XA0200235 ~
INIS-XA--472 Report
Technical Meeting of Project Counterparts on "Cyclotron Production of Iodine-123"
August 8-10, 2001 Instituto de Pesquisas Energeticas e Nucleares (IPEN) Sao Paulo, Brazil PLEASE BE AWARE THAT ALL OF THE MISSING PAGES IN THIS DOCUMENT WERE ORIGINALLY BLANK Summary of Technical Meeting of Project Counterparts on Cyclotron Production of Iodine-123
August 8-10, 2001 Institute de Pesquisas Energeticas e Nucleares (IPEN) Sao Paulo, Brazil
Introduction
Several cyclotron laboratory facilities are very much interested in the production of Iodine-123 for medical applications in view of its optimal physical and chemical properties. Some of these countries have in the past used the solid target technology based on the utilization of enriched Tellurium targets and are currently, quite involved in the development of enriched Xe-124 gas targets to improved the radionuclidic purity as required by the needs of modern nuclear medicine. With the purpose of discussing the advances in the later route of production and to foster mutual co-operation among the developing countries interested in this technology, a meeting was convened with the participation of scientists from Argentina, Brazil, Iran, Korea and Syria. A scientist from the United States of America was also invited as an expert to provide advise on particular aspects of the technology.
The list of participants is attached as Annex I and the presentations of individual scientists are included in Annex II.
During the meeting the following topics were discussed:
Gas versus solid target
There is no question that the xenon gas target produces higher purity 1-123 than the solid tellurium target. The higher cost of the xenon is justified in the ease of recovery and the purity of the final product. The quantity of 1-123 that can be produced is also higher from the xenon target in part as a result of the higher beam currents, which can be used on this type of target. The solid target can be a useful option for those places where there is not an established demand for the 1-123 in the Nuclear Medicine departments. It is possible to gain experience with this technology and then switch over to the higher purity xenon process. The cost of the enriched material for the tellurium complete system including all necessary equipment is 20 to 30K$ while the xenon gas will be on the order of 200K$.
Availability of enriched Xenon
Xenon gas is currently widely available and the price of the gas has fallen over the past few years by more than a factor of two. The xenon must be of high purity and an enrichment of at least 99% is highly recommended by the group. Lower levels of enrichment can result in other impurities such as 1-125. There was a question as to how to check the isotopic purity on a routine basis. Summary of nuclear data
The group felt that there was sufficient nuclear data for the relevant reactions. Although there was still some question in the exact cross-section, there was sufficient information for the routine production. There was one question as to the level of impurity introduced by the n Xe(p,a)121I nuclear reaction. The 1-121 decays with a 2.2 hours half-life to Te-121m, which has a 154-day half-life. The Te-121 ground state decays with a 16.8-day half-life.
Target geometry
There was a general feeling that the conical target is preferred over the cylindrical target. The increased volume has some disadvantages in the amount of gas, which must be used during an irradiation, but the yield should be higher with the conical target since the beam is completely contained in the gas and does not hit the walls of the target. The data comparing the two target geometries was not conclusive and there seemed to be little difference in the reported yields from the two designs. The cylindrical target is considerably easier to machine and therefore less expensive to produce. In those centers where there are machine shop facilities available, this is not a major concern.
The length of the target was discussed and the general consensus was that a longer target run at a lower pressure was to be preferred over a shorter target run at a higher pressure. The chance of rupturing the foils is significantly reduced by using the lower pressure. There is a limit in the length of the target in the ability to machine a longer target with a conical design. The optimum pressure seemed to be about 2 bar.
Recovery of iodine
There are two basic strategies for the recovery of the iodine from the target after irradiation. The first is to cryogenically pump the xenon gas out of the target into a decay in storage vessel immediately after the end of bombardment. The xenon containing xenon-123 is allowed to decay for 6.6 hours when the level of 1-123 reaches the maximum value. At that point the xenon is cryogenically pumped out of the decay vessel and into a storage vessel for next use. In the second method, the xenon (put real values for the amount of iodine lost) is allowed to decay in the target for 6.6 hours and then the xenon is cryogenically pumped from the target into a storage vessel for next use. The target is then washed with water and the iodine recovered. After the water rinse is removed from the target, the target is placed under vacuum and heated to remove any water from the interior of the target.
The disadvantage of removing the xenon from the target immediately after the end of bombardment is that the yields will be lower since any 1-123 created during the irradiation will be lost. This can be a considerable amount depending on the length of the irradiation. The disadvantage of the second method is that the target must be cleaned and dried thoroughly after use, any impurities in the target will be washed out with the iodine and the target is unavailable for use until the cleaning procedure is complete. For small- scale production intended to produce enough for use within a single facility, the removal immediately after bombardment is preferred. For large-scale production, the added yield from allowing the decay in the target is advantageous.
Design of system
The interior of the target should be a polished surface for either type of recovery. The material of choice for the target body is aluminum of good machining quality. The experience from the members of this group to date is that coating of the interior surface is not essential. There was a consensus that a two-foil design was preferred over a four foil design. The added complexity is not justified in the added level of safety provided by having two additional windows.
The question of a fast-closing valve was discussed. If there is sufficient space on an existing beamline, then it is a viable option and gives an added level of security against the loss of the xenon gas. It is required to have a distance of at least 10 meters in order for the fast-closing valve to be effective. In a new installation, it was felt that the cost of the fast-closing valve (35K$) plus the cost of the additional length of beam line including steering and focusing magnets which might be needed (10-50 K$) did not justify the security against the loss of the xenon. With the cost of the beamline and valve, an additional 1 to 2 liters of enriched xenon could be purchased.
There was discussion of the pumping system for the beamline. The possibility of using a cryogenic pumping system instead of the conventional diffusion pump backed by a rotary pump was discussed. A turbomolecular pump backed with a cold finger for trapping any released xenon was also evaluated. The competing factors are the cost of the pumping system versus the cost of the xenon gas in the case it is lost.
There are also regulatory concerns for the loss of the xenon in certain situations. If a release of activity and loss of xenon would cause complete shutdown of the facility with concurrent problems in restating the facility, then the additional cost for a doubly or triply redundant system are necessary.
Computer Control
There was general agreement that the system had to be at least semi-automated. It was strongly recommended that the system not be completely under manual control. The complete automation of the system under computer control is a worthwhile goal, but is not always necessary. In the case of complete computer automation, there must be the ability for the chemist to intervene in the process and take over control of the system from the computer. This manual control of the system is also required for maintenance.
-3- Chemistry
There was discussion of the requirements for a cationic resin prior to the anionic resin. There needs to be some additional work done on this aspect, but the general feeling was that the cationic impurities would pass through the anionic resin if a small amount was used. They would therefore not be present in the final solution to be used for labeling. Further study of the effect of low levels of impurities on the labeling efficiency is needed and this could be an area for further study.
The question of the radiochemical purity was discussed. The chemical form of the 1-123 is in most cases iodide. The formation of iodate has been noted in some centers. The source of the oxidation was discussed. There appear to be two potential sources of the iodate. The first is from incomplete removal of the water from the target prior to the next irradiation. This could result in the formation of some oxidizing chemical species. The second was from the introduction of oxygen into the xenon gas from leaks in the system or other sources. This again would result in oxidizing species in the target during irradiation. These two sources of radiochemical oxidation need to be explored in the future to determine the cause and to suggest a cure, hi practice the second possibility can be eliminated or reduced by careful purification of the xenon prior to irradiation. This can be done with any oxygen removal system.
Quality Control
The work in quality control is mainly concerned with the radionuclidic purity and the radiochemical purity. The presence of other iodine isotopes and other radionuclides such as Te-121 must be checked at the time of the validation of the process with gamma spectroscopy. The presence of other radiochemical forms of the iodine should also be checked on every batch. Solvent systems for the separation of iodide from iodate are available from several centers and are in the literature.
Future Work
In future work there were several basic science projects related to this program which could be undertaken. The first is the measurement of the 124Xe(p,o:)121I nuclear reaction. The energy dependence of this reaction needs to be evaluated with respect to the best energy interval to use for the production of 1-123 from the reaction of protons on xenon.
The second project is the measurement of the oxygen impurities in the xenon gas and the effect on the chemical form of the iodine. If a small oxygen impurity causes the 1-123 to be in the chemical form of iodate, then care must be taken to eliminate all traces of oxygen from the xenon.
The effectiveness of the cation resin in reducing the level of impurities in the final iodide preparation needs to be evaluated. If this resin column can be eliminated from the system, it will be simpler and therefore more reliable. The effect of any cations on the yield of the labeling reactions should also be evaluated.
A simple design for the xenon target was discussed and a general consensus was that the target should be: conical in design, as long as is feasible with machining considerations, lower pressure of about 2 bar, with two foils on the target to prevent loss of the xenon gas, an expansion volume for the xenon outside the target, no fast closing valve. Xenon left in the target or allowed to decay outside depending on the length of irradiation and the requirements for yield. The xenon gas purified for removal of traces of oxygen
International Co-operation
The current state of the participating countries is as follows:
Iran and Brazil are currently producing 1-123 routinely.
Argentina is in the later stages of construction of the target and production trials will start towards the end of the year. There was information presented at this meeting which will allow some slight modifications to the final design of their target.
Korea is both building its own back-up target system as well as buying the commercial target system.
Syria is currently designing the target system and will incorporate many of the characteristics described by the other participants in this meeting.
There will be continuing cooperation between Iran and Syria as to the design and construction of the target system. An automated system has been developed by Brazil and Iran. Argentina is in an advanced stage of developing automation for this system.
General comments of the participants
The general consensus of the participants was that this was a valuable meeting. Each participant brought some ideas into the meeting, which were reinforced by the other participants. This helped to give each participant confidence that they were on the right track in the design of the target and recovery system. The countries that have working systems heard about some additional ideas that may improve their systems in the future. For those who are in the midst of building the targets, some additional features can be added to the final design that could improve the yields. Potential problems were pointed out by the participants who currently doing the research which can be avoided by those just starting. This seemed to be the ideal time to have this meeting with some countries having completed their systems, some in the final stages of design and construction and some in the early stages of design. There was a free exchange of information that helped all concerned and there were several detailed discussions of the technical aspects of the system, which resulted in new ideas for solutions being brought out.
There was a discussion concerning writing a paper about the target design. It was felt that as long as the paper was a summary of the points discussed with recommendations for others on how to proceed, it would be a worthwhile project. It was felt that details of the calculations and research that had gone into the design should belong to the institution, which carried out the research and should be published by that institution separately. Annex I
Summary of Technical Meeting of Project Counterparts on Cyclotron Production of Iodine-123
8-10 August 2001
Institute of Nuclear and Energy Research (IPEN), Sao Paulo, Brazil
PARTICIPANTS' LIST
Dr. Kwon Soo Chun Dr. Abdul Hamid Al-Rayes Cyclotron Application Laboratory Atomic Energy Commission of Syria Korea Cancer Centre Hospital (KCCH) P.O. Box 6091 Seoul Damascus Korea Syrian Arab Republic Fax.: +88502 9701340 Fax.: 00963116112289
Dr. Valdir Sciani - local Dr. Carmelo Rocco Dr. Marycel Barboza - local Centro Nuclear Ezeiza Dr. Constancia Pagano de Silva - local Comision nacional de Energia Atomica Comissao Nacional de Energia Nuclear (CNEA) Instituto de Pesquisas Energeticas e Buenos Aires Nucleares] Argentina Departamento de Processamento de Material Fax.: 00541 3798288 Radioativo Travessa R 400, Cidade Universitaria Dr. D. Schlyer 05508-900 Sao Paulo Brookhaven National Laboratory Brazil Chemistry Department Tel: 005511-8169185 Bldg. 555, Upton Fax.: 005511-8160257 New York 11973-5000 E-mail: [email protected] USA Tel.: 0015163444587 Dr. Hossein Afarideh Fax: 0015163447350 Atomic Energy Organization of Iran E-mail: [email protected] Nuclear Research Centre for Agriculture and Medicine Dr. H. Vera Ruiz Rajaei-Shahr Head, P.O. Box 31585-4395 Industrial Applications and Chemistry Karadj Section, NAPC Iran, Islamic Rep. of Int. Atomic Energy Agency (IAEA) Tel.: 009821 8007395 P.O. Box 100 Fax.: 009821 8006095 Wagramer Str. 5 E-mail: [email protected] A-1400 Vienna Tel: +43-1-2600x21748 Fax.: +43-1-2600721748 E-Mail: [email protected] Annex II
Presentations of Individual Scientists XA0200236
TECHICAL MEETING ON CYCLOTRON PRODUCTION 1-123
8-10 AUGUST 2001.
ARGENTINA CYCLOTRON FACILITY
The Production Cyclotron Facility, installed at the Ezeiza Atomic Center, started its operations in 1994. The principal function is the production of radioisotopes It is isochronous cyclotron model CP-42, manufactured by The Cyclotron Corporation company; and further modified in Germany by Kraftanlagen Heidelberg. The cyclotron accelerates H" up to 42 MeV of energy with a maximal current of 200uA. It is possible to select the energy of the proton-beam between 25 and 42 MeV and through an extraction system, a beam line and a switching magnet, transport it towards 3 irradiation rooms.
In 1999, in the frame of a Project of Technical Assistance with the International Atomic Energy Agency (IAEA), some cyclotron improvements were made, increasing the initial maximal current from 100 to 200uA. Also the software control system of the accelerator operation was modified (the original PDP-11 computer was replaced by a PC).
At present, the cyclotron is used for Tl-201 production; F-18 and 1-123 production will be incorporated during this year. Regarding to Tl-201 production, a radiochemical process was developed: the Tl-203 target is irradiated with a lOOuA proton beam (29 to 18 MeV) during 14 h; 2000mCi of Tl- 201 are obtained at EOS.
Concerning to 1-123 production, a system for the irradiation of a gaseous target has been developed in the frame of a Project of Technical Assistance with IAEA (ARG4085).
A system for the production of F-l 8 and the synthesis of F18DG was also developed. Finally, the cyclotron is used for other special applications, such as the study of neutron damage in semiconductors used in satellites and grafting by proton beam.
CONSIDERATIONS ON GAS TARGET DESIGN.
For the design of a target, the first choice that must be made is the which nuclear reaction is going to be used to produce a given radionuclide. This depends on the energy of the cyclotron, the particles available and the specific activity required for the chemical processing. The body target has six parallel ducts; a ring-shaped system allows water circulate through them from inside towards outside by the outer duct. That system allow to remove the amount of heat generate during the irradiation is removed.
The water distributors are pieces machined with a conical cavity in order to mix the water; these pieces have six holes to connect with the target channel ducts, the cold water enters by the external distributor and the heat water goes out by the internal distributor. Is very important to point out that, in this kind of design, the target temperature is the same in the azimuth plane. Over its external surface, the target body has four cavities to house four resistances in order to elevate the temperature during the iodine washout process. Two little orifices situated on both side of the target allow target loading, before the irradiation, and exit solution to the hot cell after a decay time
TARGET DIMENSIONS.
Length: 264.5 mm External Diameter: 92.0 mm Xe-124 Chamber Diameter: 20.0 mm Chamber Deep: 250 mm Chamber Volume: 78.53 cm3
FOIL SYSTEM
The target window has two havar foils, one with 50 urn of thickness (nearest the target body) and another with 25 um. The system is prepared for He-cooling in case it were necessary to increase the beam current beyond 50 uA,. The foils are assembled allowing a safety volume in front of the target. The system foil consists of two foils, and each foil is placed between two pieces of aluminium. In order to irradiate the gas target, the beam has to pass through the safety volume; in case the target foil were ruptured during the irradiation, the gas would expand into the safety volume and then would be recovered via a cryogenic process in one storage vessel. If the second foil ruptures at the same time, the gas would expand into the diagnostic box, the collimator box and the beam line. In order to prevent the gas expanding until the pumping system, the collimator box has a sensor that triggers a signal to a fast closing valve, which shut down the beam line in 12 msec. Residual gas can be removed cooling the target with cryogenic system.
IRRADIATION SPECIFICATIONS
The iodine production system delivers an ultra pure radioisotope, via these nuclear reactions: 124Xe(p,2n)123Cs -* 123Xe -* 123I 124Xe(p,pn)123Xe-»123I The nuclear reaction for the production of a radionuclide will determine the optimum energy. Once the energy has been chosen it is necessary to calculate the thickness of the target in order to reduce the energy up to the optimal values according the yield of the principal and secondary reactions.
If high beam currents are to be used, the density reduction in the target beam must be considered, as well as the increase of the pressure into the target. It is convenient to design the target body with a conical form in order to minimize the amount of gas used, considering all scattered beam. The scattering distribution is determined by the foil material and beam energy. The cost of a conical target must be also considered because it is more expensive than a cylindrical one. The distribution of space angle "cp" between the incoming and outgoing direction of a particle passing through a thing foils, result of a multiple scattering, must be take account for the target design. In this sense there is a variety of computers program to estimate the scattering angle. For instance for 26.6 MeV of proton beam over Havar or Aluminium foil, the experimental determined scattering angle are the follow.
Foil Thickness (mg/cm2) Foil Material Scatter angle 20 Havar 0.45° 40 Havar 0.60° 20 Aluminium 0.34° 40 Aluminium 0.49°
DESCRIPTION.
The target for 1-123 production, has been manufactured in aluminium of high quality with the following characteristics:
Material Name: Alumee 89 Manufactured: British Aluminium Limited Thermal Conductivity: 165W/°C (25°C) Specific Heat: 890J/Kg°K Brinell Hardness: 180-200 Hb
The cylindrical shape target consists of a Nickel-Plated chamber to lodge the Xe- 124. This chamber is sealed by a system of double foil in the beam line direction, with a safety volume between both foils. In order to distribute the cooling water during the irradiation, two pieces are situated at the back of the target On the bottom side, there is a piece that holds the target system in work position. A Siemens Simatic S-5 system controls the entire process: from 124Xe loading until iodine solution transference into the hot cell. For this a controller system was developed. PRODUCTION PARAMETER
Particle proton Energy 25-30 MeV Irradiation time 5 hs Target pressure 4.5 bar (without beam) Moles Xe-124 0.0147 Volume Xe-124 329 ml B earn current 5 0 uA Batch size 2.3Ci
RADIOGHEMISTR Y PROCESS
The radiochemical unit contains: ten port Rheodyne valve, double programmable Gilson pump 402 model (one of them outside the hot cell and the another inside the hot cell), dose detector, reservoir for the wash water and Peek tube 1/16". Outside the hot cell, the external pump is connected to a manifold which permit to select different reactives (water, NaOH 0.01M, ethanol) that sends inside the hot cell at programmable volume and flow. Ten port RJbeodyne valve selects different pathways in very simple system. The Gilson internal pump is used to take out the target wash water and load the ion exchange column. The external pump wash the column, elute 1-123 and rinse the unit. A Visual Basic control program running in a PC was developed in order to control all 1-123 automatic process.
DESCRIPTION. 1- Take out the wash water . Rheodyne valve in position "A", the iodine solution is sending to the hot cell after the wash water, the internal pump take out the water from the target to a vial in the radiochemical cell at high flow. A radiameter measure the 1-123 dose, this value is register in the radiochemical program file. 2- Column load. Rheodyne valve in position "B", the internal pump take the liquid and pass through the column at 1.5 ml/m. Anionic compounds are retained in the Bio-Rex 5 resin while cationic impurities as a metal traces from the target body, goes to the liquid waster reservoir. A radiameter measures the 1-123 dose and is register in the radiochemical program file. 3- Column washing. Rheodyne valve in position "A", the external pump sends water to the column selected from the manifold valve. This liquid is discarded. 4- Iodine elute. Rheodyne valve in position "B", the external pump selects NaOH from the reactive manifold and send to the column at low flow of 0.5ml/m, the dose detector measure the dose in the line out, the high activity concentration is collected , (2000-3000ul) obtaining the 1-123 batch. 5- Rinse the radiochemical unit. At the end of process, the last step is used to wash all the tubing, column and valve. First with NaOH ,then employed ethanol and finally water.
CONTROL SOFTWARE. The system has been developed on Visual Basic 3.0. It allows to run the program automatically to obtain 1-123 and another programs in the workstation at the same time. The software was thought to minimize the radiochemical operators actions during the process and to reduce the radiological dose. The principal windows shows the different steps of the process, and also allows the control over the components and equipment. It is possible too a manual control if it is necessary. Each step after the process can be seen and printed at any time.
HOT CELL
The iodine production hot cell, is divided in two compartments. One of them for the radiochemistry process and the other one in order for the fractioning of the iodine solution in glass vials.
Hot cell size. 2200x1260x1100 mm Lead shielding. 50 mm Lead window. 5 (4x OPERATION CONTROLL SYSTEM The operations to be done for the routine production employed a Simatic System. PROCEDURE • 1 - Target preparation • 2- Irradiation • 3- Decay • 4- Storage the Xe-124 after irradiation • 5- Washout the target • 6- Drying the target • 7- Xenon purification • 8- Xenon recovery by ruptured of any foil FLOW SHE El -I-123- (31-Ene-OO) V29 -CICLDTRDN- fstc piano ta slda cjKutodjjior lo CONISIDN NACIDNAL DE ENKCIA MONICA (CIIEA) tsfo prplmaa su r&prowcQan utKUadon y/o *transferenda tie XOM Infomacnn contenna a nenos que extsta autorlzadun express par escnto Qtargadd por CNtA. TSHA F mnujg FLDW SHEET PROCESD DE REFRIGERACIQN PtffiL TOTT DE BLANCDS-VERSIDN 2 - CICLDTRON mm. INSTRUMENT^™ REV. DESCRIPC1QN FEIHA CQNTR, APR. COMISION NACIONAL DE ENERGIA ATOMICA INTERNATIONAL ATOMIC ENERGY AGENCY PROJECT N° ARG-4085 PRODUCTION FOR ULTRA PURE I123 TARGET MATERIAL CHARACTERISTICS: Material Name: Alumec 89 Manufactured: British Aluminium Limited Thermal Conductivity: 165 W/°C (25°C) Specific Heat: 890 J/Kg °K Brinell Hardness: 130-200 Hb TARGET DIMENSIONS: Length: 264.5 mm External Diameter: 92.0 4nm X124 Chamber Diameter: 20.0 mm Chamber Deep: 250.0 mm Chamber Volume: 78.53 -cm3 FOILS SYSTEM: Number of foils: 2 Material: Havar Thickness: 50 u and 1$ u COMISION NACIONAL DE ENERGIA ATOMICA INTERNATIONAL ATOMIC ENERGY AGENCY PROJECT N°ARG-4085 PRODUCTION FOR ULTRA PURE I123 MULTIPLE SCATTERING OF CHARGED PARTICLES: Particle: proton Energy; 26.5 MeV l Foil Thickness (mg/cm2) Foil Material Scatter Angle 20 Havar 0.45° * 0r66° ** 40 Havar 0.60° * 0,94° ** 20 Aluminium 0.34° * 0.43° ** 40 Aluminium 0.49° * 0,62° ** (• ) D.J. Schlyer and P.S. Plascjak (**) Employing the theory of B.P. Nigam, M.K. Sundaresan and T.Y. Wu TA MS TARGET STA L -Z.O- INTERNATIONAL ATOMIC ENERGY AGENCY I123 -•"•"' Proceso Aulomalico para lodo-123 Archivo CJpciones Ayuda Estado del Proceso ? | f-.M.lui:liici I li':l (iiucf:: REACTIVESR MANIFOLD 4 GILSOH EXTERNAL PUMP column Recepcion del agua de lauado en reseruono Hello GILSOH B waste Batch IHTERNAL PUMP lodo-123 2Z- XA0200237 Institut of Nuclear and Energy Research Brazilian Nuclear Energy Commission Technical Meeting of Project Counterparts on Cyclotron Production of Iodine-123 Dr. Valdir Sciani -Z3 IPEN/BRASIL • IODINE-123 PRODUCTION SYSTEM IBIPROS "^ I I ipe/i CV - 28 CHARACTERISTICS INTERNAL EXTERNAL CURRENT CURRENT PARTICLE ENERGY (1-iA) (HA) (MeV) ENERGY ENERGY (MIN) (MAX) 2-24 200 4- 14 300 6-36 8-28 TOLERANCE : +/-0.5 MeV (Emin); +/- 1MeV (Emax) RESOLUTION: 0.5% or 50 keV (consider the max value) CYCLONE 30 CHARACTERISTICS ACCELERif PARTICLE EXTRACfli MAX. : 30 ENERGY (MeV) MIN. : 15 CURRENT 350 NUMBER OF BEAMS ION SOURCE MULTICUSP EXTRACTION CARBON FOIL TYPICAL VALUES 67 Ga: E = 30Mef i = 200 18 F: E = 18MeV i = 30 jiA TARGET: l24TeO IMPURITY :. 124 LOW BEAM CURRENT INTENSITY IPEN - CNEN / SP : CV-28 ~ 120 mCi/batch YIELD : 4 mCi / juAh w w ** -t <. \ * * - > i. t a in •»••-.,„,. if; ".. -.?-; vQi^fgp^ *- ..^r ^ >» ^,JI i :?*"- l24Xe GAS TARGET GENERAL NUCLEAR REACTION: ^Xe(p.2n)^C PARTICLE: proton ENERGY: 30 MeV f- ©- CO I CD I Ld o o GAS TARGET VOLUME: 45 ml -rSffljgm PRESSURE: 3 bar (WITHOUT BEAM) LENGHT: 200 mm WINDOW: Mo 11 mm diameter WATER FLOW RATE: 6 1/min HELIUM FLOW RATE: 2 I/sec I24Xe-GAS TRANSPOR TA TION AND CONTAINMENT S YSTEM Till' l2lXc TRANSFER FROM Tllli STORAGE BOTllS^i'WTt- TARGET AND nn; RECOVERY OF THE GAS AFTER IRRADIATION TO 1111- BOTTLE IS MADE CRYOGENICALLY WITH LIQUID NITROGEN. THROUGH STEEL LINES. IF OCCASIONALLY THERE IS A RUPTURi: IN \\\Y- I;IRSI WINDOW. TIN; l24XeGAS WILL BI-TRAPPED IN THE HELIUM COOLING SYSTEM AND Till- MIXTURE CAN BE TRANSFERED TO TI IE STORAGE BOTTLE. IN CASE OF RUPTURE OF BOTH WINDOWS. THE l24Xe GAS WILL EXPAND IN Till- BI-AM ALIGNMENT SYSTEM WHICH CONTAINS A SAFETY VOLUME COOLED WITH LIQUID NITROGEN. A LIGNMENT S YSTEM FOR PROPER ADJUSTMENT AND CONTROL OF THE;;Biii|ipP?Mi THE IRRADIATION. THERE IS AN ALIGNMENT SYSTM THAT CONSISTS OF A PAIR OF FOUR-SEC TORS COLLIMATORS. THE; Bl-ABEAM CURRENT OF EACH COMPONENT IS DISPLAYED ON A MONITOR LOCLOCATE;!/ ) AT THE CONTROL ROOM OF" THE CYCLOTRON. AT Till- SAMI TIMI DISPLAYLD FOLLOWING PARAMETERS: a) BEAM CURRENT Oh' THE TARGET h) TEMPERATURE OF THE COOLING WATER c) TEMPERATURE OF THE HELIUM GAS USED TO COOL THE WINDOWS c() PRESSURE OF THE l2lXe THESE VALUES HELP THE OPERATOR TO OPTIMI/I- CYCLOTRON IRRADIATION PARAMETERS. fci Beam - [IODO-123 (Linha de Feiite 5)1 1-lgTx] Arquivo Ajuda rSetores Entrada Sa/da - Alvo Pressao Tmp (Agua) Tmp (He) I 'Parar ! Zerar Sair '{3 3i3 -123 [Li... €2lTabela CONTROL SYSTEM THE GAS TARGET IS REMOTELLY CONTROLLED BY SIEMENS SIMATIC S5. • THERE IS OPTION TO RUN IN MANUAL OR AUTOMATIC MODE. ALL STEPS OF THE SEQUENCE CAN BE STARTED BY PRESSING THE APPROPRIATE FUNCTION KEY. HI UNISGFT - Medidores Q .l 02 I Carregar i [AUTOMATICO| rtANUAL F1[pr6carga] F2[c NUM TYPICAL VALUES siiiil E = 30 MeV i = 20 uA Pv. = 3 bar (without beam) PXe = 4.5 bar ( during irradiation) Yield (EOB) = 8 mCi / uAh XA0200238 Institut of Nuclear and Energy Research Brazilian Nuclear Energy Commission Technical Meeting of Project Counterparts on Cyclotron Production of Iodine-123 Dr. Marycel Rosa Figols de Barboza -47- LABELING AND QUALITY CONTROL OF 123I-MIBG Marycel Figols de Barboza Labeled Compounds (CRP-MM) and Quality Control (CRQ) Groups Centro de Radiofarmacia -IPEN-CNEN/SP INTRODUCTION Radiodinated meta-iodobenzylguanidine (MIBG) has found wide-spread use in the clinical management of neuroendocrine tumors, especially carcinoid, pheochromocytoma and neuroblastoma and recently is increasingly being used to asses the status of the adrenergic nerves in the heart muscle. Based in the role of the adrenal medulla in the synthesis and storage of catecholamines, dopamine and its analogs labeled with 14C or 123I were evaluated. However, these compounds appeared, for different reasons, unsuitable for imaging the adrenal medulla. (Wieland ,1980 and Hoefnagel, 1989). In 1961, Boura et. aL, first combined the o-bromobenzyl moiety ot the bretylium molecula with the guanidine part of guanethidine and obtained powerful adrenergic neuron blocking agents. Guanethidine itself is an adrenergic neuron blocking agent Short and Darby, 1967 also reported on the chemical synthesis and the high sympathetic nerve blocking potency of a series of these so called aralkylguanidines In the late seventies, radiodine labeled analogs of the adrenergic neuron blocking agent bretylium were synthesized and investigated for this purpose. The bretylium analogs were reported to accumulate in the canine adrenal medulla.(Kom, 1977 and Wieland, 1979) Wieland et. al., 1980, investigated the distribution of o-, m- and p-[123I]benzylguanidine in dogs (OEBG, MDBG and PIBG). The m-isomer showed much less thyroidal accumulation of radioactivity compared to the others isomers, which indicated that [123I]-MD3G is more resistant to in-vivo deiodination. For this reason, [*I]-MIBG was selected for further investigations, which has led to its present wide use. (Figure 1) NH NH, Figure 1 - Chemical structure of I-MIBG Three iodine radioisotopes are commonly used as a label for MEBG: 123I; 131I and 125I. The superior physical characteristics of the radionuclide have made 123TI-MIBG an even more effective diagnostic agent. (Table I) TABLE I - Characteristics of [*I]-iodine used for labeling MIBG* *I Decay Mode Hal-life Energy y Participate emission Remarks 123y 7, EC 13,2 h 159 keV low-energy Auger electrons ideal, > cost 124j Y,EC,P+ 4,18 d 603 keV multiple |3+(366-976 keV) PET agent 125T Y,EC 60,1 d 35,5 keV Auger electrons (multiple) in vitro 131, 8,04 d 364 keV multiple 3 (69-190 keV) most used *Wafelman, A. R., etal, 1994 123I emits photons with a main energy, suited for gamma-cameras, whereas the minor contribution from low-energy Auger electrons results in relatively few absorbed doses. The y photon energy makes 123I suitable for single photon emission computer tomography (SPECT or SPET) using a dual head rotating gamma-camera which results in a more accurate quantification of photons with a planar scintigraphy. Unfortunately, the cost and physical half-life are limitations, the radioiosotope is not easily available for general use and only clinicians within the proximity of a cyclotron facility have access to the radiopharmaceutical. For the exchange labeling of MIBG with radioiode, the sulphate salt is to be preferred to the hydrochloride salt. (Mertens and Gysmans, 1991) thus preventing chloride from competition with radioiodide. Ammonium sulphate facilitates exchange radiodination (Mangner , 1982 , Mertens, 1986), this occurs in the solid phase at 140° C. Evidence has been provided that mildly oxidizing and acidic conditions are necessary for a successful exchange. Tesic, 1992 studied the kinetics of ammonium sulphate facilitated exchange radiodination of MIBG in agueous solution in a closed system. In 1986, Mertens first described the cooper (I)-assisted exchange radiodination of MDDBG which did not yield (radiolabeled) side products. The Cu1+ catalysed method was preferred, because of the approximately three times higher maximum specific activity with an acceptable labeling yield, the negligible loss of radioactivity and therefore a radioactive waste reduction (Franceschini, 1991), and it can concluded that the Cu1+catalysed isotopic exchange method is the procedure of first choice for the production of [*I]-MIBG. At the present, the labeling procedure used by some manufactures in Europe, it can be reported that Amersham Buchler (Germany) and Sorin Biomedica (Italy) both use copper ions, whereas the labeling procedure of Cis Bio International (France) a combination of cooper sulphate and ammonium sulphate is used. (Wafelman, 1994) The objective of the present work was the development of a reliable method to facilitate routine production of 123I-MIBG in Radiopharmacy Center of IPEN-CNEN/SP. -bo- MATERIALS AND METHODS The MEBG-sulphate, from Sigma, and all the reactives, solvents and resins used are pure and analytical degree. Sodium [123I]-iodide was obtained in Cyclone-30 (IBA) at IPEN-CNEN/SP. The production process uses the following nuclear reaction: mXe (p,2n) 123Cs 5.9 min.^ 123Xe 2.08 fr123 I The 124Xe gas as target material is highly enriched (> 99.8 %) which results in a ultra-pure 123I end product. Separation of123 I and recovery in small volume 0.02 N NaOH After irradiation and a decay of about 14 - 16 h, the 124Xe gas is removed cryogenically The [123I]-activity on the wall target is rinsed with 40 - 50 mL sterile water. The [123I]active solution is transferred to the hot-cell and percolated through a strong anionic resin. The 123I is eluted in 2.5 - 3.0 mL 0.02 N NaOH. Labeling process The scale of production varies with the demand and the quantities of substrate, catalyst and solvent are adjusted according Table II. The labeling process is based in Almeida (1985), Barboza (1994) and Colturato (1995) methods using MEBG-sulphate, (NJL^SCU and CuSO4 at 165 - 170° C during 30 minutes. The amounts used, according the activities of 123I-Na are illustrate in Table II. TABLE II - Amounts of reactives used in production lllllll ™|||S||| Spijjpl ^iiliiiHPiliiiiirnmii llliil liilliiiliiiIliillliiliiii :•:::::::;:::::; >: :>:::: i st': :::::;:::;:::::-:;:::::::- II! III iJHIllligl••••Si :•:•:•:•:•:•:•:•:•:::-:: *^ :::-::•:•:•:-:•:•:•::: lillllIlllllllII ::B:'<:S::::::?-!¥£5-Sfi iiifliSiSii ; : : ; : ; : : : : : : : ; : •:-:;:::;:::v::::::::':-:::-:-:::::;:-:-:::-: :•••:••:•:•:•:•:• :: : : : : ::v:-: : : : :-::-: :v:-: : : : : iliiliilliiillllllllllSfl liiil 111 llllpl iliiii! (Illlllllll 1111111 iillilll lliiiliiili •Illllll jlllllll illliiBSBBm-f: Illlllllllllll fill : iBKSJISBBBKSBBiSSSi f;BBSBB:BS!;; >: •liii i I llill i llllilllll lllllll liliBl::>:•:>;:> illjjlllllll11! : 3SESIllllllllllllllIlllllllllll :H::iS:::j3B:;;:j:J!i; ;X >>.;;;: Is II -51- After reaction time the vial is cooled at room temperature and sterile saline-benzyl alcohol 1 % solution is added to dissolve the product adhered to glass wall vial. The volume is completed until a desirable radioactive concentration and the final active solution sterilized, under aseptic conditions, by filtration through a 0.22 urn Millipore filter. The finalproduc t is kept at low temperature (freezer) before quality control approval and delivery to Nuclear Medicine Centers. Quality control 1 01 The radiochemical and radionuclide purity of I were determined in Whatmann 3MM paper (1.5 X 12cm) in 85% MeOH (Rf *r = 0.75 and Rf *IO3" = 0.40) and by y-ray spectroscopy using hipper-pure Ge-detector, respectively, before labeling procedure. The 123I-MIBG is submitted by quality control tests shortly after production, including the assessment of radiochemical, radionuclide, pyrogen and microbiological purity. The % of free [*I]iodide being the most important radiochemical impurity is evaluated in a fast paper chromatographic system: Whatman 3MM (1X8 cm), in n-butanol: acetic acid : 123 water (5:2:1) as a solvent, based in Barboza et. al. (1988-1989) reports. The Rf I-MIBG = 1.0 and free [123I]-iodide = 0.0. The radiochemical purity is also analyzed in HPLC using Ci8 (250 x 4.9 cm) column, 254 nm, flux 2 mL / minutes in THF:0.1 N NaH2PO4 (12:88) as a solvent. The Rt 123I-MIBG = 14 minutes and the Rt of free [123I]-iodide = 2.5 minutes. (Barboza, 1994). The microbiological analysis is determined in different culture-medium (sodium tioglicolate and Soybean casein tripticase broths) incubated at room temperature and at 35° C ± 2. The apirogenicity is evaluated using the "in-vitro" Limulus test (LAL). RESULTS The retention of 123I-solution, in a strong anionic resin, was greater than 99.00 % and the recovery of 123I-Na was more than 97 % of total activity in 3 mL of 0.02 N NaOH. (Figure 2 and Table III). 1 O1 The radiochemical and radionuclide purity of I-Na were 99.00 - 98.9 %, respectively. TABLE III - Retention and recovery of 123Ii from resin Batch { %) Retention i%) Recovery liililli :>:::•:":•:';:;>::: ilillliii liiiiiiSiiaii iililll!; iiiiiiiiiiii Illiliiii illiiilliiiiiiiiii Illlll iiillliill ffix BillllllilliliiiiIllSiii •mrnmmmm ; ; :•:::•:•:::::::TM:::-::•:::•:::•: :•:: iliD llll:l!i ll!l sz- 123 Recovery of I-Na from the resin 2500 2000 1500 cr CD 1000 500 Figure 2 - Recovery of •123I-Na from the anionic resin The radiochemical purity (> 98.0 %) of six 123I-MIBG routine productions are illustrated in 123 Table IV and the HPLC chromatogram in Figure 3, with Rt I-MEBG = 14 minutes and Rt I23F = 2.5 minutes. In all formulations studied (radioactive concentration range: 160 - 280 MBq / mL and specific activity: 300 - 380 MBq / mg) free [I23I]-iodide was less than 3 % at 1 and 24 hours without purification step. Others groups reported that radiochemical purity after the exchange radiodination was sufficient and no further purification was needed. Dougan (1988), Mock and Weiner (1988) and Neves (1992). From these data the preliminary conclusion is that 1 % benzyl alcohol and storage at low temperature (-10° C) are effective stabilizers of 123I-MIBG solutions during 24 hours. Verbruggen (1987) reported that the addition of 1 % benzyl alcohol and stored at 4 °C resulted in a four-fold reduction of the formation rate of free [*I] and Amartey (2001) concluded that temperature and benzyl alcohol had a slight cumulative effect in retarding decomposition and the product remained above 90 % for over 7 days at the lower specific activities. However, at the 740 MBq / mg level, the purity fell below 90 % after only two days. A small volume of I-Na used in the process contribute to the high level of labeling. It is important to obtain in a high radioactive concentration the 123I-Na because the labeling efficiency > 98 % are consistently obtained without further purification with 0. 5-0.8 mL -53- Scale J50C 1 f' Ikn \ 30— •' 123 Figure 3 - HPLC chromatogram of I-MIBG, using Cw (250 x 4.9 cm) column, 254 nm, flux 2 mL/minutes in THF: 0.1 M NaH2PO4 123 123 (12:88) as solvent. Rt ( I-MIBG) = 14 min. and Rt ( I) = 2.5 min. -54- of [*I]iodide. Rossouw (1992) related about to a fixed radioactive concentration of 123TI solutions. Mertens (1985), suggested that 123I can be oxidized by Cu2+ to [123I]l2 which is volatile, could result in loss of activity and Mock and Weiner (1998) obtained yields > 90 % adding ammonium sulphate and eliminating airflow minimized loss of volatile radiodine. TABLE IV - Radiochemical Purity of 1ZJ123I-MIB! G Batch Activity Radiochemical purity (%) (MBq) lh 24 h 1 1295 99,63 99.20 2 2331 99.15 99.56 3 2331 97.80 98.10 4 2701 99.63 99.14 5 zni 99.27 99.34 6 2183 98.66 98.88 In the radionuclide analysis low level of 121Te was detected and the pyrogen and microbiological tests were negative in all samples The labeling and quality control procedures for I23I-MIBG have been developed, validated and simplified to extend it to a large-scale productions at IPEN-CNEN/SP. The specific activity obtained is suitable for cardiac evaluation and to study the adrenergic receptor system of the heart implicated in several disease REFERENCES Boura, A.L.A.; Copp, F.C.; Green, A.F.; Hodson, H.F.; Ruffel, G.K.; Sim, M.F.; Walton, E. and Grivsky, E.M. Adrenergic neurone-blocking agents related to choline 2,6 -xylyl ether bromide (TM 10), bretylium and guanethidine, Nature 191,1312,1961 Short, J.H; and Darby, T.D. Sympathetic nervous system blocking agents, III. Derivatives of benzylguadine. J. Med. Chem. 10, 833,1967 Korn, N.; Buswink, A.; Yu, T.; Carr, Jr. E.A.; Carrol, M. and Counsell, R. A Radiodinated bretyluim analog as potencial agent for scanning the adrenal medulla. J. Nucl. Med. 18, 87, 1977 Wieland, D.M.; Swanson, D.P.; Brown, L.E. and Bierwalted, W.H. Imaging the adrenal medulla with and I-131-labeled antiadrenergic agent. J. Nucl. Med. 20,155,1979 - 55- Wieland, D.M.; Wu, I; Brown, L.E.; Manager,!".!; Swanson, D.P. and Bierwaltes, W.H. Radiolabeled adrenergic neuron-blocking agents: adrenomedullary imaging with [131I]iodobenzylguanidine. J. Nud. Med. 21, 349,1980 Magner, T.J.; Wu, J. and Wieland, D.M. Solid-phase exchange radiodination of aryl iodides facilitation by ammonium sulphate. J. Org. Chem. 47,1484,1983 Almeida, M.A., de Barboza, M.F. and Colturato, M.T. The synthesis of 131I-MEBG. In Cox, PH. & Touya, E. News Perpectives in Nuclear Medicine. Pt 2, p.185, Gordon & Breach Science Publishers, 1985 Mertens, J.J.R.; Vanryckenghem, W. and Bossuyt, A. Fast Quantitative labeling of N- isopropyl-para iodoamphetamine (IAMP) with 12 I in the presence of Cu(I) and ascorbic acid, allowing kit-form preparation. Proc. Int. Conf. on Radiopharmaceuticals and Labeled Compounds. Tokio IAEA / STI / PUB / 672, IAEA, Vienna 1985 de Barboza, M.F.; Muramoto, E. Aquino, M. e Pereira, N.S. Estudio de la distribution biologica de la 131I-MIBG en ratas. Anales del V Simposio International de Radiofarmacologia. 29 - 31 Outubro de 1986. Buenos Aires, Argentina. Mertens, J.J.R.; Vanryckenghem, W. and Carl sen, L. Cu(I) supported isotopic exchange of aryl bound iodide, new future for fast high yield labeling. In: Progress in Radiopharmacy, proceedings of the Second European Symposium on Radiopharmacy and Radiopharmaceuticals (Cox, P. Ed.) p. 101,1986. Martinus Nijhoff, The Hague de Barboza, M.F.; Muramoto, E. Colturato, M.T. Goncalves, R.S.V.; Pereira, N.S.; Almeida, M.A.T. e Silva, C.P. Controle Radioquimico y biologico da metaiodobenzilguanidina (MTBG) marcada com 13II. Publicacao EPEN No. 175,1988 Dougan, H,; Lyster, D.M.; Vicent, J.S.; and Rihela, T. Kit type labeling of [123I]- metadiobenzylguanidine. J. Label Compds. Radiopharm. 25: 531,1988 Mock, B.H. and Weiner R.E. Simplified solid-state labeling of [123I]m- iodobenzylguanidine. Appl. Radiat. Isto. 43: 39, 939,1988 de Barboza, M.F; Pereira, N.S.; Colturato, M.T. e Silva, C.P.G. Miniaturized chromatographic radiochemical procedure for 131I-MIBG. Publicacao IPEN No. 286, Dezembro 1989 Hoefnagel, C.A. The clinical use of 131I-meta-iodo-benzylguanidine (MIBG) for the diagnosis and treatment of neural crest tumors. Thesis, University of Amsterdam. 1989 Franceschini, R. Mosca, R. and Bonino, C. Updating the procedure for metaiodobenzylguanidine labeling with iodine radioisotopes employed in industrial production. J. Nucl. Biol. Med. 35,183 ,1991 Mertens, J. and Gysemans, M. Cu1+ assisted nucleophilic exchange radiohalogenation: application and mechanistic approach. In New Trends in Radiopharmaceutical Synthesis, Quality assurance, and Regulatory Control (Emra A . M., Ed.) p.53 1991. Plenum Press, New York. Neves, M.; Paulo, A. and Patricio, L. A kit formulation of [123I]-meta-iobenzylguanidine (MIBG) using Cu(I) generated "in-situ" by sodium disulphide. Appl. Radiat. Isot. 43, 737,1992 Rossouw, D.T. Routine Production and Quality Control of 123I-labeled mBGI at NAC. Appl. Radiat. Isot. 43: 1301 - 1302,1992 Wafelman, A. R.; Konings, M.C.P.; Hoefnagel, C.A.; Maes, R. A.A.; and Beijnen, J.H. Synthesis, radiolabeling and stability of radiodinated m-iodobenzylguanidina, a Review. Appl. Radiat. Isot. 45 (10): 997 - 1007,1994 de Barboza, M.F.; Santos, A.; Muramoto, E. e Pereira, N.P.S.Tadronizacao do controle radioquimico por meio de HPLC da IMP ( anfetamina), IOH ( hippuran) e MIBG (metaiodobenzilguanidina) marcados com 123 j e/ou 13 lp XRl Congresso de la Asociacion Latinoamericana de Sociedades de Biologia y Medicina Nuclear (ALASBIMN) Outubro de 1993. Cartagena, Colombia. Publicada na Revista Espanola de Medicina Nuclear. Resume N° 102. p. 30,1994 de Barboza, M.F.; Muramoto, E.; Colturato, M.T.; Herrerias, R. e Pereira, N.S.S. "Marcacao e Controle de Qualidade da MIBG- 123j" Anais do V Congresso Geral de Energia Nuclear ( CGEN), Vol. 3, p. 899 - 900, Setembro de 1994. Rio de Janeiro. Colturato, M.T.; Pereira, N.P.S.; Achando, S.S.; Hamada, E. de Barboza, M.F.; Mengatti, J. e Silva, C.P.G. "Otimizacao do metodo de marcacao da MIBG marcada com Iodo-123 ou Iodo-131 e sua aplicacao". XIV Congresso de !a Asociacion Latinoameriacana de Biologia e Medicina Nuclear (ALASBIMN), Salvador- Bahia, 1995 (Abstract) Amartey, J.K.; Al-Jammaz, I. and Lambrecht, R.M. An efficient batch preparation of high specific activity [123I] and [124I]mBGI. Appl. Radiat. Isot. 54: 711 - 714, 2001 Figure 4 - Recovery system of 123I, XA0200239 Short summary of 1-123 production in NRCAM Dr. H. Afarideh, AEOI, P.O. Box 14155-1339, Tehran- Iran Introduction: 1-123 is among the most favorable radiopharmaceuticals in nuclear medicine to study and diagnosis of various diseases in thyroid, lung, heart, liver and brain. 1-123 is more preferable than 1-131 in diagnosis due to its short half life, no beta-decay, low dose to the patients and suitable gamma energy range for imaging. Routine production of short lived radioisotope such as mRb, C, 0, N and I usually based on using gas targets in cyclotron accelerator. The incident proton beam during bombardment on target usually will lose, their energies due to the coulomb interaction, therefore the gas pressure will increase as a results of this interaction. This increment of pressure may effect the safety or rupture of gas target container's window. In the case of enriches gas target such as Xe, which is relatively very expensive, the rupture of window should kept as minimize as possible. The increment of pressure will reduce effective target thickness and therefore reduction of yield production. Design of suitable gas target cooling system will prevent of its fast increment of temperature and pressure. Study of gas pressure increment with beam current will also help in the determination of both applied current on target and design of its effective thickness. In practice, can irradiate gas target with suitable current of charged particles as protons in order to avoid the breakage of target window due to increment of its pressure. The knowledge of gas target pressures is essential in the design of effective target thickness and prevention of yield reduction in the field of radioisotope production. Important Nuclear Reactions for the production of 1-123: 1-123 can be produced by indirect methods as follows: 127 123 I(P,5n) Xe Ep=70 to 50 MeV (1) 127 123 I(d,6n) Xe Ed =78 to 64 MeV (2) 123 Cs, La(p,spall) Xe Ep =590 to 200 MeV (3) 124 I23 Xe(p,x) Xe Ep =30 to 25 MeV (4) Then 123Xe decays to 123I by electron capture or positron emission, therefore, for cyclotron accelerator up to 30 MeV energy the method (4) is ideal. 4Xe(p,2nTXs (6 min) —> UiX& (2hrs) —> Uil and 124Xe(p,pn)I23Xe (2hrs ) —> 123I This method provides a high purity product with no 1-124 contaminant. The optimum energy is in vicinity of 30 MeV. The yield is already fair at 25 MeV (=150 mCi/ u). Direct Methods: 124Te(p,2n)123I Ep=30 to 20 MeV (5) 123Te(p,n )123I Ep=15 to 10 MeV (6) 122Te(d,n)123I Ed=16 to 8 MeV (7) The method (5) provides 1-123 contaminated with longer-lived 1-124 resulting from 124Te(p,n)124I. The best possible (124I/123I) radionuclidic purity is obtained at 24 MeV and in the order of 0.6% to 1% at EOB. The impurity level increases with time due to the 4 day half-life of 124I. Co- Specification of target: o The conical Al chamber (with 2 ) furnished with specially designed cooling system were used in this experimental work. The length and internal diameter of container were 24 cm and 15mm respectively. Two separate foils of titanium having 50 mm thickness were employed for gas target and vacuum Windows. Both of these foils were cooled with referegated N gas. There foils and their cooling system designed such a way not to reduce protons beam energy more than 1 MeV. ( fV«jv \ ) Experimental procedure: The bombardment of target started with 5JJA proton beam. Then proton current increased in each step by 5\i A. In this work variation of gas target pressure as a function of incident proton current were investigated. The studies were performed on N , Kr and Xe gasses. These gasses are used routinely as a gas target for production of C, mKr and I radioisotopes After receiving the stable condition, the gas pressure was recorded. During the experiment the beam diameter and its energy were 1 cm and 30 MeV respectively. The target schematic is shown in fig 1. The bombardment of these gasses took place at three different gas pressures of 2.5, 5 and 6.9 bars. ( $_*«_ £*'"Y 2 ") Flow diagram and steps for production of 1-123 are as follows: • Evacuation of target and pipes in order to prevent mixing of air impurities with Xe gas, it is necessary to evacuate target and relevant pipes. By operation two vacuum pumps and opening valves VI, V2, V3, V4, V5, V6, V7 and VI1 can reach easily to lxlO"3 torre. After evacuation all valves will place in close position. • Cryogenic transfer of the Xe from Bottle to Cold Finger (by LN2) The LN2 will transfer to Cold Finger, when temperature sensor T2 indicate its temperature about -140 c, the valves vl and V2 get open. At this stage all Xe gas form bottle transferred to Cold Finger. • Transfer of Xe from Cold Finger to target After above stage valves VI and V3 will close and Valve V4 get open. The heater on Cold Finger get on and Xe converting from ice to gas and filling target area. • Cryogenic transfer residual Xe to the Bottle By closing valve V4 the transfer of residual Xe to the bottle can be preformed. • Irradiation • Transfer of Xe from target to decay vessel After stopping the irradiation, the Water Reservere getting cold to -140 c by LN2, Then valves V5 and V7 get open . In this stage ciyogenic transfer of Xe gas from target to decay vessel will carried out. After completion of Xe transfer, the valves V5 and V7 get close, by turning on the heater on the decay vessel, the Xe convert from ice to gas. • Decay time ( 6 hours ): 1-123 absorbed on the surface • Cryogenic transfer of Xe from decay vessel to the bottle • Rinsing of 1-123 with water (80 °c) • Transfer of 1-123 dissolved in water to chemistry unit Chemistry • Purification Elimination of cations and anions impurities such as: Te, Cs, Fe, Al, Producing high specific activity of 1-123 (final product is T dissolved in 2-3 ml NaoH) • Ion exchange chromatography method Selection of suitable resin (based on selectivity) Resin conditioning Modification of resin structure Suitable pH determination Determination of optimum solution flow rate (based on reaction kinetics) Column optimum dimensions (based on mass transfer coefficient) • 1-123 chemistry Anion resin: Bio-Rex 5 ( CF form) Conditioning: Cl" form ^ oH" form Modification: Hafmann elimination method for rearrangement of quaternary amino groups in Bio- Rex5 resin In 135 °c R4NH —> R3N + RH Optimum PH: 5-6 Optimum flow rate: 4 ml/min Column Optimum size: Dia. 10mm, Height 2.5 mm Chemistry efficiency: 93% • Flow diagram and steps of 1-123 chemistry Um) Transfer I" dissolved in water on cation and anion resin: I" is absorbed on Bio- Rex5 resin and other impurities go to the waste. Dois) Elution of I" from the column (by 2-3 ml NaoH 0.02 M ) Tres) Rinsing of the columns • Quality control of radio chemical purity Paper chromatography Paper: 2x10 cm Wattman No.l Developing solvent: methannol:water (3:1) Rf=0.9 (for F ) Eluted F chromatogram 90% of r in 2.5 ml NaoH -U- I—Beam line 1-123 Project 2-Flange 3-Window Holder 1 4-Hz Cooling system 5-Window Holder 2 6-Target 7-Jack 1 8-Jack 2 9-Carrier 10-New Window Box 1 11-New Window Box 2 CJ1 \ 1 \ \ 1 m J J i /O y CQ O O aw o o CO o I—X—d r I—X-6 I—*••© o in I—X-«J &H o HH C i&H 1-&1 »-«-f—— —Sfl—— CM CO CO \IJ2o\ l-rr-J @ .o V7 I F6 I V9 DriUL-ing A'a.: #** Seals.1 * * * I N 8 o S3 '•n =3 a 3 \x- •0} *> 2! Q- ato o coO O o ^ c ** lodin e C lira inn tognt in 2500 2000 1500 C 0 u n I 1000 500 0 0.5 1 2.5 3 3.5 4 '1.5 Volume of 0.02 N NaoH(rnl) - I I I I f 1 I I [ T f II I I 1 I I I I I i i ? n w C3 • 20% enriched Xe; Cs separated 0 ^ 99.9 % enriched Eye-guide through our data —- Kurenkoveiot (1989) 10 I I X—L-L. 30 « Incident proton energy (MeV) Nuclear Data Relevant to the 123§ via C6SS 124 Xe (p,2n) ((stable) 5.9 min 2.08h 13.2 h 123 173 i Cs I -u • ?0% eru-iched ts separated o fl 99.9 % enriched — Cye- guide through our tint a Kurenkoy cf at [19B91 _l_l_J_L_l_l—1_. l_L_L_l_l_J _.J_ 30 t.0 Incident proloo energy (MeV) Optimum energy range: Ep = 29 —-> 23 MeV 123 l-yield: 11.2 mCi(414 MBq)/}iAh 121 ,{i 2ixe)-impurity: 10~7 % Theoretical Data (Alice code) 1-123 Production Cross-Section Calculated by ALICE-Code 1UUUU - -£- 1000 : AAAAAA, 5Cqiu ) u _D : A A •2 100: o ® . . OS S 6 10: I A(p,2n) m ; ®(p,pn) 1 •• 10 15 20 25 30 35 Energy {MeV) 1I 4 w la c o ^4 I Pressure and effective length relation (SRIM code) P(atm) L(mm) P/Po Lo/L 3 480 1 1 4 360 1.33 1.33 5 288 1.67 1.67 6 240 2 2 7 206 2.33 2.33 8 180 2.67 2.67 9 160 3 3 10 144 3.33 3.33 Target angle design The theory of charge particles multiple scattering is well known (Moliere theory). Some codes are applied based the Monte Carlo method. Following figures shows the distabut^^ beam around the central axis.of gasJUggt •H earn Xfl 03 i do ° o GO H o o o o eg o I X a, CD I XA0200240 Atomic Energy Commission of Syria Cyclotron and Medical Radioisotopes Division Technical Meeting of project counterparts on Cyclotron production of 1-123 IPEN-CNEN/SP Sao Paulo, Brazil Dr. Al Rayyes Abdul Hamid Production of !23I production consists of the I24Xe (p,x) process. It involves highly enriched 124Xe but requires only a medium-sized cyclotron. This process leads to 123I of the highest purity. The natural abundance of 124Xe is only 0.1%; consequently the highly enriched i24Xe is very expensive. The proton irradiation of 124Xe leads to the formation of 123I via three possible routs (fig .1). Experimentally, the contribution of the (p,2p) process was found to negligible, so the major production routes are (p,2n) and ( p,pn). The cross section data for these two routs were measured both radiochemically and via direct counting of irradiated cells. 'Xe (p,2n) (p,pn) • (stable) 5.9min 2.08h 13.2h 3Te ft* - * 20% enriched 'KXe: 1"Cs separoled Oi 99.9 % enriched "'Xe Eye-guide fhrough our doia Kursnkov et al U9S9) 1 i i i i I , i i i i I i i < i i i i i i I i i i t I i i 20 30 40 Incident orolnn (Fig. 1) Possible production routs of I23I via protons on highly enriched 124Xe. The lower part of the diagram gives the excitation function of 124Xe(p,pn)123Xe processes. Target system design The target move through a guiding system and pushed by piston working by air pressure pushing it forward until it is closed with the transport beam line by using the piece that contain two O- ring from the side of the target and it is punched by three small holes. 1- Evacuation by the 2 pumps and the valves Vg, V6 should be closed and the other should be opened to measure the vacuum in P1} P6, P4 should arrive to 10"3 bars. 2- Closing the valves. 3- Send LN2 to the CF (Cooling Finger). 4- Measuring the temperature by T2, which is a thermocouple, the temperature should arrive to -HOC0. 5- Open Vi, V3 to transport the Xe to the cold finguer (CF) then Xe becoming Xe ice (solidification). • The distant between the target and the bottle must be as small as possible. • All valves of the target system are below valves (pneumatic) controlled with valves close and open by air pressure which can be from Festo. 6-Closing Vl5V3. 7- Open V4 8- Heating cause Xe evaporate then Xe go to the target. 9- Close V4. 10- The rest of Xe in tubing send to Xe bottle by cryogenic transfer by putting LN2 around the Xe bottle. 11- Bombardment. 12- Opening V5, V7 the product with Xe is transfer to the decay vessel (water. Rec.) V6, V8 are closed. By cryogenic method T4 thermocouple measure -140 C°. V5, V7, V4 are closed. 13- 6 hours decay. Iodine is adsorbed on the surface. 14- Xe is transfer to Xe bottle by cooling the Xe bottle by LN2 and heating the decay vessel. 15- Send water to the decay vessel. Heating forl5min up to 80 C°. 16- The water with "I is sent to the hot cell by applying N2 gas pressure from the valve V9, by changing the position of V9 from A to B. -84- KJ -gs- Arrangement for the cooling of windows. In case of failure of any window, the Xe go and trapped on C.F. Heat Exchanger • VI He in =O[_lQ= Fast Closing Valve (10 msec) Beam Line Compressor VAT He Out Heat Exchanger e V3 A . Temp=-140° ]' LN2 In this system, there are three sensors for vacuum connected on the lines of (pumpl, pump2, line with the target) for reading the vacuum level that create the pumps 1 and 2. Also there are 3 pressure sensors to measure the pressure. 1. One mounted on the target, Measuring range (1 to 20 bar). 2. One mounted on the decay vessel, Measuring range (1 to 10, 15 bars). 3. One mounted on the Xe bottle to measure the pressure of the bottle, measuring range 1 atmosphere. Iodine purification process after the end of irradiation. 1-The column 1, containing cation exchange resin is eluted by H2O. 2-1" passes to the column (1) by HPLC pump to purify from all impurity that comes from the target carrier or other things. 3- Continue passing the solution containing I" through the column (2) containing anion exchange to adsorb F from the upper side of the column. Column (2), anion exchange, (this column contain a resin Biorex-5, 200 Mech from BioRad company). This column is activated by converting the chloride form R-Cl to the R-OH form by passing NaOH (0.5 N). The inner radius of this column is 2.5mm, length 10mm). 4- The adsorbed iodine is eluted from the column 2 by NaOH, from the bottom of the column, to go to the bulk vial in form of Nal. In the figure P] is HPLC pump and P2, P3 are peristaltic pumps. ,_n_, i|_ ]( ...::J Method of Xe purification from air 1-V], V2, V3 opened, bottle 1 closed, bottle 2 opened. 2- vacuum 3- V3 closed LN2 around bottle 2; Xe is transferred and solidifies in bottle 2 4- V3, Vi, V2, bot 1, bot 2 is opened, good vacuum. 5- close V3 cased heating bottle 2 +LN2 in bottle 1 Xe is transferred to bottle 1 and solidifies there. 6- Make the same procedure 2-3 time _f<<•)c _ J [...111 Li. XA0200241 Current status of the 124Xe target system development for the high purity 123I production in KCCH Kwon Soo Chun Korea Cancer Center Hospital(KCCH), Korea 123 The I(Ti/2=13.2h, Ey = 159keV) radioisotope has found wide application in diagnostic nuclear medicine due to its nuclear properties, which are the most suitable among the radioisotopes of iodine for in vivo studies. Over there the radiopharmaceuticals labeled with Iodine-123 is being attracted attention in nuclear medicine for its diversity in the synthesis. Although KCCH started to produce 123I routinely with 124TeO2 target in order to activate its labeling research from 1992, its radiopharmaceuticals research has been still in inactive, because the method of the 123I production from 124TeO2 target has the serious disadvantage, i.e., the co-produced unavoidable radioisotopes impurity 124I damaging the imaging and the low production yield not to meet the demand in our country. So, in order to activate the 123I radiopharmaceuticals research in Korea, the development of the 124Xe target system producing the high purity 123I and high yield is urgently necessary. The 124Xe target system that KCCH is manufacturing is composed of target chamber, He circulation loop and He control system, LN2 transfer and control system, 124Xe loading/storage device, safety box for window Mo foil blow-out, vacuum system, 123I washing out from target chamber and :23I chemical processing device and so on, is shown in Fig. 1. 124Xe target chamber, window Mo foils with He cooling, 4-sector carbon collimator to control the beam path, safety box, window Mo foils, carbon collimator and beam line valve are installed on the beam line in sequence. The reason of that 2 window Mo foils are installed behind beam line valve is to prevent 124Xe gas caused by blowout target window foils from going to the cyclotron beam line. It is expected to reduce our effort to recover 124Xe from window foils blowout. The target chamber was fabricated from aluminum and its dimension is All tube related to the 124Xe transfer and vacuum were made with stainless "i ' steel tubing suitable to high purity gas. Because of the assurance of the no leaking in the line, the welding method in the connection of the tubing and VCR type valve were adopted. Now the control system of our target system is manual type. After we get the parameters, i.e., temperature, pressure, vacuum, He/ water/ cooling water flow rate and so on, from the results of running our system with manual operation, the automatic control system equipped with PLC and PC will be established. The processes for the routine operation will be composed with the 124Xe loading into the chamber, the 124Xe irradiation, the 124Xe recovery from the chamber to the storage vessel, the target washout with water for 123I recovery after decay 123Xe to 123I, the drying chamber, the column operation for 123I chemical processing. In addition to routine process, the 124Xe recovery process from the He cooling system and tihe safety box installed on the beam line should be necessary for the preparation of the 124Xe loss caused by the window Mo foils blowout. Fig. 1. Schematic drawing of the 123Xe target system. The System is composed of the 124Xe gas storage/transfer device, vacuum line, He circulation loop for window foils cooling, 123I washing out device from chamber, safety box for the window foils blowout. Xe, washing woter outlet heater thermocouple "cooling water outlet V^lre- MPT Fig. 2. Schematic drawing of the 124Xe target chamber. The target chamber is made of aluminum. The water jacket is adopted for the target cooling during irradiation. The band and thermocouple are installed on the outside of the chamber to control the temperature of the chamber during 123I washout process from the target chamber. Iodine Radiophramceuticals produced in KCCH • Nal : Thyroid diagnostic, Thyroid tumor • mlBG : Cardiac, Neuroblastoma, Pheochromocytoma •DMIPP : Cardiac •BMIPP : Cardiac • Idoxifene: Breast cancer • o-MIMT : Tumor • Iodovinyl estradiol: Breast cancer • B-CIT : Parkinson disease 123I activity consumed in Korea 3.5 S 2-5 •> o CO 1.5 1 0.5 0 1992 1993 1994 1995 1996 1997 1998 1999 2000 year 4-sector Bean tine carbon valv collinator e cooling -Xe-124 target chamber Mo foil •Safety box <200x200X200mm) Vac. Vac. Schematic drawing of the Xe-124 target system 124Xe-target Specification 1) Particle: 30MeV proton 2) Chamber Material: Aluminum 5052 3) Dimension : 31" p s riNi )) Operation sequence of the Xe target system 1) Xe-gas loading to target chamber 2) Irradiation and decay 3) Xe recovery from chamber to storage vessel 4) Target washout with H2O 5) Drying/Vacuum target 123 J 6) Column operation for 1 elution Additional steps for Xe gas handling 1) Xe gas refill to storage vessel 2) Xe Trapping from He loop and Safety box - \oo- H3Wd i i j E?7.?S I I I I I 1 nawinwrs wwm I I ! I I I Main components of Xe-124 system 1. Valve: Pneumatic valve Valco 6-port for 1-123 solutfon 2ea VCR Type, ss-HBVCR4-C(Swagelok) 24ea Ball valve for LN2 transfer(Parker, 4F-B6LJ-V-BP) 6ea Manual valve VCR Type, ss-DLVCR4 (Swagelok) 3ea Solenoid valve BurkertType 127 4ea 2. Vacuum pump Turbo drag pump+Diaphragm pump(Pfeiffer) 2ea Diaphragm pump for He circulation (Parker MB601) 1ea 3.Vacuum gauge compact pirani gauge(Pfeiffer TPR250) • 4ea 4. Pressure gauge OMEGA, PX302-50GV(mV output, DP41-S) 2ea OMEGA, PX610-200GV(SS Diaphragm, mV) 2ea 5. Thermocouple(OMEGA) T type, K type, CN9000A 10ea 6. Heater: Watlow Band type 4ea, Tape type 2ea, Plate type 3ea 9ea 7..Tube Welding system(Caj'on) 1set 8. Water absorbent: Molecular Sieve 5A (SPELCO) 1 ea 9. Photodiode radiation detector: TRIUMF(Appl.Radiat.lsot. 45, 3, 377-378} 3ea 10. Peristaltic pump(Waston Marlow) 4ea XA0200242 PRODUCTION OF RADIOACTIVE IODINE David J. Schlyer Iodine-123 Probably the most widely used cyclotron produced radiohalogen is 1-123. It has gradually replaced 1-131 as the isotope of choice for diagnostic radiopharmaceuticals containing radioiodine. It gives a much lower radiation dose to the patient and the gamma ray energy of 159 keV is ideally suited for use in a gamma camera. The gamma ray will penetrate tissue very effectively without excessive radiation dose. For this reason, it has in many instances replaced the reactor-produced iodine-131 (Lambrecht and Wolf 1973). A great number of radiopharmaceuticals have been labeled using 1-123 and the number is increasing. One of the most promising uses of 1-123 is in the imaging of monoclonal antibodies to localize and visualize tumors. However, preclinical and clinical experiences with radiolabeled antibodies have not realized the expectations regarding specificity and sensitivity of tumor localization with these agents. It appears that much of the administered activity is not associated with the tumor site and only a small fraction actually accumulates there. Work continues in this area and tumor-associated antigens can be targets for specific antibody reagents. Another area of active research in radioiodine labeled compounds is in the area of receptor binding. This area, at the moment, is an area of basic research with only a few clinical applications. The advances made in this area will probably bring clinical diagnostic tests in the future. Receptor specific ligands have been synthesized with 1-123 for SPECT imaging and now with 1-124 for PET imaging. Radiotracers have also been synthesized for neurotransmitter reuptake sites. Production Reactions The major reactions for the production of iodine-123 are given in the following table. As can be seen from this table there are two major routes to 1-123. The first is the direct route and the second is through the Xenon-123 precursor. The advantage of going through the Xe-123 is that the xenon can be separated from the original target material and allowed to decay in isolation which gives an 1-123 with very little contamination from other radioisotopes of iodine. 1O3- Nuclear Reaction Useful Energy % Natural References Range (MeV) Abundance 127I(p,5n)123Xe : 123I 55 + 100 Adilbish et al 1980, Cuninghame et al 1976, Jungerman and Lagunas- Solar 1981, Zaitseva et al 1991. Lagunas-Solar et al 1986 127I(d,6n)123Xe : 123I 83 100 Weinreich et al 1976 122Te(d,n)123I 14 to 8 2.4 Zaidi et al 1983 123Te(p,n)123I 15 to 8 0.87 Barraletal 1981 124Te(p,2n)123I 26 to 20 4.6 Dahl and Tilbury 1972, Clem and Lambrecht 1991, Hupf et al 1968 I22Te(4He,3n)123Xe: 123I Lambrecht and Wolf 1972, Silvester et al 1969 124Xe(p,pn)123Xe : 123I 15 to 30 0.10 Graham et al 1985, Witsenboer et al 1986, Firouzbakht et al 1987, Tarkanyi et al 1991, Kurenkov et al 1989 121Sb(4He,2n)123I 15 to 25 57.4 Watson et al 1973 123Sb(3He,3n)123I 20 to 30 42.6 Watson et al 1973 - 1(34- The most common reaction for the production of 1-123 in the recent past has been the 124Te(p,2n)123I reaction on highly enriched Te-124. The high enrichment is necessary since there is a second source of 1-124 contamination and this comes from the l25Te(p,2n)lz4I nuclear reaction on any Te-125 which may be present in the target material (Guillaume et al 1975, Kondo et al 1977a). This leads to one of the basic facts of life in radioisotope production. It is not always possible to eliminate the radionulidic impurities even with the highest isotopic enrichment and the widest energy selection. An example of this is given below in Figure 3 for the production of Iodine-123 with a minimum of 1-124 impurity (Guillaume 1975, Lambrecht and Wolf 1973, Clem and Lambrecht 1991, Qaim and Stocklin 1983). Figure 1 - Cross-sections of the Te(p,2n) I and the 24Te(p,n) I reactions Production of 1-123 vs 1-124 1000 800 - 600 - .2 8 400 - o O 200 - 10 15 20 25 Proton Energy (MeV) As can be seen from this graph, it is not possible to eliminate the 1-124 impurity from the 1-123 because the 1-124 is being made at the same energy. All that can be done is to minimize the 1-124 impurity by choosing an energy where the production of 1-124 is near a minimum. In this case a proton energy higher than about 20 MeV will give a minimum of I- 124 impurity. As an example of how the impurity level can be calculated, the following equation can be written which allows calculation at any energy as long as the relevant cross sections are known (Barrall et al 1981). The percentage of 1-124 in 1-123 is given by: *'~m= Where: a = 123Te(p,n)123I a' = I24Te(p,2n)123I a* = 124Te(p,n)124I a** = 125Te(p,2n)124I N = %Te-123 N' = %Te-124 N* = %Te-125 S = (l-e"Xlt) (A,i- decay constant for 1-123, t is time of irradiation) S' = (1-e"^1) (A,2- decay constant for 1-124, t is time of irradiation) The reaction on tellurium has been gradually replaced by the 124Xe(p,pn)123Xe : 123I reaction since this gives 1-123 with greatly reduced 1-124 contamination. The dose to the patient is therefore reduced and the image is somewhat clearer. In general, the production of 1-123 through the Xe-123 precursor has replaced the direct production methods for those who can carry out the indirect production. There are two factors, which limit the production of 1-123 by the indirect methods. If the 124Xe(p,pn)123Xe : 123I method is used, the cost of the highly enriched Xe-124 is a factor. At the time of this writing, the cost of 1 liter of 99% enriched Xe-124 is about US$70,000 and a typical target takes between one to two liters of gas. This results in a substantial investment and although the gas can usually be quantitatively recovered after irradiation, the accidental loss of the gas could be a severe loss to a isotope production program. If the 127I(p,5n)123Xe : 123I reaction is used, a cyclotron energy of greater than 55 MeV is required and cyclotrons of this energy are becoming quite rare. There is still some controversy as to the correct cross-section values for the production of 1-123 from enriched xenon-124. Several studies have been published and there has been a considerable amount of discussion in the amount of 1-123 which can be produced from this reaction (Tarkanyi et al 1991, Kurenkov et al.1989, Firouzbakht 1992a, Firouzbakht et al 1992b). The conclusion is the same in both cases. One can produce quite large amounts of very high purity 1-123 from these reactions. A comparison of the cross-sections as measured by Tarkanyi et al (Tarkanyi et al 1991) and by Kurenkov et al. (Kurenkov et al.1989) shows that the agreement for the 124Xe(p,2n)123I is quite good, but the 124Xe(p,pn)123Xe reaction shows some differences. Targetry The targets used for production of 1-123 can be grouped into three types. These are solid targets, liquid or molten targets and gaseous targets. 1-123 is commonly produced in all three types of targets depending on the energy of the cyclotron being used and on the availability of enriched Xe-124 as a target material. Each type of target has its own advantages and disadvantages. There have been a set of criteria first proposed by Van den Bosch and Tertoolen (Van den Bosch et al 1977, Tertoolen et al 1977) which serve as guidelines for 1-123 target construction. These criteria are: a) Thermal and radiation stability of the target and target support under irradiation, combined with adequate thermal conductivity and heat dissipation b) Simple and almost complete separation of iodine from the tellurium within a short time period, preferably in less than half an hour. c) Simple and almost complete reprocessing of the target; the loss of expensive enriched tellurium should be kept below 1% per irradiation and separation. d) The chemical state of the iodine produced should not handicap any in vivo application or labeling procedure. These criteria, although applied to solid tellurium targets serve as good guidelines for all iodine targets. Similar guidelines were reiterated by Qaim (Qaim 1989) who emphasized the power dissipation of the targets and that efficient heat transfer is one of the prime requirements in target construction. He also emphasized the need for accurate nuclear data in order to design targets efficiently. Solid Targets: One of the most common targets for the production of 1-123 is the reaction of tellurium. The typical targets are of two different materials. The first is elemental tellurium and the second is tellurium oxide (Kondo et al 1977a, Qaim 1989). A typical target would be tellurium electrodeposited onto a copper plate, which was then irradiated internally in the cyclotron. An example of this type of target is shown in Figure 2. proton beam Leading Monitor Trailing Monitor Figure 2.- Internal cyclotron target for grazing incidence. The target material is usually electrodeposited on the surface of the plate The major advantage of this type of target is that higher beam currents can be used as a result of the low angle on incidence of the beam to the target. This general type of solid target can be used as an external target also with a somewhat higher angle of incidence and therefore at a somewhat lower beam current. The inclined plane target may also be used as an external target. An example of this is shown in Figure 3. The target has the advantage of being easy to handle after irradiation. The disadvantage is that the beam current which can be put onto external targets are less that those for internal inclined plane targets. The main reason is that the angle of incidence of the external target is, in general, greater than that of the internal target, his results in a much higher heat load per unit area and a thicker target material layer. Figure 3. Inclined plane target for 4.5" external beam. The powdered target material is pressed into a plate with or without grooves for 2.25" irradiation. 2.0' ~T 1.0" t r- 7/8 -&5 1 ...L L 5/8" Solid targets made from powdered tellurium have also been widely used for the production of 1-123 (Acerbi et al 1976, Barral et al 1981, Clem and Lambrecht 1991, Dahl and Tilbury 1972, Guillaume et al 1975, Hupf et al 1968, Kondo et al 1977b, Mahunka et al 1996, Michael et al 1981, Sodd et al 1973, Weinreich et al 1976). The tellurium powder has often been mixed with aluminum powder to increase the heat transfer characteristics of the target. A common problem with these targets is melting of the elemental tellurium and consequent loss of the radioiodine from the matrix. An internal powder target has been developed and used with the 122Te(d,n)123I reaction (Zaidi et al 1983). This target has a flow through design to extract the iodine-123 during the irradiation. Other types of alloy targets have been used for production of 1-123 such as a tellurium- gold alloy (Lambrecht et al 1977). This technique has been used extensively when the thermal conductivity of the primary material is low and/or the melting point is low. Tellurium oxide has been used for the production of 1-123. The oxide has the advantage of a high melting point and therefore a low loss of the iodine from the matrix during irradiation. A final type of solid target is the cryogenic target for the production if 1-123 from enriched xenon-124 (Firouzbakht et al 1992). This type of target has the advantage of being failsafe in the sense that the xenon is frozen and therefore won't be lost in the case of a foil rupture. The disadvantage is that the target must be kept supplied with liquid nitrogen during irradiation. Liquid targets: There were three types of liquid targets used for the production of 1-123. These were the molten salt target used for production of 1-123 from the 127I(p,5n)123Xe reaction in a sodium iodide salt with a high energy beam (Jungerman et al 1981, Mausner et al 1986). A picture of this "hockey puck" target is shown in Figure 4. Figure 4 - Sodium iodide salt target for high energy irradiations. Target shown is from the BLIP facility at Brookhaven National Laboratory This has been used by itself or as the first target of several for isotope production (Suzuki and Iwata 1977). A liquid iodine target has been used for routine production at low earn intensities with a sweep gas to remove the Xe-123 as it is made (Godart et al 1977). The last was the use of a liquid such as methylene iodide in a recirculating flowing target (Cuninghame et al 1976). This target had some problems with polymerization of the target material and was not a popular target. Gaseous targets: More and more of 1-123 is being made from the reaction of protons on enriched Xe-124 gas. This target has the advantage of producing very high purity 1-123 with easy recovery of the target material. These targets typically contain one to two liters of gas at elevated pressure. The real danger here is the possibility of losing a foil which may result in the loss of the target gas into the cyclotron and then into the atmosphere. Several designs have been published to reduce or eliminate the possibility of such a loss (Firouzbakht et al 1996). In most cases the xenon gas is trapped in a loop contained at liquid nitrogen temperatures. These loops, if properly constructed, can trap more than 99% of the xenon gas in the targets This type of target has been tested extensively and has proven to be reliable in routine operation. An example of this type of target is shown in Figure 5. Buffer volume Figure 5. "No-fail" gaseous xenon target Helium cooling inlet Target gas for the production of 1-123. The buffer inlet volume is attached to several loops of tubing submerged in liquid nitrogen. A flow of helium is pumped through the tubing after being used to cool the front foil. Radioisotope Separation The separation of the radioiodine from the target matrix is accomplished in two different ways depending on whether the 1-123 is made from the direct method or from the indirect method. In the indirect method, the xenon-123 is isolated from the matrix and then allowed to decay to 1-123 in a separate vessel. This separation is usually not a difficult one since the xenon is very unreactive and can usually be extracted from the target readily. In the case of the direct production from tellurium, the problem is slightly more difficult. A common method of extraction is the use of dry distillation. In this method, the tellurium powder or tellurium oxide powder is heated to near the melting point with a flow of gas over the plate. The iodine-123 is distilled out of the matrix and carried by the sweep gas to a receiver vessel where it is trapped. This vessel usually contains a base solution and the iodine is in the chemical form of iodide. A wet chemical method can also be used dissolving the Te powder and then oxidizing the iodide to iodine and distilling it out of the solution (Acerbi et al 1976). Iodine-124 Although 1-124 has often been considered as an impurity in preparations of 1-123, it does have attractive properties for use in some PET radiopharmaceuticals (Frey et al 1986, Lambrecht et al 1988b, Weinreich et al 1997). The half-life of 4.2 days is long enough for localization with monoclonal antibodies and the 23% positron decay allows imaging with PET. The use of 1-124 is becoming more widespread. Iodine-124 has potential as both a diagnostic and therapeutic radionuclide (Weinreich et al 1997, Sheh et al 2000). The primary problem with 1-124 is the extra dose resulting from the high energy gamma rays associated with the isotope. Production Reactions There are several reactions, which can be used to produce 1-124 depending on the cyclotron particles and energy available to carry out the irradiations. A list of the potential reactions is shown below. Nuclear Reaction Useful Energy % Natural References Range (MeV) Abundance 124Te(p,n)124I 10 to 20 4.8 Kondo et al 1977a,b, Scholten et al 1995 124Te(d,2n)124I 4.8 Lambrecht et al 1988a, Firouzbakht et al 1993, Sharma et al 1988 124Te(d,3n)124I 15 to 30 4.8 Firouzbakht et al 1993 121Sb(4He,n)124I 15 to 25 57.4 Silvester et al 1969 123Sb(3He,2n)124I 42.6 Silvester et al 1969 The most common of these is either the proton reaction or the deuteron reaction on enriched tellurium-124. The deuteron reaction gives a higher yield of 1-124 if deuterons are available. The yield for the proton reaction is about 0.09 mCi/:Ahr (Kondo et al 1977b) while the deuteron reaction produces 0.55 mCi/:Ahr (Lambrecht et al 1988). The reaction on antimony also results in a low yield of about 1 mCi/:Ahr (Silvester et al 1969). Targetry The targetry for the production of 1-124 is limited to solid targets. The target is either elemental tellurium or tellurium oxide (Stevenson et al 1995, Qaim 1989). The targets are identical to those used for the production of 1-123 from tellurium. The target plates can be made from either platinum or tantalum. Elemental tellurium can be electrodeposited on the target plate. Tellurium oxide is usually melted into a cavity on the target plate. In some cases, small amounts of aluminum oxide are added to the tellurium to add in adhesion of the oxide to the surface of the plate (Sheh et al 2000). Radioisotope Separation The separation of the iodine from the tellurium can be accomplished by distillation of the iodine-124 from the tellurium oxide matrix. This is usually done at temperatures of about 750EC. The iodine is carried away from the target with a sweep of either oxygen or helium. The oxygen tends to keep the tellurium in the oxide form and reduces the loss from distillation of the elemental tellurium (Knust et al 2000, Sheh et al 2000, Michael et al 1981). CONCLUSIONS Radioisotopes of Iodine have played a fundamental role in biomedical research and in clinical nuclear medicine. The wide variety of decay characteristics and half-lives available with these isotopes have made them useful for diagnostic imaging as well as therapy. Iodine- 123 has been a staple in diagnostic imaging and continues to be a valuable isotope for research in receptor binding assays and metabolism. Iodine-124 has recently gained new prominence in PET imaging with a 4 day half-life, it is compatible with quantitative imaging of labeled monoclonal antibodies. The future is promising for these radioisotopes and research on their production and separation will continue. ACKNOWLEDGEMENT This research was supported at Brookhaven National Laboratory under contract DE- AC02-98CH10886 with the U.S. Department of Energy and its Office of Biological and Environmental Research and by the National Institutes of Health (National Institutes of Neurological Diseases and Stroke NS-15380). — I lot" REFERENCES: [I] Acerbi, E., Birattari, C, Castiglioni, M., Resmini, F. (1975), Produciton of 123I for Medical Purposes at the Milan AVF Cyclotron Int. J. Appl. Radiat, Isot. 26:741-747. [2] Adilbish, M., Chumin, V.G., Khalkin, V.A., Knotek, O., Kuznetsova, M, JA., Norseev, V., Fominykh, V.I., and Zaitseva, N.G. (1980), 123I Production from Radioxenon Formed in Spallation Reactions by 660 MeV Protons for Medical Research, Int. J. Applied Radiat. Isot. 31:163-167,. [3] Barrall, R.C., Beaver, J.E., Hupf, H.B., Rubio, F.F. (1981), Production of Curie Quantities of High Purity 1-123 with 15 MeV Protons. Eur. J. Nucl. Med 6:411-415. [4] Clem, R.G., and Lambrecht, R.M. (1991), Enriched 124Te Targets for Production of 123I and 124I, Nucl Instr Methods A303 115-118. [5] Cuninghame, J.G., Morris, B., Nichols, A.L., Taylor, N.K. (1976), Large Scale Production of 123I from a Flowing Liquid Target Using the (p, 5n) Reaction. Int. Jour. Appl Radiat Isot. 27:597-603. [6] Dahl, J.R., and Tilbury, R.S. (1972), The Use of a Compact Multiparticle Cyclotron for the Production of 52Fe, 67Ga, inIn and 123I for Medical Purposes, Int. J. Appl. Radiat Isot. 23:431-437. [7] Firouzbakht, M.L., Teng, R.R., Schlyer, D.J., and Wolf, A.P. (1987), Production of High Purity Iodine-123 from Xenon-124 at Energies Between 15 and 34 MeV Radiochimica Acta, 41:1-4. [8] Firouzbakht, ML, Schlyer, DJ, Wolf, AP (1992) Production of Iodine-123 from Xenon- 124: Cross-sections and Yields Radiochimica Acta, 56:167-171. [9] Firouzbakht ML, Schlyer DJ, Wolf AP (1992), Effect of Foil Material on the Apparent Yield of the 124Xe(p,x)123I Reaction. Appl. Radiat. Isot. 43:741-745. [10] Firouzbahkt, M. L., Schlyer, D. J., and Wolf, A. P. (1992), A Solid Xenon Ice Target for the Production of 1-123 Proceedings IXth International Symposium on Radiopharmaceutical Chemistry. Paris, France 6-10 April 1992. [II] Firouzbakht, M.L., Schlyer, DJ., Finn, R.D., Laguzzi, G. and Wolf, A.P. (1993), Iodine-124 Production: Excitation Function for the 124Te(d,2n)124I and the 124Te(d,3n)123I Reactions from 7 to 24 MeV. Nucl. Instru. Meth. in Phy Res. B79:909- 910. [12] Firouzbakht, ML, Schlyer, DJ, Wolf, AP (1995) "Failsafe" gas target for the production of 1-123 from Xe-124, Proceedings of the Sixth Workshop on Targetry and Target Chemistry, Aug. 17-19 Vancouver, B.C. Canada, 1995, p. 79-81. [13] Frey, P.E., Townsend D.W., Flattet, A., De Gautarrd, R., Widgren, S., Jeavons, A., Christin, A., Smith A., Long, A., Donath, A.(1986), Tomographic imaging of the human thyroid using 124I, J. Clin. Endocrnol. Metab. 63:918-927. [14] Godart, J., Barat, J.L, Menthe, A., (1978), In Beam Collection of 123Xe for Carrier-free 123I Production, Int. J. Appl. Radiat. Isot. 28:967-969. [15] Graham, D., Trevena, I.C., Webster, B., and Williams, D. (1985), Production of High Purity Iodine-123 Using Xenon-124. J. Nucl. Med. 26:105. -113- [16] Guillaume, M., Lambrecht, R.M., and Wolf, A.P. (1975), Cyclotron Production of 123Xe and High Purity 123I: A Comparison of Tellurium Targets. Int. J. Appl. Radiat. Isot. 26:703-707. [17] Hupf, H.B., Eldridge, J.S., and Beaver, J.E. (1968), Production of Iodine-123 for Medical Applications, Int. J. Appl. Radiat. Isot. 19:345-351. [18] Jungerman, J.A., Lagunas-Solar, M.C. (1981), Cyclotron Production of High Purity Iodine-123 for Medical Applications, J. Radioanalytical Chemistry, 65:31-45. [19] Kondo, K., Lambrecht, R.M., and Wolf, A.P. (1977a), Iodine-123 Production for Radiopharmaceuticals XX* Excitation Functions for the 124Te(p,2n)123I and 124Te(p,n)124I Reactions and the Effect of Target Enrichment on Radionuclidic Purity. Int. J. Appl Radiat. Isot. 28:395-401. [20] Kondo, K., Lambrecht, R.M., Norton, E.F., and Wolf, A.P. (1977b), Improved Target and Chemistry for the Production of 123I and 124I Int. J. Appl. Radiat. Isot. 28:765-771. [21] Knust, E.J., Dutschka, K., Weinreich, R. (2000), Preparation of 124I Solutions After 124 Thermodistillation of Irradiated TeO2 Targets, Appl. Radiat. Isot. 52:181-184. [22] Kurenkov, N.V., Malinin, A.B., Sebyakin, A.A., Venikov, N.I. (1989), Excitation Functions of Proton-Induced Nuclear Reactions on 124Xe: Production of 123I, J. Radioanal. Nucl. Chem. Lett. 135:39-50. [23] Lagunas-Solar, M.C., Carvacho, O.F., Liu, B-L, Jin, Y., Sun, Z.X. (1986), Cyclotron Production of High Purity 123I I. A Revision of Excitation Functions, Thin-Target and Cumulative Yields for 127I(p,xn) Reactions, Appl. Radiat. Isot. 37:823-833. [24] Lambrecht, R.M., and Wolf, A.P. (1973), Cyclotron and Short-Lived Halogen Isotopes for Radiopharmaceutical Applications. In New Developments in Radiopharmaceuticals and Labelled Compounds. Vol. 1, IAEA Vienna, 1973, pp. 275-290. [25] Lambrecht, R.M., Wolf, A.P. (1972), The 122Te(4He, 3n)123XeD123I Generator, Radiat. Res. 52:32-46. [26] Lambrecht, R.M., Mantescu, C, Redvanly, C, and Wolf, A.P. (1972), Preparation of High Purity Carrier-free 123I-Iodine Monochloride as Iodination Reagent for Synthesis of Radiopharmaceuticals, IV. J. Nucl. Med. 13:266-273. [27] Lambrecht, R.M., Ritter, E., Becker, R., and Wolf, A.P. (1977), Cyclotron Isotopes and Radiopharmaceuticals- XXI. Fabrication of 122Te-Au Targets for Isotope Production. [28] Int. J. Appl. Radiat Isot. 28:567-571. [29] Lambrecht, R.M., Sajjad, M., Qureshi, M.A., and Al-Yanbawi, SJ. (1988a), Production of Iodine-124. J. Radioanal. Nucl. Chem Letters, 127:143-151. [30] Lambrecht, R.M., Woodhouse, N., Phillips, R., Wolczak, D., Qureshi, A., Delos Reyes, E., Graser, C, Al-Yanbawi, S., Al-Rabiah, A., Meyer, W., Marlais, W., Syed, R., Banjar, F., Rifai, A., Miliebari, S. (1988b), Investigational Study of Iodine-124 with a Positron Camera, Am J. Physiol. Imaging, 3:197-200. [31] Mahunka, L, Ando, L., Mikecz, P., Tcheltsov, A.N., and Suvorov, LA. (1996), Iodine- 123 Production at a Small Cyclotron fro Medical Use. J. Radioanal. Nucl. Chem. Letters 213:135-142. [32] Mausner, L.F., Srivastrava, S.C., Mirzadeh, S., Meinken, G.E., Prach, T. (1986), I23I Research and Production at Brookhaven National Laboratory, Appl. Radiat. Isot 37:843-851. -1(4- [33] Michael, H., Rosezin, H., Apelt, H., Blessing, G., Knieper, J., Qaim, S.M. (1981), Some Technical Improvements in the Production of 123I via the 124Te(p,2n)123I Reaction at a Compact Cyclotron, Int. J. Appl. Radiat. Isot. 32:581-587. [34] Qaim, S.M., and Stocklin, G., Production of Some Medically Important Short-Lived Neutron Deficient Radioisotopes of Halogens. (1983), Radiochimica Acta, 34:25-40. [35] Qaim, S.M., (1989) Target Development for Medical Radioisotope Production at a Cyclotron. Nuc. Instr. Methods in Phys. Research. A282 289-295. [36] Scholten, B., Kovacs, Z., Tarkanyi, F., Qaim, S.M. (1995), Excitation Functions of the 124Te(p,xn)124>123I Reactions from 6 to 31 MeV with Special Reference to the Production of 124I at a Small Cyclotron. Appl. Radiat. Isot. 46:255-259. [37] Sharma, H.L., Zweit, J., Downey, S., Smith, A.M., and Smith, A.G. (1988), Production of 124I for Positron Emission Tomography, J. Labelled Cmpds Radiopahrm. 26:165-167. [38] Sheh, Y., Koziorowski, J., Balatoni, J., Lorn, C, Dahl, D.R., and Finn, R.D. (2000), Low Energy Cyclotron Production and Chemical Separation of "no carrier added" Iodine-124 from a Reusable, Enriched Tellurium-124 Dioxide/Aluminum Oxide Solid Solution Target. Radiochim. Acta, 88:169-173. [39] Silvester, D.J., Sugden, J., Watson, I.A., Preparation of Iodine-123 by Alpha Particle Bombardment of Natural Antimony, (1969), Radiochem. Radioanal. Letters 2:17-20. [40] Sodd, VJ, Blue, JW, Scholz, KL, Oselka, MC, (1973) A gas-flow powder target for the cyclotron production of pure 123I. International Journal of Applied Radiation Isotopes 24, 171-177. [41] Stevenson, N.R., Buckley, K., Gelbart, W.Z., Hurtado, E.T., Johnson, R.R., Ruth, T.J., and Zeisler, S.K. (1995), On-Line Production of Radioiodines with Low Energy Accelerators. Proceedings of the Sixth Workshop on Targetry and Target Chemistry, Aug. 17-19, 1995 Vancouver, B.C., Canada, p 82-83. [42] Suzuki, K., Iwata, R. (1977), A Multi-Target Assembly in an Irradiation with High 123 62 13 Energy Particles. Simultaneous Production of I, Zn and NH3, Int. J. Appl. Radiat. Isot. 28:663-665. [43] Tarkanyi, F., Qaim, S.M., Stocklin, G., Sajjad, M., Lambrecht, R.M., Schweickert, H. (1991), Excitation Functions of (p,2n) and (p,pn) Reactions and Differential and Integral Yields of 123I in Proton Induced Nuclear Reactions on Highly Enriched 124Xe. Appl. Radiat. Isot. 42:221-228. [44] Tertoolen, J.F.W., van den Bosch, R., Goeij, J.J.M., van der Heide, J.A., Theelen, H.M.J., Zegers, C. (1977), A New Approach to Target Chemistry for the Iodine-123 Production via the 124Te(p,2n)123I Reaction. J. Label Comp. Radiopharm. 13:232. [45] Van den Bosch, R., De Goeij, J.J.M., Van der Heide, JJ. et al. (1977), A New Approach to Target Chemistry for the Iodine-123 Production via the 124Te(p,2n)123I Reaction. Int. J. Appl. Radiat. Isot. 28:255-261. [46] Watson, LA., Waters, S.L., and Silvester, DJ. (1973), Excitation Functions for the Reactions Producing 121I, 123I and 124I from Irradiation of Natural Antimony with 3He and 4He Particles with Energies up to 30 MeV, J. Inorg. Nucl. Chem. 35:3047-3053. [47] Weinreich, R., Qaim, S.M., Michael, H., Stocklin, G. (1976), Production of 123I and 28Mg by High Energy Nuclear Reactions for Applications in Life Sciences. J. Radioanal. Chem. 30:53-66. [48] Weinreich, R., Wyer, L., Crompton, N., Gunther, I., Roelcke, U., Leenders, K.L., Knust, E.J., Finn, R.D., and Blasberg, R.G. (1977), Production and Quality Assurance of 5-[124I]Iodo-2-deoxyuridine for Functional Imaging of Cell Proliferation in vivo. J. Labelled Cmpds Radiopahrm 40:346-347. [49] Witsenboer, A.J., De Goeij, J.J.M., Reiffers, S. (1986), Production of Iodine-123 via Proton Irradiation of 99.8% Enriched Xenon-124, Proceedings of the Sixth International Symposium of Radiopharmaceutical Chemistry, Boston, MA June 29-July 3, 1986, p. 259. [50] Zaidi, J.H., Qaim, S.M., and Stocklin, G. (1983), Excitation Functions of Deuteron Induced Nuclear Reactions on Natural Tellurium and Enriched 122Te: Production of 123I via the 122Te(d,n)123I-Process. Int. J. Appl. Radiat. Isot. 34:1425-1430. [51] Zaitseva, N.G., Deptula, C, Knotek, O., Khan, K.S., Mikolaewski, S., MikeD, P., Rurarz, E., Khalkin, V.A., Konov, V.A., Popinenkova, L.M. (1991), Cross Sections for the 100 MeV Proton-Induced Nuclear Reactions and Yields of some Radionuclides Used in Nuclear Medicine, Radiochim. Acta 54:57-72. List of Figures 1. Reaction cross-sections for the production of 1-123 and 1-124 as a function of the proton energy. (Image file from Sigma Plot) 2. Typical inclined plane target for irradiation in the internal beam of a cyclotron, (file: internal l.wpg) 3. Typical inclined plane target for the irradiation of low-melting materials in an external cyclotron beam, (file: Se-targ2.wpg) 4. Molten salt target from BLIP facility at BNL. 5. "No-fail" gas target for the irradiation of Xe-124. -HI- "'S^tefif'""-:' Rfpfeisotope Production of fodine-123 and lodine-124 David J. Schlyer Brookhaven National Laboratory Sao Paulo, Brazil August 2001 Brookhaven Science Associates BROOKHDVtf EN U.S. Department of Energy NATIONAL LABORATORY '-'.. Clinical Uses of Radioidine Thyroid Studies Renal excretion Cardiology Receptor binding Monoclonal antibody labeling Brookhaven Science Associates BROOKHJ&lf EN U.S. Department of Energy NATIONAL LABORATORY Uses in Cardiology MIBG - 123I metaiodobenzylguanidine • Considered to reflect cardiac sympathetic function • Associated with beta-ad renergic receptor mechanism BMIPP - 123I 15-(p-iodophenyl)-3-R,S- methylpentadecanoic acid • Images fatty acid metabolism Brookhaven Science Associates BROOKHJStf EN U.S. Department of Energy NATIONAL LABORATORY s in Receptor Binding Dopamine Receptor Agents • Epidepride - D2 receptors • IPT pre-synaptic transporter • IBZM Muscarinic acetylcholine receptors • IQNP Serotonin receptors Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY Excitation Labeling Halogen Exchange Labeling Labeling with oxidizing agents Labeling via Organoboranes Labeling via Organostannanes Labeling via Demetaiiation reactions (Finn 2001) Brookhaven Science Associates BROOKHJWEN U.S. Department of Energy NATIONAL LABORATORY of Iodine (Finn 2001) Nuclide Half-life SAof Decay Mode Photons product Abundance 1-122 3.6 m B+1363keV 563(21) 1-123 13.1 h >1900 EC (99.99) 159 (83.4) Ci/mg -p- + I 1-124 4.2 d B (23.3) 602 (59) EC (76.7) 1691(10.1) 1-125 60.1 d >17 EC (100) Ci/mg 1-131 8.04 d >5 B-181 (99.9) 364(81.2) Ci/mg 637 (7.3) Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY of How Much Can be Produced What is the Energy Dependence of the Yield Are There Impurities Present Can the Radioisotope be Separated Is It in a Useful Chemical Form Brookhaven Science Associates BROOKHAUEN U.S. Department of Energy NAT1ONAL O Reactions for the High Production of H23 pjliear E % References Reaction 127 123 Adilbish et al. 1980; Cuninghame l(p,5n) Xe : 55 + 100 et al. 1976; Jungerman and 123| Lagunas-Solar 1981; Zaitseva et al. 1991. Lagunas-Solar et al. 1986 127l(d,6n)123Xe : 83 100 Weinreich et al. 1976 123| Brookhaven Science Associates BROOKHJ&VEN U.S. Department of Energy NATIONAL LABORATORY ar Reactions for the uctionofM23 pliicleaf E % References Reaction 122Te(d,n)123l 14-8 2.4 Zaidietal. 1983 123Te(p,n)123l 15-8 0.87 Barralletal. 1981 124Te(p,2n)123l Dahl and Tilbury 1972; Clem and 26-20 4.6 Lambrecht 1991; Hupf et al. 1968; Acerbi et al 1975, Kondo et al 1977; Schloten et al. 1995. 124 123 Graham et al. 1985; Witsenboer et Xe(p,pn) Xe 30-15 0.1 al. 1986; Firouzbakht et al. 1987; ;123| Tarkanyi et al. 1991; Kurenkov et al. 1989 Brookhaven Science Associates BROOKHAlfEN U.S. Department of Energy NATIONAL LABORATORY -• Nuclear Reactions for the of H23 - 3He and4 He puclear E % References -Reaction 122 4 Lambrecht and Wolf 1972; Silvester Te( He,3n) 30-20 2.4 et al. 1969 123Xe : 123| 121Sb(4He,2n) 25-15 57.4 Watson etal. 1973 123| 123Sb(3He,3n) 30-20 42.6 Watson etal. 1973 123| Brookhaven Science Associates BROOKHAUEN U.S. Department of Energy NATIONAL LABORATORY Uses the 124Te(p,2n)123l Reaction to produce 1-123 Powder has poor thermal conductivity Plated targets require care in preparation and recovery Brookhaven Science Associates BR00KHA1IEN U.S. Department of Energy NATIONAL LABORATORY ^sPta*" * * 'jr ?*." * •"' -- *' Cross-section 1-123 Cross-section Summary 1400 124 123 • Acerbi Te(p,2n) l 1200- • Kondo A Scholten 1000- a B m 800- o § 60CH CO o 400 H o 200 - B a 0 - 10 15 20 25 30 35 Energy (MeV) Brookhavei. «**,.»..«,*, *-.*WVWIUIW, W tsROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY 1-124 Cross-section Summar 1-124 Cross-section Summary 700 Energy (MeV) Brookhaven Science Associates BROOKHAUEN U.S. Department of Energy NATIONAL LABORATORY j -* ^ Ratio of 1-123 to 1-124 Production of 1-123 vs 1-124 1000 10 15 20 25 Proton Energy (MeV) Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY es of Tarqets ,» _<•,. Internal • Electrodeposited • Flow through powder External • Perpendicular Incidence • Inclined plane • Flow Through Brookhaven Science Associates BROOKHfitf EN U.S. Department of Energy NATIONAL LABORATORY mat - Solid Plate Alpha beam 45- I Leading Monitor Trailing Monitor Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY rnal - Inclined Plane Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY Flowing Te-122 Powder He Flow Incident Beam CO2 Bath .Liq N2 -78 C -196C Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY - ;- b'-S "f *• f. Window Boron Powder Material of Construction - Aluminum Brookhaven Science Associates BROOKHJMfEN U.S. Department of Energy NATIONAL LABORATORY • Plate GP Brookhaven Science Associates BROOKHAUEN U.S. Department of Energy NATIONAL LABORATORY nil - Inclined Plane 4.5' 2.25' 2,0' \ 1,0' _tr7/8r i iU 5/8' Brookhaven Science Associates BROOKHfiVEN U.S. Department of Energy NATIONAL LABORATORY External - Inclined Plane o Brookhaven Science Associates BROOKHJMfEN U.S. Department of Energy NATIONAL LABORATORY fml Flowing Targets M^ ' Target Material — Beam He + iodine ^ q -fc. I Cooling water Vacuum Chamber Heater Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY ods of Extraction Distillation Dissolution Liquid Extraction Supercritical Extraction Brookhaven Science Associates BROOK Hfitf EN U.S. Department of Energy NATIONAL LABORATORY *-*••* i>«.: Jf* Stillation O + He Gas Inlet 2 xTeO Target Holder 1-124 Out Thermocouple Probe Furnace Brookhaven Science Associates BROOKHAUEN U.S. Department of Energy NATIONAL LABORATORY Extraction What is a supercritical fluid? Above a certain temperature, a vapor can no longer be liquefied regardless of pressure critical temperature - Tc -fc.. supercritical fluid region 0) to solid CO 0) L temperature Brookhaven Science Associates BROOKHAtfEN U.S. Department of Energy NATIONAL LABORATORY GasTa Xenon-124 reaction uses low energy cyclotron The purity of the lodine-123 is very high i The recovery of the enriched target material is very easy and efficient Brookhaven Science Associates BROOKHAtf EN U.S. Department of Energy NATIONAL LABORATORY 124 Gas There is some controversy concerning the cross-section for the 124Xe(p,2n)123Cs 124Xe(p,pn)123Xe 124Xe(p,2p)123l nuclear reactions and the yields Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY on enriched Xenon-124 * >-;. *\s-4. a-~ ' <•<-' Protons on Xenon Yield Comparison >t • BNL 1—"^s 3500- • KIAE A JUL 3000-- TI iro I ntu j Q) 2500- \ 2000- A A A A \ «• AA \" b 1500- A #\ a / £ ^ A A ®mral A A 2 1000 F 500 - 0 - I 1 1 1 1 1 1 14 16 18 20 22 24 26 28 30 32 34 36 Energy (MeV) Brookhaven Science Associates BROOKHJMfEN U.S. Department of Energy NATIONAL LABORATORY ''? \ ' enon-124 Gas Targets The cross-section for the 124Xe(p,2n)123Cs nuclear reaction seems quite close, The difference lies mainly in the 124Xe(p,pn)123Xe Brookhaven Science Associates BROOKHJMfEN U.S. Department of Energy NATIONAL LABORATORY action Comparison of Cross-sections auu - 700 - ® KIAE • JUL 600 - if 500- c o 400 - "G 0 - i i i i 15 20 25 30 35 40 45 50 Energy (MeV) Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY ms with Xenon Gas Target • Enriched isotope is expensive 1 > */ Beam Current is limited by density 3j.> ~ V'!' reduction Target design must minimize the chance for loss of target material Brookhaven Science Associates BROOKHAUEN U.S. Department of Energy NATIONAL LABORATORY |rs3r" FaHrtte* Gas Targets Xenon Torget Recovery System He iCooling "Inlet Vacuum Insulato Isolation Liquid Foil Nitrogen Buffer Volume BEAM- zr O Cold Finger He ^— Cooling Outlet Liquid Nitrogen Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY Gas Targets Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY Buffer volume Helium cooling inlet Target gas ' r' inlet Water jacket Cold finger Helium cooling outlet Brookhaven Science Associates BROOKHJMfEN U.S. Department of Energy NATIONAL LABORATORY Brookhaven Science Associates BROOKHAtfEN U.S. Department of Energy NATIONAL LABORATORY Cryogenic Targets V. *. •***-$. ,-; en Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY 0\ Material of Construction - Silver Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY enic Targets 1 << %§& 'sfc«- ; '. t i -+J I Brookhaven Science Associates BROOKHAtlEN U.S. Department of Energy NATIONAL LABORATORY enic Target and \ I Brookhaven Science Associates BROOKHAUEN U.S. Department of Energy NATIONAL LABORATORY lems with the Cryogenic Target ••;- »*" ~P'r Beam current is limited to less than 20uA Liquid Nitrogen cooling bath must be replenished frequently during long irradiations Brookhaven Science Associates BROOKHAUEN U.S. Department of Energy NATIONAL LABORATORY ces in Cyclotron Taraotr Need to Go to Higher Power Heat Dissipation Stategies • Increase Surface Area • Make Beam Distribution More Uniform • Make the Water Cooling More Efficient Brookhaven Science Associates BROOKHAVEM U.S. Department of Energy NATIONAL LABORATORY wamr Targstry Power is given by the Beam energy multiplied by the Beam Intensity P = E(MeV)*l(uA) At 30 MeV and 100 uA, the total power deposited is 3 kW Brookhaven Science Associates BROOKHAVEN U.S. Department of Energy NATIONAL LABORATORY *. . 'gab?,^ Conclusions 1 The Radioisotopes of iodine are ^C-" ; extremely important tools in Nuclear Medicine and research The utility of these radioisotopes is still increasing Advances in targetry will come in heat dissipation Advances in extraction will improve the efficiency Brookhaven Science Associates BROOKHAUEN U.S. Department of Energy NATIONAL LABORATORY