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THALLIUM-201 FOR MEDICAL USE. I

E. Lebowitz, M. W. Greene, R. Fairchild, P. R. Bradley-Moore, H. 1. Atkins,A. N. Ansari, P. Richards,and E. Belgrave Brookhaven National Laboratory

Thallium-201 merits evaluation for myocar tumors (7—9), the use of radiothallium should also dial visualization, kidney studies, and tumor be evaluated for this application. diagnosis because of its physical and biologic Thallium-201 decays by with a properties. A method is described for prepara 73-hr half-. It emits K-x-rays of 69—83 tion of this radiopharmaceutical for human use. keY in 98% abundance plus gamma rays of I 35 and A critical evaluation of 501T1 and other radio 167 keV in 10% total abundance. Because of its pharmaceuticals for myocardial visualization is good shelf-life, photon energies, and mode of decay, given. 201T1was the radioisotope of thallium chosen for development.

Thallium-20 1 is a potentially useful radioisotope MATERIALS AND METHODS for various medical applications including myocardial Thallium-201 is produced by irradiating a natural visualization and possible assessment of physiology, thallium target in the external beam of the 60-in. as a renal medullary imaging agent, and for tumor Brookhaven with 3 1-MeV . The detection. nuclear reaction is 203Tl(p,3n)201Pb. -201 has The use of radiothallium in was a half-life of 9.4 hr and is the parent of 201T1.The first suggested by Kawana, et al (1 ) . In terms of thallium target, fabricated from an ingot of 99.999% organ distribution (2) and neurophysiologic function pure natural thallium (29.5% isotopic abun (3), thallium is biologically similar to . dance of 203Tl), is I .3 cm in diameter and weighs The physical—chemicalexplanation for the biologic 0.7 gm. The target thickness and incident similarity of @+and [email protected] is that the hydrated ionic beam energy are chosen to minimize the production radius of 11+ is between K+ and Rb+ in size and of other radioisotopes of lead, which could lead to this radius has been suggested as the property that impurities in the 2011'lproduct. After irradiation, the determines passive penetration through a mem thallium target is dissolved in concentrated nitric brane (4). acid, then evaporated to dryness. This salt is then These facts suggest that radiothallium should be dissolved in 50 ml of 0.025 M EDTA at pH 4 and a good potassium analog and therefore has potential passed through a Bio-Rad Dowex 50 X 8 resin col for myocardial visualization and the early detection umn (Nat form, 50—[email protected] X 6 cm) . Most of areas of diminished perfusion and of the thallium target material adheres to the column uptake as “coldspots―(regions of decreased ac and the eluate contains radioactive 203Pband 201Pb. tivity). The eluate is acidified by adding an equal volume of Presently used renal agents concentrate in the conc. [email protected] the thallium is oxidized by the addi cortex; unlike these, thallium preferentially concen tion of “Clorox.―Forty micrograms of Pb(N03)2 trates in the renal medulla (5) . This property may carrier are added to the eluate and the solution is be clinically useful. passed through a Bio-Rad Dowex 1 X 8 resin col The [email protected] is taken up more by tissues in pigmented umn ([email protected] [email protected],50—100mesh, 2.5 X 6 cm). Thal than in albino rabbits, suggesting the use of radio thallium for the diagnosis of melanoma (6) . Because Received June 10, 1974; revision accepted Sept. 23, 1974. of the similarity of thallium to alkali such as For reprints contact: Elliot Lebowitz, Bldg. 801, Brook cesium, which has been shown to concentrate in haven National Laboratory, Upton, N.Y. 11973.

Volume 16, Number 2 151 LEBOWITZ, GREENE, FAIRCHILD, BRADLEY-MOORE, ATKINS, ANSARI, RICHARDS, AND BELGRAVE

hum adheres to this column and the lead activities are eluted. TABLE1. CHEMICALANALYSIS This eluate containing 203Pband 201Pbis allowed PRODUCTOFQuantityQuantityElement(/Lg)Element(‘ug)TI<2Ni<2Ca60Al1B<2Mo0.2Mg1Cu6Mn<0.2Ag<0.2Si0.2Ti1Fe1V1THE 201Tl to stand overnight to permit the 201Pbto decay into 201Tl It is then passed through another Bio-Rad Dowex 1 X 8 column to which the 2olTl+3 adheres and through which the lead activities are eluted. The 201'fl activity is then eluted with 20 ml of hot hy drazine-sulfate solution (20% w/v) , reducing [email protected] to Tl+l This TI +1 eluate is evaporated to dryness twice with conc. HNO:4 and once with conc. HC1. The product is then dissolved in 5 ml of 10_i M NaOH and the pH is adjusted to 7 by further addi tion of NaOH. The product is sterilized by ifitration by paper chromatography to differentiate [email protected] and into a sterile multiinjection bottle through a 0.22- [email protected] No. 3 MM paper and a solvent 1/10 micron sterilized Millipore filter. (Na2HPO., -5H20) and 9/ 10 (acetone) are used. A Rhodamine B spot test is used to detect carrier The 11+1 stays at the origin. To demonstrate that thallium in the product before injection. The test the 20111is not in particulate form, the product is can detect 0.02 @gof thallium. The sample tested passed through a 250 A filter. is typically 1% of the total product; thus a negative Radionuclidic purity is analyzed by multichannel spot test insures that less than 2 @gof thallium is pulse-height analysis, utilizing a Ge(Li) detector. present in the product. A few weeks after the 20111 The gamma spectrum of the product is also followed is produced, a complete chemical analysis of the for approximately 1 week to confirm the half- of product is performed by emission spectroscopy. the product and impurity gamma rays. The radiochemical purity of the product is checked Product batches are tested for pyrogenicity by an

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FIG. 1. Ge(ti)spectrumof‘@TIproduct.

152 JOURNAL OF NUCLEAR MEDICINE 201T1FORMEDICALUSE. independent laboratory. All glassware is rendered 1000 r I I I apyrogenic by autoclaving at 180°Cfor 3 hr. Measurements of the excitation function (the pro duction cross section as a function of energy) are performed by irradiating a stack of thin (approxi 500 mately 0.2 gm/cm2) foils of thallium and analyzing the activities produced with a Ge(Li) detector. Lead -a 201 is determined by analysis of its 331-keV photon, E which is present in 82% abundance. b

RESULTS Emission spectroscopic chemical analysis of an entire product batch is shown in Table 1. Figure 1 shows the Ge(Li) spectrum of the product, the main 00 peaks being the x-rays and photons of 20111.The 10 20 30 40 radioisotopic purity is @99%, as is shown in Table E ( MeV) 2. The product is at neutral pH, isotonic, sterile, and pyrogen-free. FIG.2.‘°‘TI(p,3n)'°@Pbexcitationfunction. The excitation function for the production of 201Pb,the parent of 20111,is seen in Fig. 2. By choos ing an energy range near the peak of the excitation the heart. Although the radioisotopes of potassium function, the production of 200Pb and 202Pb (the and cesium can both be used for myocardial visual parents of 200'fl and 202Tl) radiocontaminants is ization, their differences in biologic behavior are re minimized. With a natural thallium target, the pro flected in their clinical usefulness. duction rate of 20111is 0.7 mCi/@AH or correspond Advantages of potassium over cesium. First, be ingly higher with an enriched 20311target. The mi cause of its more efficient myocardial uptake and tial development work is being done on the Brook lack of recirculation, K+ is superior for quantitative haven 60-in. cyclotron but it should be possible to studies following intracoronary arterial injection evaluate the production capability of 20111 in the (10) . Second, because of its rapid blood clearance BLIP (Brookhaven Linac Producer) using and myocardial extraction, K+ can be used in the the 205Tl(p,5n)201Pb reaction. assessment of patients with transient myocardial is chemia (e.g., angina pectoris) by visualizing the myo DISCUSSION cardium before and after stress (11,12). Using the myocardial uptake of the analogs of Disadvantage of potassium. The rapid leakage of potassium, there are several alternatives for myo potassium from the myocardium constitutes a dis cardial visualization including the radioisotopes of advantage due to the inability to visualize the myo potassium, cesium, thallium, , and I3NH,+. cardium with potassium after the first hour post We start by comparing the biologic behavior of [email protected] injection (1 1 ), compared with the ability to use and [email protected] (10) . Potassium is more rapidly cleared cesium for this purpose for several hours (10,13). from the blood and extracted by the myocardium Since Tl+ is a good biologic analog of potassium, than is cesium. Potassium is extracted by the myo it should have the biologic advantages of [email protected] listed cardium with 71% efficiency on a single circulation earlier. Furthermore, Harper has observed that the compared with 22% efficiency for cesium. Following thallium activity remained in the myocardium even its extraction, potassium is cleared more rapidly from 18 hr postinjection in the one patient they scanned

TABLE 2. RADIOISOTOPIC ANALYSIS OF 201Tl PRODUCT

At time of preparation 18 hr later Isotope tim (%) (S/s) 73 hr later 146 hr later

‘°@Pb 52 hr 1.6 X 10' 1.5 X 102 1.2 X i0' 9.0 X 10' “TI 26 hr 1.3 X 10' 9.0 X 102 3j X [email protected] 1.1 X 10' ‘@Tl 12.2 days 1.2 X 10' 1.4 X 101 2.0 X 10T' 3.4 X 101

Volume 16,Number 2 153 LEBOWITZ, GREENE, FAIRCHILD, BRADLEY-MOORE, A1KINS, ANSARI, RICHARDS, AND BELGRAVE

Rubidium is a good analog of potassium (15) TABLE 3. RADIOISOTOPES FOR and it is expected to be almost as good an analog MYOCARDIAL VISUALIZATION as thallium since the hydrated of thai hum is between potassium and rubidium. energy radiation The metabolic behavior of [email protected]}j is sufficiently Radionuclide (keV) and dose complex so that diagnosis with it has been difficult (md/mCi)Comments'‘@[email protected](l6)and half-lifePhotonabundanceWhole-body todate(16).

10mm 200%0.005511 Table 3 compares radioisotopes for myocardial visualization. An important new development is the “Rb(17) use of O9mTc..g,@omplexesfor visualization of necrotic 4367%0.10(1)‘@Cshr511 tissue as a “hotspot―(region of increased uptake) (18) (30,31 ) . The combined use of 201Tl and an agent 88%0.21(2)‘@‘mCs9.7 days29 such as 99mTc..tetracycline may greatly enhance the (19) 14%0.24(3)“Rb2.9 hr—1-;8 value of cardiac diagnosis by nuclear medical tech niques. Thallium-201 might demonstrate the size (20,21) and location of regions of and necrosis 75192%@O.001(4)‘3Ksec511 whereas 99mTc.tetracycline might perform the differ (22) 22103°[email protected] ential diagnosis between ischemic and necrotic re gions by demonstrating only regions that are necrotic. (23,24) As is essential, our production method yields 20111 45%0.17°°‘Tl32 hr375 in high chemical, radiochemical, and radioisotopic purity and with high specific activity. The chemical 135 (2%) 7369—83(98%)0.07(5)[email protected](8%) purity demonstrated in Table 1 allows the material to be clinically suitable. The presence of <2 @gof 7.4hr45516%[email protected]'l(and'°'l)— carrier thallium in the entire product, which is in sured both by the reproducibility of the chemical fatty acids separation and by a spot test of the product, is 4,000 13 hr (25—28)159 83%(6)5110.01(6),(7) times less than the dose at which some toxic effects ‘1C-norepi first appear in humans and 100,000 times less than nephrine the lowest fatal dose (32). 20 mm (29) 200% The radioisotopic purity shown in Table 2 insures S (1) Efforts are underway in a number of laboratories to that the effects of high-energy photons and long-lived also utilize the 13-sec mmKr daughter of “Rbto measure regional myocardial blood flow. impurities are negligible. These would degrade the (2) This energy is undesirably low for in vivo visualiza image obtained and increase the patient radiation tion of the myocardium. (3) Contamination with long-lived 1MC5is a limiting fac dose. tor in the shelf-life and use of [email protected]@mCsbecause of the in creasingpatient radiation dosewith shelf-time.Chandra, et al ACKNOWLEDGMENTS also mention the suitability of °°‘Tlfor myocardial imaging. (4) This daughter of 25-day ‘°Sris under evaluation. Imag The authors gratefully acknowledge valuable conversa ing is difficult in the short time inerval between the time the blood pool is cleared of activity and the time the physi tions with P. V. Harper, H. W. Strauss, T. Budinger, J. Mc cal decay of °°Rbhas reduced its activity to an insufficient Alec, W. L. Ashburn, and R. A. Moyer. The authors also level. acknowledge the assistance of C. Baker and the staff of the (5) A good shelf-life is convenient as well as being in Brookhaven 60-in. cyclotron in carrying out the cyclotron valuable for availability in emergency use. Using the Anger camera and low-energy collimation, ‘°‘Tlshould give more irradiations. This work was supported by and performed un counts/whole-body radiation dose than any of the other der the auspices of the Atomic Energy Com potassiumanalogs (except for mRb,“NH,@),with at least as mission. good resolution. (6) Under evaluation. (7) A more complete discussion of Table 3 can be found REFERENCES in BNL 18943 (1974). 1. KAWANAM, Kiuzinc H, PORTERJ, Ct al: Use of “TI as a potassium analog in scanning. I Nuci Med 11: 333, 1970 2. GENRING PJ, HAMMOND PB : The interrelationship with a mixture of thallium (14) . If con between thallium and potassium in animals. I Pharmacol firmed, this removes the disadvantage (3) of potas Erp Ther55: 187—201,1967 sium from thallium. The ability to take many views 3. MULLINSU, MOORERD: The movement of thallium ions in muscle. I Gen Physiol 43 : 759—773,1960 may be crucial if it is necessary to view small infarcts 4. KORTUMFA, BocKius JO: Tertbook of Electrochem in profile in order to visualize them and delayed istry, vol 2, Amsterdam, Elsevier, 1951, p 701 scans may yield improved resolution. 5. RAYNAUDC, COMARD, BulssoN M, et al : Radioac

154 JOURNAL OF NUCLEAR MEDICINE 201TlFORMEDICALUSE.I tive thallium : A new agent for scans of the renal medulla. administration of cesium-131.Am Heart I 68: 627—636, In in Nephrology, Blaufox MD, Funck-Bren 1964 tano JL, eds, New York, Grune & Stratton, 1972, pp 289— 19. CHANDRA R, BRAUNSTEIN P, SmEuu F, et al : lMmCs, 294 a new myocardial imaging agent. I Nuci Med 14: 243—245, 6. Porrs AM, Au PC: Thallous ion and the eye.Invest 1973 Ophthal10:925—931,1971 20. YANO Y, ANGERHO: Visualization of heart and kid 7. [email protected] ND, SXLAROFFDM, GERSOHN-COHENJ, neys in animals with ultrashort-lived ‘@Rband the positron et al: Tumor scanning with radioactive 131-cesium. J Nucl scintillation camera. I Nucl Med 9 : 412—415,1968 Med 6: 300—306,1965 21. BUDINGERT: Private communication, 1974 8. [email protected] IPC, STEWARTRDH, INDYK JS: Thyroid 22. HURLEY PJ, COOPER M, REBA RC, et al: “KCl: A scanning with 131-Cs. Br Med I 4: 653—656,1970 new radiopharmaceutical for imaging the heart. J Nucl Med 9. NISHIYAMAH, SODDVJ, AUGUSTL, et al: Tumor 12: 516—619,1971 scanning agent: reappraisal of cesium, 129-CsCl. I Nucl 23. YANO Y, VAN DYIE D, BUDINGERTF, et al: Myo Med 14:635,1973 cardial uptake studies with “'Csand the scintillation cam 10. POE ND: Comparative myocardial uptake and clear era. I NuclMed 11: 663—668,1970 ance characteristics of potassium and cesium. I Nuci Med 24. FELLER PA, KEREIAKESJG : Dosimetry of “'Cs 13:557—560,1972 Further comments.Phys Med Biol 19: 220—221, 1973 11. Smuss HW, ZARET BL, MARTIN ND, et at: Non 25. EVANS JR, GUNTON RW, BAKER RG, et al : Use of invasive evaluation of regional myocardial perfusion with radioiodinated fatty acid for photoscans of the heart. Cir Potassium 43. Radiology 108: 85—90,1973 culationRes 16:1—10,1965 12. ZARET BL, STENSON RE, [email protected] ND, et al: Potas 26. GUNTON RW, EVANSJR, BAKERRG, et al: Demon sium-43 myocardial perfusion scanning for the noninvasive stration of myocardial infarction by photoscans of the heart evaluation of patients with false-positive exercise tests. Cir in man. Am I Cardiol 16: 482—487,1965 culation48:1234—1241,1973 27. BONTE FJ, GRAHAM KD, MOORE JG : Experimental 13. ROMHILT DW, ADOLPHRJ, Sooo VJ, et al: Cesium myocardial imaging with 131-I-labeled oleic acid. Radiology 129 myocardial to detect myocardial infarc 108:195—196,1973 tion.Circulation48: 1242—1251,1973 28. POEND, RoBINsONGD, MACDONALDNS: Myocar 14. HARPERPV, Private communication, 1972 dial extraction of variously labeled fatty acids and car 15. [email protected], ISHIHARAY, LYON LD, Ct al : Differences boxylates. I Nucl Med 14: 440, 1973 in the relationships between coronary blood flow and myo 29. ANSARIAN, ATKINS HL, CHRISTMANDR, et al: “C- cardial clearance of , rubidium and Norepinephrine as a potential myocardial scanning agent. cesium. Am. Heart I 76: 353—355,1968 JNuclMed 14:619,1973 16. HARPERPV, [email protected] J, MAYORGAA, et al: Demon 30. HOLMANBL, DEWANJEEMK, IDOINEJ, et al: De stration of myocardial ischemia in images produced with tection and localization of experimental myocardial infarc intravenous [email protected] Presented at the 20th Annual Meeting tion with °“'Tc-Tetracycline.I Nuci Med 14: 595—599,1973 of the Society of Nuclear Medicine, June 1973 31. BONTEFJ, PARKEYRW, [email protected], et al : A new 17. BUDINGERTF, YANOY, MCRAEJ: Rubidium-81 used method for radionuclide imaging of myocardial infarcts. as a myocardial agent. LBL-2157, 1973 Radiology 110: 473—474,1974 18. CARR EA, GLEASONG, SHAW J, et al: The direct 32. [email protected] CH, HALEY TJ: Clinical Toricology. Phila diagnosis of myocardial infarction by photoscanning after deiphia, Lea and Febiger, 1964, p 295

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