PRODUCTION OF CARRIER-FREE 123I USING

THE 127l(p,5n)123Xe REACTION

M. A. Fusco, N. F. Peek, J. A. Jungerman, F. W. Zielinski, S. J. DeNardo, and G. L. DeNardo University of California at Davis, Davis, California

Iodine is notable among the elements which are part iodine were present but did not indicate the amount of man's composition in that it has more different ra- of these contaminants. Sodd, et al (J) and other dioisotopes than any other element natural to man. investigators (4-8) have provided an extensive list These radioisotopes of iodine have different physical of nuclear reactions leading to the production of 123I. characteristics and no one radioisotope is optimal Their list does not include the production method for all biomédicalapplications. Iodine-123 has physi to be described in this publication (Table 1). Most cal characteristics which are optimal for most in vivo of the previously described methods for the produc medical procedures, particularly those which are tion of 123Iresult in contamination with 124Iwhich completed within 24 hr. Iodine-123 decays solely reduces the spatial resolution of imaging procedures by electron capture; the photon-to-electron ratio is and increases the radiation dose to the patient (9). high, indicating a low level of undesirable paniculate We wish to describe a new method for the produc radiation. Iodine-123 emits 159-keV gamma rays in tion of 123Iwhich eliminates virtually all radioactive 84% of the disintegrations, thus providing a high contaminants (Table 2). yield of photons suitable for use with imaging sys tems. The 13.1-hr half-life of 123Iis long enough to MATERIALS AND METHODS allow for target processing, chemical manipulation, Research irradiations. The 123Xeproduction cross- purification, extensive quality control, delivery to the section information was collected using a small iodine patient, and subsequent development of clinical in target. A tantalum plate with a recess 1.2 mm deep formation. In all respects then, '123Iis a more ideal and 6.5 mm in diam was used as the target holder gamma radionuclide than any other radioisotope of for resublimed high-purity natural iodine. To prevent iodine for in vivo diagnostic procedures (1). In 1962 Myers, et al (2) described the merits of 123Iand several methods for production. They indi Received Jan. 31, 1972; revision accepted Apr. 27. 1972. For reprints contact: Neal Peek. Crocker Nuclear Lab cated that contaminants of other radioisotopes of oratory, University of California, Davis, Calif. 95616.

1^1ActivityReactionTABLE 1. COMPARISON OF VARIOUS REPORTED METHODS OF PRODUCTION OF

mlI21Sb(a,2n)12''l (mCi/M/hr) »,0.62 US, Réf.ni w\

ni«iaTe(d,n)ial 0.23 0.00190.19 0.015 30.96 ni ni'•" 0.13 0.0061 0.12 3ni 0.07 '-r"1TcIcK.jn)l 1 \1 --v AC / rt —_ . ^Teond"3!"'M=T ( 0.009ni.5 0.03 3ni ni ni^JÕS-*"("u"'.)?«»!* 0.007 nini ni 3ni ni

"'^Tela^nJ^Xe °-°°14 nini ni 3ni ni ni1!nl(p^n)12aXe 0.3 ni— <0.2 7— ni —* 3.0 0.1 —m\ — Présentwork

Not indicated in publication.12<|

Volume 13, Number 10 729 FUSCO, PEEK, JUNGERMAN, ZIELINSKI, DENARDO, AND DENARDO

et al (7) was used to separate the xenon from the target. At the end of the irradiation, the target block was remotely removed from the cyclotron and trans ferred to the radiochemical laboratory. The iodine target was dissolved in an aqueous solution of po tassium iodide. Helium was circulated in a closed system through the dissolved sample and subse quently through dry-ice-acetone and liquid-nitrogen traps (Fig. 2). Water vapor and iodine released from the dissolution flask were removed by the dry-ice- acetone-cooled trap and the xenon gas was collected in the liquid nitrogen-cooled trap. Cooling was main tained for about 6 hr to allow the 123Xe to decay 50 55 to 123I. E protón (MeV) Methods of identification and assay. Serial gamma- FIG. 1. Relative yield of u>:ilas function of incident proton en ray spectroscopy was used to identify the kinds and ergy. 121Utargets used were about 2.5 MeV thick. Yield is given in amounts of radionuclides present by virtue of their arbitrary units. Some uncertainty results because of possible loss of xenon from iodide crystal lattice if target is overheated by inci characteristic photopeak energies and half-lives. A dent beam of protons. 30 cc Ge(Li) detector coupled to a 4,096-channel analyzer was used for the gamma-ray spectroscopy of the irradiated target and the final product. The resulting spectra were processed using a PDF 15/40 computer to integrate the area under the respective gamma-ray photopeaks. Yields were determined by IODINE TARGET ON TANTALUM PLATE comparison with an IAEA 22Na calibrated standard source counted in a standard geometry. Figure 3 MAGNETIC BAR LIQUIDN2 shows the gamma-ray spectrum of the final 123I t-196'C) MAGNETIC STIRRING product. MOTOR To further establish product purity and suitabil TARGET DISSOLUTION ity for clinical use, paper and cellulose acetate elec- trophoresis of 123I dissolved in distilled water was FIG. 2. System for isolation of xenon isotopes from 'L target performed. Paper electrophoresis for 75 min at 170 following proton irradiation. volts in 0.05 ionic strength barbitol buffer (Beckman buffer B-l, pH 8.6) and cellulose acetate electro loss of volatile products during irradiation a 0.25- phoresis for 15 min at 340 volts in the same buffer mm-thick tantalum cover foil was used. The assem system were followed by a determination of the bled chemical target block was cooled by circulating distribution of the radioactivity by radiochromato- water on the back and helium across the front of graphic scanning. the target. A series of irradiations were made at The product 123Iwas tested for sterility according proton energies increasing from 42.5 to 62 MeV to the U. S. Pharmacopeia using thioglycollate me in 2.5-MeV steps to establish the optimum proton dium incubated at 32°Cfor 7 days and Sabouraud energy for producing 123Xe (Fig. 1). medium incubated at 25 °Cfor 10 days. Production irradiations. Having established the relative cross sections as a function of proton energy RESULTS for the 127I(p,5n)123Xe and 127I(p,3n)125Xe reac Yields measured as a function of proton energy tions, a system was designed for the production and showed that the optimum energy for 12SXeproduc recovery of large quantities of carrier-free 123I for tion is about 54 MeV for a thin target (Fig. 1). The subsequent chemical and biomédicalstudies. The 123I activity recovered from the liquid-nitrogen- area of iodine target was increased to 4.5 cm2, the cooled trap 6 hr after the termination of a production thickness to 1.6 mm, and the beam intensity to 6 /¿A irradiation was 24 mCi. This figure is based on the of 57.5-MeV protons. To minimize the production following experimental conditions: 127Itarget thick of 125Xe, it was decided to irradiate the target for ness of 1.0 gm/cm2 (7 MeV thick) with an irradia 3 hr, which would produce 63 % saturation of 123Xe. tion time of 1.0 hr at 6 /uA at 57.5 MeV and target Methods of separation and recovery. A cyclic or area of 4.5 cm2. batch processing method similar to that of Sodd, Because the isotopes of xenon, including 123Xe,

730 JOURNAL OF NUCLEAR MEDICINE PRODUCTION OF CARRIER-FREE 123I

FIG. 3. Gamma spectrum of final product. Only !l !l is observed after sepa SCO 600 ration. Line energies are given in keV. CHANNEL can be readily separated from the target and final product, which was cultured in Sabouraud and thio- product, the only contaminants in the product are glycollate media to establish clinical suitability fur isotopes of iodine from xenon decay (Table 2). Ra- ther, was found to be sterile. dionuclides of iodine produced directly in the target remain in the dissolution flask. Furthermore, 124Xe DISCUSSION and 126Xe are stable so they do not result in 124I The merits of 123Ifor diagnostic biomedicai appli and 126I.Xenon-125 is a contaminant initially (17-hr half-life) which constitutes about 5% of the 123Xe cations have been appreciated for some time; its (2.1-hr half-life) activity at the end of irradiation advantages of decreased radiation exposure and in with 57.5-MeV protons. If the residual xenon is re creased spatial resolution can only be fully realized moved at the optimal time for maximum 123Iactivity if other radioactive contaminants are absent or negli (6 hr), only 22% of the I25Xe will have decayed to gible. A variety of production methods have been 126I. This results in 125Icontamination of 0.1% of proposed or developed (Table 1). These production methods may be direct, that is, the I23I is produced the 123Iactivity. Also some 122Xe (20-hr half-life) is produced by 127I(p,6n)122Xe. This isotope is not immediately in the target by the irradiation, or in direct, that is, 123Xe is produced in the target and a problem because the 122Xeis removed as described subsequently decays to 123I. Several investigative previously, and the 122Idaughter promptly decays groups (2,4,5,6,10) have described a variety of di to stable tellurium with a half-life of 3.5 min. rect methods for the production of 123I.These meth Electrophoresis of the final aqueous 123Iproduct indicates that the 123Imigrates as one substance and ods also result in the production of radioactive contaminants including 124I, 125I, 12«I,130I, and 1S1I in the same manner as the I2r'I-iodide standard. The (Table 2). The amounts and combinations of these contaminants varies with the production method, but in all cases the radiation dose to a patient is TABLE 2. POSSIBLE AND increased and spatial resolution in imaging is sub- METHODSReaction OF REMOVALMethod optimal (9). This is particularly true for 124Ibecause

Isotope^l(p,xn) removalDecays of of its positron and 604-keV gamma emissions. Blue, '~Xe to 3.5 min m| et al (4) and Sodd, et al (7,8) described two indirect ^Xe Stable, is blown off methods for the production of 123I following the ""X.^e""l(p,xnd)»Ì«,ral(p,xna)Decays to and remains a 0.1% decay of 123Xewhich is produced by the irradiation 1JSIcontaminant of 122Teor 123Te.These indirect production methods Stable, is blown off Proton energy too high for sig eliminate all contaminants except 12SI.For imaging, productionAllnificant 125Icontamination does not affect spatial resolution because all its photon emissions are less energetic resultant iodine remains in than the 159-keV gamma ray of 123I. Iodine-125 dissolution flask or is col trapAlllected in CO»-acetone does, however, result in increased radiation dose to

Te1) the patient. In the iodide form, the thyroid irradia resultant tellurium remains tion from 12r'Iis 40 times greater than from an equal in dissolution flask or is col 5:CONTAMINANTSlected in CO. -acetone trap amount of 123I. All methods previously described require relatively expensive isotopically enriched tar-

Volume 13, Number 10 731 FUSCO, PEEK, JUNGERMAN, ZIELINSKI, DENARDO, AND DENARDO

gets which usually must be processed before re- in 24 isolable mCi of 123I.The only detectable con irradiation. In addition, the indirect methods pre taminant in the final product was 125I which was viously described do not result in high yields. The about 0.1% of the 123Iactivity. method described in this publication has several A reasonable extrapolation of our irradiation ex advantages. It uses inexpensive, readily available perience indicates that a yield of 89 mCi can be iodine as a target. Moreover, it results in relatively obtained in practice. This production figure is based large yields of carrier-free 123Iwith only 0.1% 125I on a target thickness of 1 gm/cm2 and an irradiation contamination and no contamination from 124I.The time of 3 hr at 10 ¿iA. 123Ican be readily processed for immediate use in The advantages of this method over existing meth vivo or for subsequent incorporation into biologically ods are (A) readily available, inexpensive, isotopi- active compounds. cally pure targets; (B) multimillicurie yields of The disadvantages one encounters are the follow carrier-free 123I,and (c) significantly reduced radio- ing: The proton beam energy required (>50 MeV) nuclidic contamination. When used in vivo the radia is not readily available from most cyclotrons, and tion dose to the patient is reduced and optimal spatial the poor thermal conductivity afforded by the crys resolution is possible for imaging procedures. This talline iodine requires careful handling of the beam. method, however, requires 50-60-MeV protons Both theoretical calculations and experimental ob which are not universally available. servations indicate that beam intensities at 57.5 MeV exceeding 3 /¿A/cm2result in "burn out" of the ACKNOWLEDGMENTS target material. This necessitates establishing a uni We are pleased to acknowledge the assistance of Eugene form beam density over the entire target area, and Russell of the Crocker Nuclear Laboratory cyclotron in restricts the thickness of the target to 1 gm/cm2 (7 achieving the irradiation of the 1S7I2targets and that of Ralph MeV thick). Rothrock in target fabrication. The research for this paper The total yield of 123Ican be increased by using was supported in part by NIH Research Grant No. 571900. a longer bombardment time and increased current. If a 3-hr bombardment were used with a beam cur REFERENCES rent of 10 /¿A(beam current density of approxi 1. MYERS WG: Radioisotopes of iodine. In Radioactive mately 2 MA/cm2), a yield of 0.9 Ci of 123Xe will Pharmaceuticals, Andrews GA, Kniseley RM, Wagner HN, be obtained at the end of bombardment and 89 mCi eds, USAEC Symposium Series 6, CONF-651111, Spring of 123Iwould be available at 6.0 hr after irradiation. field, Va, National Bureau of Standards, 1966, pp 217-243 2. MYERS WG, ANGER HO: Radioiodine-123. / Nucí SUMMARY Medi: 183, 1962 3. Soon VJ, SCHOLZ KL, BLUE JW, et al: Cyclotron A cyclotron procedure for the production of high- Production of '"I. An Evaluation of the Nuclear Reactions purity, carrier-free 123Isuitable for immediate radio- Which Produce this Isotope. USHEW Report BRH/DMRE 70-4, Oct 1970 pharmaceutical use has been developed. Proton irra 4. BLUE JW, SODDVJ : 1MIproduction from the B* decay diation of natural elemental iodine results in the of lalXe. In Uses of Cyclotrons in Chemistry, Metallurgy production of 123Xe which subsequently decays to and Biology, Amphlet CB, London. Butterworth, 1970, pp 123I. The primary reaction for 57-MeV protons is 137-148 127I(p,5n)123Xe; other reactions yield 125Xeand the 5. SODDVJ, BLUE JW, SCHOLZ KL: ral production for neutron-deficient radioisotopes of iodine. At the end pharmaceutical use. In Uses of Cyclotrons in Chemistry, Metallurgy and Biology, Amphlet CB, London, Butterworth, of bombardment, the target iodine is dissolved in 1970, pp 125-137 aqueous KI, and helium gas is bubbled through the 6. HUFF HB, ELDRIDGEJS, BEAVER JE: Production of solution, sweeping the xenon through a recirculating 123Ifor medical applications. Ini J Appi Radiât 19: 345-351, 1968 system. The xenon gas is collected in a liquid 7. SODDVJ, BLUE JW, SCHOLZ KL: Pure I23Iproduction nitrogen-cooled trap. The isolated xenon is contained with a gas-flow target. / NucíMed 12: 395-396, 1971 for 6 hr during which time the 123Xe (T,/2, 2.1 hr) 8. SODDVJ, BLUE JW: Cyclotron generator of high pur decays to 123I.The 123Imay be recovered by adding ity ""I. / NucíMed 9: 349, 1968 a small volume of physiological saline. 9. WELLMAN HN, MACK JF, SAENGEREL, et al: Study of parameters influencing the clinical use of 123I.J NucíMed An irradiation on the Crocker Nuclear Laboratory isochronous cyclotron of 1 hr, using a 1 gm/cm2 10: 381, 1969 10. GOOLDEN AWG, GLASS HI, SILVESTER DJ: The thickness of iodine (7-MeV proton energy loss in choice of a radioactive isotope for the investigation of thy the target) and 57.5-MeV protons at 6 /¿A,resulted roid disorders. Brit J Radial 41: 20-25, 1968

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