Tantalum-183: Cyclotron production of a neutron-rich biomedical tracer

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Appl. Radiat. lsot. Vol. 47, No. 2, pp. 171-174, 1996 Copyright© 1996ElsevierScienceLid Printed in Great Britain. All rights reserved 0969-8043/96 $15.00+0.00

Tantalum- 183: Cyclotron Production of a Neutron-Rich Biomedical Tracer NORIKO

S H I G E T A 1., R I C H A R D M. L A M B R E C H T I t , H. M A T S U O K A l, A. O S A 1, M. K O I Z U M P , K. K O B A Y A S H I 2, M. I Z U M O 2, K. H A S H I M O T O 2 and T. S E K I N E '

tTakasaki Radiation Chemistry Research Establishment, 1233 Watanuki, Takasaki 370-12, Japan 2Department of Radioisotopes, Japan Atomic Energy Research Institute, Tokai-mura, Naka-gun, Ibaraki-ken 319-11, Japan (Received I1 May 1995) No-carrier-added tantalum-183 was produced free of radiotantalum impurities by the ~s6W(p,~t)~S3Ta nuclear reaction using 13.6 MeV protons on thick targets of isotopically enriched ~S6WO3. The proton energy was optimum for the simultaneous production of ~S6Reand 'S3Ta. The ALICE code was used to theoretically determine the optimum irradiation conditions for the production of ~SYrawith proton and deuteron nuclear reactions. A Bio-imaging analyser was used to illustrate the migration of ~S3Taspecies into a grass plant (Cyperus microiria steud), tS3Tahas potential applications as a tracer for ¢cotoxicity studies, and for developmental studies for radiotantalum pharmaceuticals.

Introduction Neutron-rich radionuclides suitable for radiotherapeutic pharmaceuticals such as IS6Re, ~66Ho, 153Smand mAg are produced in a nuclear reactor. We are interested to explore the feasibility of cyclotron production of carrier-free neutron-rich radionuclides suitable for therapeutic nuclear oncology. Earlier work from this laboratory (Shigeta et al., 1994) illustrated that no-carrier added teRe can be produced using the Is6W(p,n)n6Re nuclear reaction on highly isotopically enriched n6W. We now report that the neutron-rich radionuclide lS3Ta can be simultaneously produced with l~Re by the nWC(p,a)n3Ta nuclear reaction. There is potential interest in using a carrier-free radiotracer of Ta in order to do ecotoxicity studies, or pharmacokinetic studies of Ta. Earlier work (Beililes, 1979) has suggested the use of radiotherapeutic treatment of bladder cancer with reactorproduced radiotantalum. The l~sW (h/2=21.6 days)/tT~ra (tl/2--9.3 min) has been proposed for heart blood flow studies (Neirinckx et al., 1978a). Limited biodistribution studies of the raTa generator

*Author for correspondence. tPartieipant from the Department of Chemistry, University of Wollongong, Australia in the Foreign Researcher Inviting Program, JAERI Officeof International Affairs. Pre~nt address: Eberhard--Karls---Universitfit Tfibingen, PET--Zentrum des Universiffitsklinkum, 15 R6ntgenweg, 72076 Tfibingen, Germany.

eluent of 0.1-0.03 N HCI were reported (Wilson et al., 1987) in rabbits, dogs and mice. There is controversy concerning the chemical form(s) of the radiotantalum species in 0.1-0.03 N HCI. Medical imaging and dosimetry estimates were determined in dogs, monkeys and humans (Lacy et al., 1988; Verani et al., 1992). The time course was limited to ~ 100rain after intravenous injection due to the 9.3 min half-life of 'TSTa. This led to the assumption (Lacy et al., 1988) that the Ta species is uniformly distributed in the blood pool and eliminated by a single excretion route via the urine. However, the human toxicity and pharmacodynamics of Ta are poorly documented (deMeester, 1988). The longer-lived raTa radionuclide offers considerable advantages as a biomedical tracer. ~83Ta has suitable nuclear decay properties with a half-life of 5.1 days; and decay by fl-radiation (EM~ = 0.61 MeV, >95%) with accompanying y-radiation at 246keV (27%), 353 keV (11.7%), and 108 keV (11.9%). Earlier studies of the nuclear decay scheme of ~S3Tabased on the 'SlTa(n,~,)mTa(n,y)mTa double neutron capture reaction resulted in low specific activity ~S3Ta which is not suitable for biomedical studies due to the long-lived (t,/2 = 114.4 days) radiocontaminant of 82Ta"

Experimental Isotopically enriched Is6W (99.79%) was obtained from Isotec, U.S.A. The 186WO3 was pressed into a

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172

pellet (o.d. = 10 or 13 mm) at 680 k g / c r n 2, then baked in air at 900°C for 24 h. Gamma spectrometry measurements were made with a Ge detector (34.7%) having a resolution of 0.7keV for 122keV and a SEIKO EG&G Model 7800 MCA. Peak analysis was done using SEIKO MCA emulation software. Energy and efficiency calibration was made with calibrated standards sources (errors < 3%) obtained from JAERI, Tokaimura. Liquid samples were counted at calibrated counting distances from the Ge detector, and could be regarded as a point source. Relevant nuclear data were used (Lederer and Shirley, 1978). A FUJIX Bio-imaging Analyser, BAS 2000 was used to image and measure sub-Bq amounts of ~S3Ta in a specimen. The base of a blade of freshly cut native grass (Cyperus microiria steud) was placed for 3 h in a 10 mL solution (1.8 k Bq) of the ~S3Ta species as eluted from the anion exchange column with 0.5 M NaOH + 0.5 M NaC1. The BAS plates were exposed for 3 days. Results and Discussion Theoretical

The ALICE code (Blann and Bisplinghoff, 1975) was used without incorporating precompound nucleon emission to estimate the features of the lsrW(p,ct)~SJTa excitation function. The calculations predicted a rather flat maximum cross section of ~0.02 mb for 13-18 MeV protons. See Fig. 1. The excitation function of the ls6W(p,n~t)'Srl'a nuclear reaction was also calculated. The theoretical data indicate that the incident proton energy should be < 14 MeV to maximise the yield of ~SJTa, and to assure that lS2Ta (t~/2= 115 days) was not produced as a radionuclidic impurity. ALICE code calculations of the excitation functions of ls6W(d,n~@S3Ta and the ls6W(d,2n~t)tS2Ta . . . .

I

. . . . . . . . .

I

. . . . . .

SI86W(p,a)tS3Ta 100

.o

&186W(p,n a)lS2Ta

10_2

ALICE-code calculation d+186W I

I

I

(d,2n ~z)182Ta

100

-~10 -1 co

(d,na)

(13

m 10-2 e

10-3 10

20 Energy/MeV

30

Fig. 2. ALICE code calculations of the excitation functions of the tsrW(d,nc@S3Ta and the tsrW(d,2n~t)tS2Ta nuclear reactions. nuclear reactions indicated little advantage over proton activation for the production of no-carrier-added lS3Ta (Fig. 2). Production

A water-cooled A1 target block and a He-cooled A1 window was used for the irradiations with ~ 1 to ~5 #A beams of the TIARA cyclotron. A uniform beam of ~ 8 mm diameter was used for all irradiations with the proton beam degraded by AI absorbers from 20 to 13.6 MeV, under conditions that optimize the radionuclidic purity of ~S6Re (Shigeta et al., 1995). The thick target yield of ~g3Ta was ~0.1% of the thick target yield of ~SrRe under the production conditions tested. After the irradiation the ~srWO3 target was dissolved in 1 M NaOH. Proton activation of 186W results in co-production of ~83Ta and lS6Re, while an impurity of ~s7W results from neutron activation of the target (Shigeta et al., 1994). The ~83Taand lsTW were separated from ~SrRe by anion exchange chromatography using DIAION SA 100 (100-200 mesh) and an eluent of 0.5 M NaOH-0.5 M NaC1 (Shigeta et al., 1995). The radiochemical yield of 183Ta after separation of the 'SrRe radionuclide from the lSrW target ranged from 90 to 95%. The '83Ta was assayed after the ~sTWhad decayed. The t83Ta could be separated from W with the highly selective chromatographic separation

.o 10-4

10 .... ~ gO. . . . . . Energy/MeV Fig. 1. ALICE code calculation of the excitation functions of the '~W(p#)lS~ra and the I~W(p,n~)m2Ta nuclear reactions.

Table 1. Production of ~S3Ta by 13.6 MeV proton irradiation of ~86WO3 Target (mg/cm2) 729 550 735 648

Beam current ~ A) 1 0.9 3 3.5

Tirnadiatit~n (h)

9.8 9.7 5 3

Production rate (Bq/g Ah) 3.15 x 9.98 × 5.73 × 2.35 x

102 102 101 102

Yield (lkl) 3.09 8.72 8.6 3.2

× x x x

103 103 102 103

Fig. 3. Image of the bio-distribution of lS3Ta species into a blade of grass (Cyperus microiria steud).

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Noriko Shigeta et al.

utilized for the 17sw/178Ta generator, i.e. with AGI-X8, CI form, (200-400 mesh) and an eluent of 0.03 N HCI, 0.1% H202 (Lacy et al., 1988). The thick target production yields were determined at 13.6_ 0.15 MeV using 186WO3 targets of 550-729 mg/cm 2 to give resultant yields of I83Ta of 516 + 342 Bq/#Ah. See Table 1. No radiotantalum impurities were detected during 4 irradiations of 8.7-15#Ah. It is presently not permitted to scaleup production at the TIARA cyclotron as it is a multi-purpose, multi-user facility. The experimental variation in ~83Ta yields is probably due to uncertainty in the measurement of the proton fluxes since a monitor nuclear reaction was not used during the radioisotope production runs; variations in energy spread of 0.5% FWHM in the incident 20 MeV beam energy and the degradation of beam in the Ai absorbers. There was a 5% variation in the separation yields. The ALICE code calculations (Fig. 1) suggest a factor of 2 in cross-section is possible over 0.2 MeV in the chosen irradiation conditions. Tracer study

An example of the applicability of the tracer for environmental studies is illustrated in Fig. 3. The Bio-imaging analyser is just as applicable for the measurement of 183Ta in biological tissues.

Conclusion The larger scale production of lS3Ta on a compact cyclotron using a 300-3000 p A proton beam seems feasible due to the high melting point of the tungsten oxide (1473°C) and tungsten metal (3410°C) target. The production yield could be enhanced by a factor of ~ 1.6 by use of ~86W metal rather than ls6WO3 targets. Recent advances in the ion sources for the IBA compact cyclotron indicate beam currents of up to 3 mA are attainable, so larger quantities of lS3Ta may be produced in the future*. This work is the first report that #Ci amounts of carrier-free lS3Ta can be produced for biomedical research studies. The availability of carrier-free J83Ta may promote the further development of the 17SW/178Ta generator (Zaitseva et al., 1994) and ~TSTa radiopharmaceuticals

*A referee suggested consideration of the 183W(n,p)lS3Ta reaction as an alternate method to produce no-carrieradded ~S3Ta, since neutron fluxes of 10~4n'cm-2-s are attainable at several nuclear reactors. The fission spectrum cross section is very low, 0.003 mb.

(Neirinckx et al., 1978b). ~83Tais particularly suited to laboratory studies where the 5-day half-life of the tracer allows for detailed measurements of the chemical states of the Ta species, and the biological behaviour of tantalum.

References Beililes R. P. (1979) In Toxicity of Heavy Metals in the Environment, Part 2 (Oehme F. W., Ed.) p. 567. Marcel Decker, New York. Blann M. and Bisplinghoff J. (1975) Code ALICE. Lawrence Livermore National Laboratory Report COO3494 27. Holman B. L., Harris G. L. and Neirinckx R. D. (1978) Tantalum-178--A short lived nuclide for nuclear medicine. J. Nucl. Med. 19, 510-513. Lacy J. L., Ball M. E., Verani M. S., Wiles H. B., Babich J. W., LeBlanc A. D., Stabin M., Bolomey L. and Roberts R. (1988) An improved tungsten-178/tantalum-178 generator system for high volume clinical applications. J. Nucl. Med. 29, 1526 1538. Lederer C. M. and Shirley V. S. (Eds) (1978) Table of Isotopes (7th edn). Wiley, New York. de Meester C. (1988) Tantalum. In Handbook on Toxicity of Inorganic Compounds (Seiler H. G., Sigel H. and SigelA., Eds). Dekker, Basel. Neirinckx R. D., Jones A. G., Davis M. A., Harris G. I. and Holman B. L. (1978a) Tantalum-178--a short-lived nuclide for nuclear medicine: development of a potential generator system. J. Nucl. Med. 19, 514-519. Neirinckx R. D., Holman B. L., Davis M. A. and Zimmerman R. E. (1978b) Tantalum-178 labeled agents for lung and liver imaging. J. Nucl. Med. 20, 1176-1180. Shigeta N., Matsuoka H., Osa A., Koizumi M., Kobayashi K., Izumo M., Hashimoto K. and Sekine T. (1994) JAERI TIARA. Annual Report 1993. Shigeta N., Matsuoka H., Osa A., Koizumi M., Izumo M., Kobayashi K., Hashimoto K., Sekine T. and Lambrecht R. M. (1995) Production method of no-carrier-added 186Re. J. Radioanal. Nucl. Chem. (in press). Verani M. S., Guidry G. W., Mahmarian J. J., Nishimura S., Athanasoulis T., Roberts R. and Lacy J. L. (1992) Effects of acute, transient coronary occlusion on global and regional right ventricular function in humans. J. Amer. Coil. Cardiol. 20, 1490-1497. Wilson R. A., Kopiwoda S. Y., Callahan R. J., Moore R. H. and Boucher C. A. (1987) Biodistribution of tantalum178: a short-lived radiopharmaceutical for blood pool imaging. Eur. J. Nucl. Med. 13, 82-85. Zaitseva N. G., Rurarz E., Khalkin V. A., Stegailov V. I. and Popinenkova L. M. (1994) Excitation function for ~78W production in the ~8~Ta(p,4n)~TaWreaction over proton energy range 28.8-71.8 MeV. Radiochimica Acta 64, 1-6.