Cyclotron Radiopharmaceuticals Production at the V.G.Khlopin Radium Institute L.M.Solin, B.K.Kudelin, V.A.Jakovlev, T.S.Potapova, E.A.Gromova V.G.Khlopin Radium Institute, 2nd Murinsky pr., 28, 194021 St.Petersburg, Russia Abstract. For more than 10 years Radium Institute is producing radiopharmaceuticals for St. Petersburg (Russia) hospitals. We have developed technologies for sodium iodide, sodium iodohippurate, MIBG and BMIPP, labeled by iodine-123, and gallium-67 citrate. Radionuclidic purity of 99,98% is reached for radiopharmaceuticals labeled by iodine-123. Radionuclidic purity is over 99.9% for gallium-67 citrate on the date of delivery. Radiochemical purity of 95% and more is reached through the application of appropriate technologies for each RPH. It takes no longer than 4 hours for all technologies. Over 150,000 patients were investigated. isotopes for single-photon diagnostics are presented in table 1. INTRODUCTION Now it is difficult to imagine modern medicine without the application of radiopharmaceuticals (RPH). Radiopharmaceutical are substances labeled by radioisotopes and designed to reach a certain place in human body. There are different kinds of RPH used for diagnostics of practically any human organ. Now rapid growth is seen in the field of RPH for therapy. This report deals with RPH for diagnostics. Depending on the mode of production, radioisotopes for RPH synthesis can be divided into two groups: reactor and cyclotron. Isotopes of the first group are produced by neutron irradiation from nuclear reactor, and the second group of isotopes is obtained by means of charged particles irradiation from cyclotron. Cyclotron medical isotopes with positron emission are used for PET (Positron Emission Tomograph) investigations, and gamma-emitting isotopes for single-photon diagnostics. As a rule every PET has a special cyclotron providing short-lived isotopes (with halflives from 2 min to 2 hours). Positron Emission Topography is a very sensitive and precise method, but it is also a rather expensive one. In many cases it is not necessary to get such detailed information and a single-photon analysis is quite sufficient; huge amounts of investigations are performed with gammacameras, scanners and other detectors by means of single-photon studies. The most important cyclotron TABLE 1. The Most Important Cyclotron Isotopes for Single-Photon Diagnostics. RadioMedical Application isotope I-123 Tl-201 Ga-67 In-111 Thyroid, kidney, endocrine system, myocardial imaging, brain, cerebral blood flow, neurological disease (Alzheimer's) Clinical cardiology, heart imaging, myocardial perfusion Oncology for malignant neoplasm and soft tissue inflammation Detection of heart transplant rejection, imaging of abdominal infections, soft tissue infection This article is devoted to the production of the most claimed by St.Petersburg radiologists cyclotron radiopharmaceuticals labeled by iodine-123 and by gallium-67. CP680, Application of Accelerators in Research and Industry: 17th Int'l. Conference, edited by J. L. Duggan and I. L. Morgan © 2003 American Institute of Physics 0-7354-0149-7/03/$20.00 1090 applied in investigations of endocrine system, and as an unique method for imaging of pheochromocytoma and neuroblastoma in children. 123I-BMIPP (123I-betamethyliodophenyl-pentadecanoic acid) – is a powerful tool for various heart disease studies; Gallium-67 citrate is used for tumor imaging and localization of inflammatory infections. RADIUM INSTITUTE MGC-20 CYCLOTRON It was 1989 when the first proton beam was extracted from the Radium Institute cyclotron MGC20. Cyclotron MGC-20 has been developed by the Efremov Scientific Research Institute of Electrophysical Apparatus (ESRIEA, St.Petersburg) more than 30 years ago for fundamental and applied research. 4 machines of such type were installed in Russia and 4 abroad (Finland, Hungary, North Korea, Egypt). Now most of them are used for medical isotopes production. The last cyclotron MGC-20 was put into operation last year in Cairo and it is supposed to be used for both gamma-emitting and positronemitting isotopes. The main requirements for RPH technologies introduced at the Radium institute were: simplicity and economy of radioisotopes production; high quality of a final product; short time for the total cycle from the EOB to the dispatch to customers (especially for iodine-123 labeled RPH) IODINE-123 AND GALLIUM-67 RADIOISOTOPES PRODUCTION The wide application of a cyclotron of such type is obliged to the possibilities of particle acceleration with a broad range of variable energies (Table 2) and a relatively low cost of facilities Many authors consider iodine-123 as an ideal radionuclide for Nuclear medicine. I-123 is a gamma emitter with electron capture mode of decay. The main gamma ray energy is 159 keV that is convenient for registration. Relatively short half-life (an 13.2 hours half-life), soft gamma rays and the absence of beta emission provide a low dose for patients. I-123 may be applied to pregnant and the newborn. Iodine is excellent for the synthesizes of a number of compounds. Therefore many investigations were performed to find an effective and cheap method of iodine-123 production. About 20 nuclear reactions were tried to produce iodine-123. At the Radium Institute it is produced via nuclear reaction 123 Te(p,n)123I. Enriched tellurium-123 dioxide is used as a target. To prevent its overheating under irradiation water and helium cooling is used. Iodine-123 formed in the target under proton bombardment is extracted by a rather simple dry distillation method in a form suitable for labeling a number of compounds. At high temperatures (about tellurium dioxide melting point) iodine is released from the target. Then by air flow iodine is carried to vessel with sodium hydroxide where iodine is associated. TABLE 2. The Main Characteristics of Accelerated Particles. Internal Beam External Beam Accelerated Energy Current Energy Current Particles MeV µA MeV µA e Protons 2-20 200 5-18 50 Deuterons 1-11 300 3-10 50 Helium-3 4-27 50 8-24 20 Helium-4 2-22 50 8-20 20 Iodine-123 as well as gallium-67 may successfully be produced by means of MGC-20 cyclotron in p,n nuclear reaction. RADIOPHARMACEUTICALS PRODUCED AT THE RADIUM INSTITUTE Table 3 shows a list of RPH produced in the Radium Institute which are labeled by iodine-123 and gallium-67. Gallium-67 is a gamma emitter with electron capture decay mode, 78.1 hours half-life. The main gamma ray energies are 93.3, 184.6, and 300.2 keV. Nuclear reaction is 67Zn(p,n)67Ga. Enriched zinc-67 oxide is used as a target. Water and helium are used for cooling. Irradiated zinc is solved in the hydrochloric acid and then gallium-67 is extracted by means of ion exchange column with high efficiency. TABLE 3. Radiopharmaceuticals Produced by V.G.Khlopin Radium Institute. Labeled by I-123 Labeled by Ga-67 Sodium Iodide Gallium Citrate Sodium-Iodohippurate MIBG BMIPP Sodium iodide is used for thyroid glands investigations; Sodium iodohippurate – manly for kidney studies; MIBG (metaiodobenzylguanidine) – is Extracted radioisotopes (iodine-123 and gallium67) are used to prepare radiopharmaceuticals. 1091 (approximation 1). Table 4 shows the influence of target composition on RNP for targets used at different time at the Radium institute. RADIOPHARMACEUTICALS QUALITY The quality assurance is provided by means of GMP (Good Manufacturing Practice) for every pharmaceutical production. Radioactivity presence has two specific characteristics: radionuclidic purity RNP and radiochemical purity RCP. TABLE 4. Isotope Composition of Tellurium Targets and 124I Content in a Final Product . Mass 1990 1994 1997 Number Year Year Year 120 <0.1 <0.1 <0.01 122 1.6 0.5 0.6 123 95.6 98.5 99.3 124 2.7 0.9 0.06 125 <0.1 <0.1 <0.01 126 <0.1 <0.1 <0.01 128 <0.1 <0.1 <0.01 130 <0.1 <0.1 <0.01 124 I Impurities in % of Activity for 1 Hour Irradiation 0.37 0.16 0.024 RNP 99.63% 99.84 % 99.976 % Radionuclidic purity (RNP) is determined by the contribution of the main isotope activity (in%) in the total radiopharmaceutical activity. Impurities radiation may deteriorate the image contrast in diagnostics and increase the exposure dose to the patient. RNP depends on: the nuclear reaction, the target material chemical purity and the target material isotope enrichment. In recent years there has been a trend to increase RNP for a longer preparation application time and a better quality of images. It is easy to see that the impurity content (iodine-124) was reduced by factor 12 (table 6) at the expense of the increased enrichment. However, we can expect reduction in 45 times in accordance with the tellurium124 content change. It may be possible there is another reaction for iodine-124 production [1] 123 Te(p,γ)124I and we have approximation 2 The highest RNP for iodine-123 labeled RPH can be achieved through a nuclear reaction 124 123 123 123 Xe(p,2n) Cs(β+) Xe(e,β+) I It employs a cyclotron with the energy of about 30 MeV, Xenon-124 with high enrichment and complicated targetry. In the case of nuclear reaction 123 Te(p,n)123I RNP depends on the isotopic enrichment on 123Te. A 124 A 123 It is obvious that we have to apply enriched tellurium-123. When tellurium-123 enrichment reaches 95%, only iodine-124 remains as an impurity. Let us consider simple relations taken that A124 impurity iodine-124 activity, A123 – iodine-123 activity, then Imp ≈ A124/A123 ×100% (1) RNP ≈ (1-A124/A123)×100% = C124 C123 pγ × 0.136 × F + A 124 ( 5) To fit the experimental data it should be = 0.017% and it will determine a limit for impurity of iodine-124 at the tellurium-124 content reduction. And, consequently, the limit for RNP should be 99.983% (at the EOB of 1hour irradiation). (2) H.B. Hupf et. al. [2] had the same tellurium-123 (99.3% enrichment) as in our last investigation; and they received RNP of 99.9+% at EOB and thirty hours after EOB, the average RNP - 99.8+%. It is consistent with approximation 2 – 99.96% and 99.87% correspondingly, but not with approximation 1 – 99.99% and 99.96% correspondingly. Thus we have indirect confirmation of the RNP limitation reached by enrichment of tellurium-123. (1 − exp( − λ 124 × t)) × F(E p ) (3) A 123 C123 (1 − exp( − λ 123 × t)) C124, C123 - isotopes concentrations in the target λ124, λ123 – are the constants of decay for 124I and 123I, F(Ep) – is a function of proton energy For t=1 hour and for Ep constant F(Ep) = F It is seen that the reduction of tellurium-124 A 124 × C124 123 124 pγ A 124 is an artificial addition from the Te(p,γ) I nuclear reaction It is easy to show that in the case of target irradiation during “t” hours at the proton energy of Ep we have A 124 = As we have the limitation on RNP at the expense of tellurium-124 content, we can use target material with a slightly smaller enrichment on tellurium-123 keeping the content of tellurium-124 at the same level. It means that we will use cheaper material. We have added to C124 = × 0.136 × F (4) A 123 C123 content leads to a proportional increase of RNP 1092 the highly enriched tellurium-123 of about 10% of highly enriched tellurium-122. RNP measurements showed that we have about the same value. Technological yield is over 99%. RCP is over 98%. Sodium iodide, 123I, is a raw material for other radiopharmaceuticals. For all the targets under consideration the impurity of I in the final product does not affect the image quality, and the 124I radiation exposure on the production date was considerably less than that of 123I. Sodium o-iodohippurate, 123I. Sodium iodide, 123I, and O-iodohippuric acid are used as start materials. The isotope exchange reaction is a method for production. Isotope exchange time is 40 min. Total time of RPH preparation is 2 hours. Technological yield is over 99%. This technology provides RCP of 98% and higher. 124 For using 123I produced by proton irradiation of tellurium target with 124Te content of <0.9%, the radiopharmaceuticals in 30 hours after EOB, has about the same quality as for using iodine obtained from 124 Xe(p,2n) reaction. 123 I-MIBG. Solid phase isotope exchange in the presence of sulfate-ions is a production method. Sodium iodide, 123I, with high specific activity (10-12 GBk/ml) and M-iodobenzylguanidine sulfate are used as start materials. Isotope exchange time is 50 min. Total time RPH preparation is 2 hours. Technological yield is over 97%. RCP is over 98% For gallium-67 the product radionuclidic purity depends on the isotope composition of target zinc. The isotope composition of the starting material used at the Radium Institute is presented in Table 5. TABLE 5. The Isotope Composition of the Target Zn. Zn-64 Zn-66 Zn-67 Zn-68 Zn-70 Contents (in %) 1.59 3.13 90.06 5.16 0.06 123 I-BMIPP. Catalytic isotope exchange is applied to 123I-BMIPP production. Sodium iodide, 123I, and 15(p-iodophenyl)-3-methylpentadecanoic acid are used as start materials. Isotope exchange occurs in the presence of a copper catalyst. Isotope exchange time is 20 min. There is only one-stage chromatographic extraction and purification of a final product on a disposable cartridge. Total time for RPH preparation is 3 hours. Technological yield is 90-92%. RCP is over 96%. Radioisotopes produced by proton irradiation except 67 Zn are short-lived enough to decay in a few hours after the end of bombardment. The only product which could compete with 67Ga is 66Ga with the 9.4 hours half-life and 511, 1039 and 2752 keV gamma ray energies. It is a product of both 66Zn(p,n) and 67 Zn(p,2n) reactions. At the end of bombardment its activity achieves a value of about 20% of total product activity. However, after cooling for 2 days its contribution became negligible. The product radionuclidic purity in two days is over 99.2 %. No other gamma and beta emitters are present. Gallium-67 citrate. Chemical complex formation reaction is used to produce RPH. Gallium-67 chloride solution in HCl and sodium citrate are used as start materials. Total time RPH preparation is 1 hour. Technological yield is 95%. RCP is over 95%. Radiopharmaceuticals technologies introduced at the Radium Institute take no longer than 4 hours to prepare a drag form ready for application. Radiochemical purity (RCP) is defined by the amount (in %) of isotope activity in the appropriate chemical form. Concentration of RPH in the target part of body is determined by RCP. It is depends on: the isotope production technology which determine a raw material chemical form, the reagent chemical purity and the labeling method. Isotopes production technologies were discussed earlier. Reagents chemical purity is dependent on the supplier. Labeling methods are vary between all of produced radiopharmaceuticals. REFERENCES 1. Solin L. M,.Jakovlev V. A, Kaliteevsky A. K., Godisov O. N.,.Mjazin L. P,.Shepelev P. K Cyclotron and their Applications 1998, Proceedings of the 15th International Conference, Caen, France, 70-73 (1998). 2. Hupf H. B., Beaver J. E., Armbruster J. M. and Pendola J. P., 16th International Conference on the Application of Accelerators in Research and Industry 2000 Sodium iodide, 123I. It is produced through interaction between iodine-123 vapor and the sodium hydroxide. In this case, different iodine chemical forms may be produced. As a rule, following our technology, 95% of iodine is produced in the form of iodide. To get a higher RCP, it is necessary to use autoclaving. Total time of RPH preparation is 2 hours. 3. Johansson L., Mattsson S., Nosslin B., Leide-Svegborn S Eur. J. Nucl. Med., 19, 933 (1992). 1093
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