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 myocardial visualization, kidney studies, and tumordiagnosis because of its physical and biologic

properties. A method is described for preparation of this radiopharmaceutical for human use.A critical evaluation of 501T1 and other radiopharmaceuticals for myocardial visualization isgiven.

Thallium-20 1 is a potentially useful radioisotopefor various medical applications including myocardialvisualization and possible assessment of physiology,as a renal medullary imaging agent, and for tumordetection.

The use of radiothallium in nuclear medicine wasfirst suggested by Kawana, et al (1 ) . In terms oforgan distribution (2) and neurophysiologic function(3), thallium is biologically similar to potassium.

The physical—chemicalexplanation for the biologicsimilarity of @+and K@ is that the hydrated ionicradius of 11+ is between K+ and Rb+ in size andthis radius has been suggested as the property thatdetermines passive penetration through a membrane (4).

These facts suggest that radiothallium should bea good potassium analog and therefore has potentialfor myocardial visualization and the early detectionof areas of diminished perfusion and radionuclideuptake as “coldspots―(regions of decreased activity).

Presently used renal agents concentrate in thecortex; unlike these, thallium preferentially concentrates in the renal medulla (5) . This property maybe clinically useful.

The Tl@ is taken up more by tissues in pigmentedthan in albino rabbits, suggesting the use of radiothallium for the diagnosis of melanoma (6) . Becauseof the similarity of thallium to alkali metals such ascesium, which has been shown to concentrate in

tumors (7—9), the use of radiothallium should alsobe evaluated for this application.

Thallium-201 decays by electron capture with a73-hr half-life. It emits mercury K-x-rays of 69—83keY in 98% abundance plus gamma rays of I 35 and167 keV in 10% total abundance. Because of itsgood shelf-life, photon energies, and mode of decay,201T1was the radioisotope of thallium chosen fordevelopment.

MATERIALS AND METHODS

Thallium-201 is produced by irradiating a naturalthallium target in the external beam of the 60-in.Brookhaven cyclotron with 3 1-MeV protons. Thenuclear reaction is 203Tl(p,3n)201Pb. Lead-201 hasa half-life of 9.4 hr and is the parent of 201T1.Thethallium target, fabricated from an ingot of 99.999%pure natural thallium metal (29.5% isotopic abundance of 203Tl), is I .3 cm in diameter and weighs0.7 gm. The target thickness and incident protonbeam energy are chosen to minimize the productionof other radioisotopes of lead, which could lead toimpurities in the 2011'lproduct. After irradiation, thethallium target is dissolved in concentrated nitricacid, then evaporated to dryness. This salt is thendissolved in 50 ml of 0.025 M EDTA at pH 4 andpassed through a Bio-Rad Dowex 50 X 8 resin column (Nat form, 50—100mesh@2.5 X 6 cm) . Mostof the thallium target material adheres to the columnand the eluate contains radioactive 203Pband 201Pb.The eluate is acidified by adding an equal volume ofconc. HNO@and the thallium is oxidized by the addition of “Clorox.―Forty micrograms of Pb(N03)2carrier are added to the eluate and the solution ispassed through a Bio-Rad Dowex 1 X 8 resin column (H@ f@yrm,50—100mesh, 2.5 X 6 cm). Thal

Received June 10, 1974; revision accepted Sept. 23, 1974.For reprints contact: Elliot Lebowitz, Bldg. 801, Brook

haven National Laboratory, Upton, N.Y. 11973.

Volume 16, Number 2 151

THALLIUM-201 FOR MEDICAL USE. I

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TABLE1. CHEMICALANALYSISTHE 201TlPRODUCTOFQuantityQuantityElement(/Lg)Element(‘ug)TI<2Ni<2Ca60Al1B<2Mo0.2Mg1Cu6Mn<0.2Ag<0.2Si0.2Ti1Fe1V1

LEBOWITZ, GREENE, FAIRCHILD, BRADLEY-MOORE, ATKINS, ANSARI, RICHARDS, AND BELGRAVE

hum adheres to this column and the lead activitiesare eluted.

This eluate containing 203Pband 201Pbis allowedto stand overnight to permit the 201Pbto decay into201Tl It is then passed through another Bio-RadDowex 1 X 8 column to which the 2olTl+3 adheresand through which the lead activities are eluted. The201'fl activity is then eluted with 20 ml of hot hydrazine-sulfate solution (20% w/v) , reducing Tl@to Tl+l This TI +1 eluate is evaporated to drynesstwice with conc. HNO:4 and once with conc. HC1.The product is then dissolved in 5 ml of 10_i MNaOH and the pH is adjusted to 7 by further addition of NaOH. The product is sterilized by ifitrationinto a sterile multiinjection bottle through a 0.22-micron sterilized Millipore filter.

A Rhodamine B spot test is used to detect carrierthallium in the product before injection. The testcan detect 0.02 @gof thallium. The sample testedis typically 1% of the total product; thus a negativespot test insures that less than 2 @gof thallium ispresent in the product. A few weeks after the 20111is produced, a complete chemical analysis of theproduct is performed by emission spectroscopy.

The radiochemical purity of the product is checked

by paper chromatography to differentiate Tl@1 andTl@3.Whatman No. 3 MM paper and a solvent 1/10(Na2HPO., -5H20) and 9/ 10 (acetone) are used.The 11+1 stays at the origin. To demonstrate thatthe 20111is not in particulate form, the product ispassed through a 250 A filter.

Radionuclidic purity is analyzed by multichannelpulse-height analysis, utilizing a Ge(Li) detector.The gamma spectrum of the product is also followedfor approximately 1 week to confirm the half-lives ofthe product and impurity gamma rays.

Product batches are tested for pyrogenicity by an

8 MED RUN P12 SE000S

§

8

8

8

U,

z

LIR

a

a

8

82

FIG. 1.Ge(ti)spectrumof‘@TIproduct.

1______@

/

54.00 1ie4X@ i@.m 25S.@ @O.OO @4.OO I@.OO 532.00@ 640.00 7OS.@CHANNEL NUFIOER

‘N.m eà.m s@.a, %O.OO@

152 JOURNAL OF NUCLEAR MEDICINE

so'

135isV

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TABLE 2. RADIOISOTOPIC ANALYSIS OF 201Tl PRODUCT

At time ofpreparation 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 10@ 1.1 X 10'‘@Tl 12.2 days 1.2 X 10' 1.4 X 101 2.0 X 10T' 3.4 X 101

201T1FORMEDICALUSE.

independent laboratory. All glassware is renderedapyrogenic by autoclaving at 180°Cfor 3 hr.

Measurements of the excitation function (the production cross section as a function of energy) areperformed by irradiating a stack of thin (approximately 0.2 gm/cm2) foils of thallium and analyzingthe activities produced with a Ge(Li) detector. Lead201 is determined by analysis of its 331-keV photon,which is present in 82% abundance.

RESULTS

Emission spectroscopic chemical analysis of anentire product batch is shown in Table 1. Figure 1shows the Ge(Li) spectrum of the product, the mainpeaks being the x-rays and photons of 20111.Theradioisotopic purity is @99%, as is shown in Table2. The product is at neutral pH, isotonic, sterile, andpyrogen-free.

The excitation function for the production of201Pb,the parent of 20111,is seen in Fig. 2. By choosing an energy range near the peak of the excitationfunction, the production of 200Pb and 202Pb (theparents of 200'fl and 202Tl) radiocontaminants isminimized. With a natural thallium target, the production rate of 20111is 0.7 mCi/@AH or correspondingly higher with an enriched 20311target. The mitial development work is being done on the Brookhaven 60-in. cyclotron but it should be possible toevaluate the production capability of 20111 in theBLIP (Brookhaven Linac Isotope Producer) usingthe 205Tl(p,5n)201Pb reaction.

DISCUSSION

Using the myocardial uptake of the analogs ofpotassium, there are several alternatives for myocardial visualization including the radioisotopes ofpotassium, cesium, thallium, rubidium, and I3NH,+.We start by comparing the biologic behavior of K@and Cs@ (10) . Potassium is more rapidly clearedfrom the blood and extracted by the myocardiumthan is cesium. Potassium is extracted by the myocardium with 7 1% efficiency on a single circulationcompared with 22% efficiency for cesium. Followingits extraction, potassium is cleared more rapidly from

I I I

-aE

b

1000 r

500

0010 20 30 40

E ( MeV)

FIG.2.‘°‘TI(p,3n)'°@Pbexcitationfunction.

the heart. Although the radioisotopes of potassiumand cesium can both be used for myocardial visualization, their differences in biologic behavior are reflected in their clinical usefulness.

Advantages of potassium over cesium. First, because of its more efficient myocardial uptake andlack of recirculation, K+ is superior for quantitativestudies following intracoronary arterial injection(10) . Second, because of its rapid blood clearanceand myocardial extraction, K+ can be used in theassessment of patients with transient myocardial ischemia (e.g., angina pectoris) by visualizing the myocardium before and after stress (11,12).

Disadvantage of potassium. The rapid leakage ofpotassium from the myocardium constitutes a disadvantage due to the inability to visualize the myocardium with potassium after the first hour postinjection (1 1 ), compared with the ability to usecesium for this purpose for several hours (10,13).

Since Tl+ is a good biologic analog of potassium,it should have the biologic advantages of K@ listedearlier. Furthermore, Harper has observed that thethallium activity remained in the myocardium even18 hr postinjection in the one patient they scanned

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Radionuclideand half-lifePhoton

energy(keV) and

abundanceWhole-body

radiationdose

(md/mCi)Comments'‘@NHa@(l6)

10mm

“Rb(17)43 hr511

200%0.005511

67%0.10(1)‘@Cs

(18)9.7 days2988%0.21(2)‘@‘mCs

(19)2.9 hr—1-;814%0.24(3)“Rb

(20,21)75 sec511192%@O.001(4)‘3K

(22)22 hr380103°!.0.7@Cs

(23,24)32 hr37545%0.17°°‘Tl

73 hr167(8%)135 (2%)

69—83(98%)0.07(5)19S@l

7.4hr45516%0.046@2'l(and'°'l)—

fatty acids13 hr (25—28)159 83%(6)5110.01(6),(7)

LEBOWITZ, GREENE, FAIRCHILD, BRADLEY-MOORE, A1KINS, ANSARI, RICHARDS, AND BELGRAVE

Rubidium is a good analog of potassium (15)and it is expected to be almost as good an analogas thallium since the hydrated ionic radius of thaihum is between potassium and rubidium.

The metabolic behavior of 13@}j is sufficientlycomplex so that diagnosis with it has been difficulttodate(16).

Table 3 compares radioisotopes for myocardialvisualization. An important new development is theuse of O9mTc..g,@omplexesfor visualization of necrotictissue as a “hotspot―(region of increased uptake)(30,31 ) . The combined use of 201Tl and an agentsuch as 99mTc..tetracycline may greatly enhance thevalue of cardiac diagnosis by nuclear medical techniques. Thallium-201 might demonstrate the sizeand location of regions of ischemia and necrosiswhereas 99mTc.tetracycline might perform the differential diagnosis between ischemic and necrotic regions by demonstrating only regions that are necrotic.

As is essential, our production method yields 20111in high chemical, radiochemical, and radioisotopicpurity and with high specific activity. The chemicalpurity demonstrated in Table 1 allows the materialto be clinically suitable. The presence of <2 @gofcarrier thallium in the entire product, which is insured both by the reproducibility of the chemicalseparation and by a spot test of the product, is 4,000times less than the dose at which some toxic effectsfirst appear in humans and 100,000 times less thanthe lowest fatal dose (32).

The radioisotopic purity shown in Table 2 insuresthat the effects of high-energy photons and long-livedimpurities are negligible. These would degrade theimage obtained and increase the patient radiationdose.

ACKNOWLEDGMENTS

The authors gratefully acknowledge valuable conversations with P. V. Harper, H. W. Strauss, T. Budinger, J. McAlec, W. L. Ashburn, and R. A. Moyer. The authors alsoacknowledge the assistance of C. Baker and the staff of theBrookhaven 60-in. cyclotron in carrying out the cyclotronirradiations. This work was supported by and performed under the auspices of the United States Atomic Energy Commission.

REFERENCES

1. KAWANAM, Kiuzinc H, PORTERJ, Ct al: Use of “TIas a potassium analog in scanning. I Nuci Med 11: 333,1970

2. GENRING PJ, HAMMOND PB : The interrelationshipbetween thallium and potassium in animals. I PharmacolErp Ther55:187—201,1967

3. MULLINSU, MOORERD: The movement of thalliumions in muscle. I Gen Physiol 43 : 759—773,1960

4. KORTUMFA, BocKius JO: Tertbook of Electrochemistry, vol 2, Amsterdam, Elsevier, 1951, p 701

5. RAYNAUDC, COMARD, BulssoN M, et al : Radioac

TABLE 3. RADIOISOTOPES FORMYOCARDIAL VISUALIZATION

‘1C-norepinephrine

20 mm (29) 200%

S (1) Efforts are underway in a number of laboratories to

also utilize the 13-sec mmKr daughter of “Rbto measureregional myocardial blood flow.

(2) This energy is undesirably low for in vivo visualization of the myocardium.

(3) Contamination with long-lived 1MC5is a limiting factor in the shelf-life and use of l@@mCsbecause of the increasingpatient radiation dosewith shelf-time.Chandra, et alalso mention the suitability of °°‘Tlfor myocardial imaging.

(4) This daughter of 25-day ‘°Sris under evaluation. Imaging is difficult in the short time inerval between the timethe blood pool is cleared of activity and the time the physical decay of °°Rbhas reduced its activity to an insufficientlevel.

(5) A good shelf-life is convenient as well as being invaluable for availability in emergency use. Using the Angercamera and low-energy collimation, ‘°‘Tlshould give morecounts/whole-body radiation dose than any of the otherpotassiumanalogs (except for mRb,“NH,@),with at least asgood resolution.

(6) Under evaluation.(7) A more complete discussion of Table 3 can be found

in BNL 18943 (1974).

with a mixture of thallium isotopes (14) . If confirmed, this removes the disadvantage (3) of potassium from thallium. The ability to take many viewsmay be crucial if it is necessary to view small infarctsin profile in order to visualize them and delayedscans may yield improved resolution.

154 JOURNAL OF NUCLEAR MEDICINE

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201TlFORMEDICALUSE.I

administration of cesium-131.Am Heart I 68: 627—636,1964

19. CHANDRA R, BRAUNSTEIN P, SmEuu F, et al : lMmCs,a new myocardial imaging agent. I Nuci Med 14: 243—245,1973

20. YANO Y, ANGERHO: Visualization of heart and kidneys in animals with ultrashort-lived ‘@Rband the positronscintillation camera. I Nucl Med 9 : 412—415,1968

21. BUDINGERT: Private communication, 197422. HURLEY PJ, COOPER M, REBA RC, et al: “KCl: A

new radiopharmaceutical for imaging the heart. J Nucl Med12: 516—619,1971

23. YANO Y, VAN DYIE D, BUDINGERTF, et al: Myocardial uptake studies with “'Csand the scintillation camera. I NuclMed 11: 663—668,1970

24. FELLER PA, KEREIAKESJG : Dosimetry of “'CsFurther comments.Phys Med Biol 19: 220—221, 1973

25. EVANS JR, GUNTON RW, BAKER RG, et al : Use ofradioiodinated fatty acid for photoscans of the heart. CirculationRes 16:1—10,1965

26. GUNTON RW, EVANSJR, BAKERRG, et al: Demonstration of myocardial infarction by photoscans of the heartin man. Am I Cardiol 16: 482—487,1965

27. BONTE FJ, GRAHAM KD, MOORE JG : Experimentalmyocardial imaging with 131-I-labeled oleic acid. Radiology108:195—196,1973

28. POEND, RoBINsONGD, MACDONALDNS: Myocardial extraction of variously labeled fatty acids and carboxylates. I Nucl Med 14: 440, 1973

29. ANSARIAN, ATKINS HL, CHRISTMANDR, et al: “C-Norepinephrine as a potential myocardial scanning agent.JNuclMed 14:619,1973

30. HOLMANBL, DEWANJEEMK, IDOINEJ, et al: Detection and localization of experimental myocardial infarction with °“'Tc-Tetracycline.I Nuci Med 14: 595—599,1973

31. BONTEFJ, PARKEYRW, GIt@uAMKD, et al : A newmethod for radionuclide imaging of myocardial infarcts.Radiology 110: 473—474,1974

32. Thn-@ CH, HALEY TJ: Clinical Toricology. Philadeiphia, Lea and Febiger, 1964, p 295

tive thallium : A new agent for scans of the renal medulla.In Radionuclides in Nephrology, Blaufox MD, Funck-Brentano JL, eds, New York, Grune & Stratton, 1972, pp 289—294

6. Porrs AM, Au PC: Thallous ion and the eye. InvestOphthal10:925—931,1971

7. Cn@Kr.s ND, SXLAROFFDM, GERSOHN-COHENJ,et al: Tumor scanning with radioactive 131-cesium. J NuclMed 6: 300—306,1965

8. Muiu@tv IPC, STEWARTRDH, INDYK JS: Thyroidscanning with 131-Cs. Br Med I 4: 653—656,1970

9. NISHIYAMAH, SODDVJ, AUGUSTL, et al: Tumorscanning agent: reappraisal of cesium, 129-CsCl. I NuclMed 14:635,1973

10. POE ND: Comparative myocardial uptake and clearance characteristics of potassium and cesium. I Nuci Med13:557—560,1972

11. Smuss HW, ZARET BL, MARTIN ND, et at: Noninvasive evaluation of regional myocardial perfusion withPotassium 43. Radiology 108: 85—90,1973

12. ZARET BL, STENSON RE, MA@RTtN ND, et al: Potas

sium-43 myocardial perfusion scanning for the noninvasiveevaluation of patients with false-positive exercise tests. Circulation48:1234—1241,1973

13. ROMHILT DW, ADOLPHRJ, Sooo VJ, et al: Cesium129 myocardial scintigraphy to detect myocardial infarction.Circulation48: 1242—1251,1973

14. HARPERPV, Private communication, 197215. Lovi@WD, ISHIHARAY, LYON LD, Ct al : Differences

in the relationships between coronary blood flow and myocardial clearance of isotopes of potassium, rubidium andcesium. Am. Heart I 76: 353—355,1968

16. HARPERPV, AL-S@m J, MAYORGAA, et al: Demonstration of myocardial ischemia in images produced withintravenous 13-NH@. Presented at the 20th Annual Meetingof the Society of Nuclear Medicine, June 1973

17. BUDINGERTF, YANO Y, MCRAEJ: Rubidium-81 usedas a myocardial agent. LBL-2157, 1973

18. CARR EA, GLEASONG, SHAW J, et al: The directdiagnosis of myocardial infarction by photoscanning after

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1975;16:151-155.J Nucl Med.   E. Lebowitz, M. W. Greene, R. Fairchild, P. R. Bradley-Moore, H. L. Atkins, A. N. Ansari, P. Richards and E. Belgrave  Thallium-201 for Medical Use. I

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