.1 % of 18 F were calculated to be 21-32 min after EOS. In another 18 F-FDG sample we measured radioactivity decay until complete decay for over 3 days, and confirmed that no radioactivity with a longer half-life than 18 F was detected using measurement with a radioisotope calibrator.
18 F-Fluoride target solutions, 18 F-NaF and 18 F-FDG were analyzed by IC (Supplementary Fig. 8). Short halflife 17 F (t 1/2 = 64.5 s) was hardly detected by IC because of the period to the start analysis and the retention time of 18 F-fluoride. On an anion-exchange column 18 F-fluoride target solution and 18 F-NaF showed a minor radioactive peak of nitrate (8.9 min, 0.6 %) and two minor radioactive peaks corresponding to nitrite (4.3 min, 0.2 %) and nitrate (1.5 %), respectively, in addition to 18 F-fluoride. 18 F-FDG showed a main peak (2.5 min) and minor unknown and fluoride peaks. Because the 18 F-fluoride increased slightly in successive analyses (data not shown), it was probably derived from radiolysis of 18 F-FDG [15].
On a cation-exchange column, a main radioactive peak for all 18 F-fluoride target solution, 18 F-NaF, and 18 F-FDG, . Left side analysis on an anion-exchange Shim-pack IC-SA2 column; right side analysis using a cation-exchange Shim-pack IC-C4 column. Upper row conductivity; lower row radioactivity was eluted at 2.0 min, and a minor radioactive peak was detected in the 18 F-fluoride target solution (1.8 min) and 18 F-FDG (2.3 min). In successive analyses, the 1.8-min peak area decreased faster than a half-life of 18 F, indicating that the peak included 13 N-and 18 F-chemicals. The percentages of each component on both ion-exchange columns are summarized in Supplementary Table 11.
In clinical use of 18 F-NaF, a preparation time is very short and 13 N was detected in it as radionulidic impurities. It is preferable that quality assurance or release of 18 F-NaF for clinical use is delayed for appropriate time after the EOS until 13 N-radioactivity decays to a negligible level.

Detection of long half-life c-emitters in positronemitting compounds
The presence of impure metal ions emitting c-rays in aqueous target materials is well known [2 and references therein]. We measured long half-life c-emitters in aqueous target solution and related compounds using a high-purity Ge detector (Supplementary Table 12).
In the 13 N-ammonium target solution (average yield = 13.5 GBq, n = 3), 11 of 15 c-emitters investigated were detected in the order of 10 -6 -10 -9 compared with 13 N of interest: 51 Cr, 52 Mn, 54 Mn, 55 Co, 56 Co, 57 Co, 58 Co, 57 Ni, 95 Tc, 96 Tc, and 181 Re. Most of these nuclides were removed in the synthesis process of 13 N-NH 3 (average yield = 7.4 GBq, n = 3), and very small amounts of five c-emitters ( 51 Cr, 52 Mn, 55 Co, 56 Co, and 58 Co) in the order of 10 -13 -10 -14 compared with 13 N of interest remaining in 13 N-NH 3 . Theoretically, 13 N-ammonium target solution was expected to contain the same c-emitters as 18 F-fluoride target solution described below, because we used the same target system: a Nb-body target with a Havar foil. A finding that two c-emitters, 67 Ga and 93m Mo, were not detected in 13 N-ammonium target solution was possibly because of the shorter irradiation times. In the production of 13 N-NH 3 , extremely small amounts of c-emitters were left, because we limited the irradiation time to a practical level for clinical use of 13 N-NH 3 .
In 18 F-fluoride target solution (average yield = 93.8 GBq, n = 3), 13 of 15 c-emitters were detected in the order of 10 -8 -10 -10 compared with 18 [2]. Undetected two c-emitters 22 Na and 48 V were included as potential radionuclides which were present in the production process of PET tracers depending on the target body and foils [the report on the waste of short half-life radionuclides by Japan Radioisotope Association (May 2003, in Japanese)]. For example, 48 V was detected using a silver-body target with titanium foil [16]. In the synthesis processes of 18 F-NaF (average yield = 78.3 GBq, n = 3), six c-emitters were under detection, two ( 54 Mn and 56 Co) were reduced, and the other five ( 51 Cr, 93m Mo, 95 Tc, 96 Tc, and 181 Re) were not reduced. In 18 F-FDG (average yield = 63.4 GBq, n = 3), nine c-emitters were below the level of detection, two ( 56 Co and 181 Re) remained, and two ( 95 Tc and 96 Tc) were reduced.
We examined contaminant by c-emitters in PET tracers derived from gaseous target materials: 11 C-CO 2 gas via 11 C-CH 3 I and 11 C-CH 3 OTf, and 18 F-F 2 . Selected PET tracers were 11 C-methionine and 18 F-FBPA. The former was prepared without HPLC separation. Both tracers showed no c-emitters. These findings were reasonably well expected, because it was hardly considered that radiolabeled metal contaminants were derived from gaseous target materials.

Radionuclidic identity and purity in the quality control of PET tracers
In the present study, we investigated radionuclides and radiochemical species in radiosynthesis processes from target materials to PET tracers. In gaseous and aqueous target materials, a couple of positron emitters were found. However, regarding to radionuclidic purity the tracers produced by chemical reactions: 11 C-labeled methionine, ITMM and CB184, 15 O-H 2 O, 18 F-FBPA, and 18 F-FDG had only one positron emitter of interest. On the other hand, 15 O-gases, 18 F-NaF, and 13 N-NH 3 which were produced by passing through catalytic columns or ion-exchange cartridges without chemical reactions, contained minor positron impurities in addition to the positron emitter of interest. Regarding to positron impurities, it was noted that measurement of radioactivity decay was more sensitive than IC. IC could not detect 18 F in 13 N-NH 3 and 15 Ocomponents in 13 N-target solution. The radionuclidic purity of each of the three 15 O-gases was less than 99.5 %; however, an impurity, that was inert 13 N-N 2 , was reasonably acceptable for clinical use, because it interfered in neither measurement of aimed functions/imaging quality nor the welfare of subjects. The radionuclidic impurities of 18 F-NaF: 13 N-nitrite and 13 N-nitrate decreased rapidly to be less than 0.1 % of 18 F by 21-32 min after EOS as discussed above. Thus, 30-60 min after EOS, the radionuclidic purity of 18 F-NaF satisfied the acceptance criteria for 18 F-NaF required by USP/NF (greater than 99.5 %) and EP (minimum 99.9 %). The amounts of c-emitters found in 18 F-FDG, 18 F-NaF, and 13 N-NH 3 were extremely low compared with acceptance criteria for the radionuclidic purity required by USP/NF and EP. The ratios of radionuclidic impurities observed in PET tracers could be slightly changed depending on the integrated beam currents; however, we considered that examinations of the radionuclidic identity and purity were not necessarily for quality assurance of PET tracers in routine production when the radionuclides were produced using a specific cyclotron with fixed energy of proton or deuteron beam (CYPRIS HM-20 in this study) and fixed target and synthesis systems, and when once the radionuclides in target materials and final PET tracers were reasonably analyzed from a scientific point of view. Regarding 15 O-gases, radiochemical impurities 13 N 2 in 15 O-O 2 and 15 O-CO corresponded with radionuclidic impurity, and the ratios of radionuclidic impurity in three 15 O-gas species were 0.5-0.8 % of total radioactivity. The criteria of radionuclidic purity for PET tracers such as these 15 O-gases should be determined based on quality for the measurement of the aimed functions and welfare of subjects, but not in the same way as other tracers such as 18 F-FDG and 18 F-NaF.

Conclusion
Gaseous target materials used for the production of PET tracers had considerable levels of several short half-life positron emitters in addition to the positron of interest, and aqueous target materials had extremely low levels of many longer half-life c-emitters in addition to positron emitters. Five tracers produced from gaseous target materials via chemical reactions had no radionuclidic impurities, whereas 18 F-FDG, 18 F-NaF, and 13 N-NH 3 produced from aqueous target materials had extremely low levels of several c-emitters as well as impure positron emitters. Three 15 O-labeled gases had impure positron-emitting 13 N-N 2 (slightly over 0.5 %).