Production of no-carrier-added 186Re via deuteron inducedreactions on isotopically enriched 186W

Xiaodong Zhanga,*, Qingnuan Lia, Wenxin Lia, Rong Shengb, Shuifa Shena

aShanghai Institute of Nuclear Research, The Chinese Academy of Sciences, P.O. Box 800-204, Shanghai 201800,

People's Republic of ChinabZhejiang Medical University Pharmacy Department, Zhejiang 310031, People's Republic of China

Received 23 July 1999; accepted 28 February 2000

Abstract

Rhenium-186 was produced from the reaction induced by 16 MeV deuterons on isotopically enriched 186W metalpowder target. Following its separation from 187W, 183Ta and the bulk of target materials 186W through an acidalumina column, the 186Re was converted to HNO3 solution through an anion exchange column, or to ammoniasolution by extracting with N-235-dimethylbenzene, and ®nally the no-carrier-added 186Re saline solution was

obtained. The radionuclidic purity of 186Re was >99.9% and the isotopic impurities were mainly 183Re (5.0 �10ÿ3%) and 184gRe (4.6� 10ÿ2%). The experimental thick-target yield of 186Re was determined to be approximately529 mCi/mA h and the overall chemical recovery yield was >80%. 7 2000 Elsevier Science Ltd. All rights reserved.

1. Introduction

Rhenium-186 (T1/2 = 90.64 h, Ebmax=1.07 MeV,Eg=137 keV (9.2% abundance)) is regarded very suit-

able for radiolabelling monoclonal antibodies and forvarious other therapeutic applications, because of its

emission of an energetic bÿ and its 90.64 h half-life.The half-life is just compatible with the pharmacoki-netics of tumor localization and clearance of mono-

clonal antibodies (Breitz et al., 1992). However, highspeci®c activity 186Re is usually required for radiolabel-ling antibodies. Unfortunately, only 186Re with med-

ium speci®c activity can be produced from the 185Re(n,g)186Re reaction in most released nuclear reactors. In

order to radiolabel antibodies more e�ciently with186Re, production of no-carrier-added 186Re using acyclotron is an important possibility.

There are two possible routes for the production of

no-carrier-added 186Re, namely 186W( p,n ) 186Re and186W(d,2n ) 186Re reactions. The ®rst route was

reported in 1996 for the ®rst time (Shigeta et al.,

1996). In that work, the excitation function for the186W( p,n ) 186Re reaction was measured and no-car-

rier-added 186Re was prepared by using a scheme

based on a single DIAION SA100 anion exchange col-

umn separation step. The maximum value and its pos-

ition of the cross section were reported to be 128 mb

and at 9.59 MeV, respectively. However, the exper-

imental thick target yield was not reported. Recently,

we have measured the excitation functions for thenatW( p,xn )181±186Re reactions, and also obtained no-

carrier-added 186Re via the 186W( p,n )186Re reaction

(Zhang et al., 1999). Compared with the results of Shi-

geta et al. (1996), the maximum value of the cross sec-

tion for the 186W( p,n )186Re reaction was 42 mb, i.e.,

only about one-third of the reported value. The reason

for this large discrepancy is not known. However, the

Applied Radiation and Isotopes 54 (2001) 89±92

0969-8043/00/$ - see front matter 7 2000 Elsevier Science Ltd. All rights reserved.

PII: S0969-8043(00 )00268-2

www.elsevier.com/locate/apradiso

* Corresponding author.

thick target yield of 50 mCi/mA h, determined exper-imentally in our work, is in agreement with the calcu-

lations based on the excitation function we havemeasured. In addition, a radiochemical separationscheme consisting of an acid alumina column followed

by an anion exchange column, was used and a betterseparation was obtained.Because of the low cross section for the

186W( p,n )186Re reaction, it is di�cult to produce highenough levels of no-carrier-added 186Re for medicalapplication using a common cyclotron. In this case,

the second route, namely 186W(d,2n )186Re reactionseems more favorable due to its larger cross section ifthe deuteron beams are available. Although there arequite large discrepancies between the cross sections for

the 186W(d,2n )186Re reaction measured by two di�er-ent research groups (Nassi� and MuÈ nzel, 1973; Pementand Wolke, 1966), the maximum cross section value is

at least three times of that measured by Shigeta et al.(1996) and about decuple of that measured by Zhanget al. (1999) for the 186W( p,n )186Re reaction.

In order to explore the feasibility of producing 186Revia the 186W(d,2n ) 186Re reaction for medical use, inthis paper isotopically enriched 186W targets were irra-

diated by 16 MeV deuterons. Following the separationfrom 187W, 183Ta and a block of target materials 186Wthrough an alumina column, 186Re was converted tobe in vaporizable solution through two kinds of

methods Ð the elution from an anion exchange col-umn and a solvent extraction with N-235-dimethylben-zene. These two methods were evaluated for the

conversion e�ect. We have demonstrated for the ®rsttime, that no-carrier-added 186Re can be produced viathe 186W(d,2n ) 186Re reaction.

2. Experimental

2.1. Target and irradiations

Isotopically enriched W (98.85% 186W metal pow-der, Teknowledge, Sweden) was pressed into a groovedaluminum holder to form a 10-mm diameter pellet

with a surface density of 336 mg/cm2. The aluminumholder was covered with a 9.43 mg/cm2 thick copperfoil, used as a beam monitor, and was then ®xed onthe target block cooled by running water. The ir-

radiation was carried out with 16 MeV deuteron beamdelivered from a 1.5-m diameter cyclotron at ShanghaiInstitute of Nuclear Research. The energy window for

the 186W( p,2n ) 186Re reaction was calculated by theRange-energy Table (Ziegler et al., 1985) to be 15.246 MeV, due to the energy loss in a Havor membrane

and the copper foil. The 65Cu( p,n ) 65Zn reaction wasused for monitoring the integrated beam current, withthe cross section for the reaction taken as 250 mb (Ful-

mer and Williams, 1970). The irradiations lasted forabout 2 h. After the irradiations, the target assembly

was left to cool for about 24 h to allow the decay ofshort-lived radioisotopes.

2.2. Radiochemical separation

The separation scheme reported in detail in Zhanget al. (1999) was used to separate 186Re from irradiated

tungsten target. Moreover, a new liquid±liquid extrac-tion method was attempted as an alternative of theanion exchange separation method. The radiochemical

processing of the irradiated target is discussed brie¯yas follows.The irradiated 186W metal target was dissolved in

30% H2O2 and 1 mol/l NaOH with heating. After ®l-

tration, the solution was adjusted to pH = 3±4 with 4mol/l HCl and loaded on an acid alumina column(100±150 mesh, f 0.78 � 7.5 cm). Then 186Re was

eluted with saline from the column. The 187W, 183Ta aswell as the target materials were eluted subsequentlywith 0.5 mol/l NaOH. In order to obtain high speci®c

volume activity of no-carrier-added 186Re saline sol-ution, the 186Re solution eluted from the alumina col-umn must be converted to vaporizable or dissolvable

solution for which two methods were evaluated. In the®rst method, the 186Re solution was loaded directlyonto a Dowex-1 anion exchange resin column (100±200 mesh, f 0.3� 2.4 cm) (Zhang et al., 1999) and was

then eluted with 7.2 mol/l HNO3 solution. In the sec-ond method, a liquid±liquid extraction approach wasemployed. After acidi®cation with HCl to [H+] 1 0.2

mol/l, the 186Re solution was extracted twice with 4 mlvolumes of N-235-dimethylbenzene (v/v = 1/9), andthen the 186Re was back-extracted three times with 3

ml 13 mol/l ammonia. The 186Re solution, resultingfrom the back-extractions, was washed with ether.Finally, the 186Re solution in ammonia was obtained.The solution of 186Re in HNO3 reagent, obtained from

the anion column and the solution of 186Re in ammo-nia, was evaporated to dryness and dissolved in water.This step was repeated until the pH 1 7 was obtained.

The resulting 186Re solution was heated to drynessagain, and then dissolved in a small volume of saline,which is suitable for the radiolabelling experiment.

Prior to each step, small aliquots were taken fromthe 186Re solution to be separated, to monitor thechemical yield of the separation. Radioactivity of the

samples was measured by a calibrated HPGe g-raydetector coupled to CANBERRA S80 multichannelanalyzer.

3. Results and discussion

The elution curves through the acid alumina col-

X. Zhang et al. / Applied Radiation and Isotopes 54 (2001) 89±9290

umn are shown in Fig. 1. Satisfactory separation of186Re from the 186W target material as well as 187W

and 183Ta was achieved. The latter two radionuclides,

that is, 187W and 183Ta, were produced via the186W(d,p ) 187W reaction and 186W (d, an) 183Ta or186W(d,2p3n ) 183Ta reactions, respectively. Chemical

yields of >96% were achieved in a volume of about

10 ml of the 186Re eluate. The decontamination factors

were >3.0 � 104 for 187W and >3.2 � 102 for 183Ta,

respectively. The recovery of enriched 186W was suc-

cessful with a yield of >90% in 20 ml eluate, when

the column was eluted sequentially with 0.5 mol/l

NaOH solution.

About 10 ml of 186Re eluate could be converted to

a volume of 2 ml in 7.2 mol/l HNO3 solution via use

of the anion exchange column with a recovery of

about 94%. In the evaporation step, the loss of activity

was observed to be about 5% and the overall recovery

of 186Re was approximately 85%.

In the liquid±liquid extraction system, N-235 wasused as the liquid anion exchanger. The N-235 is a

kind of industrial mixed tertiary amine extractant withC8±C10, like Alamine-336. A volume of 10 ml of the186Re eluate could be converted to 9 ml ammonia sol-

ution via extraction with N-235-dimethylbenzene andback-extraction with ammonia. The recovery in thisstep was about 88%, which was lower than that of

elution from the anion exchange column, however, lesstime was needed in this case.There is no di�erence in nuclidic purity between the

products obtained by these two separation methods.The radionuclidic purity of ®nal 186Re saline solutionwas >99.9%. The experimental levels of isotopicimpurities were found to be 183Re (5.0 � 10ÿ3%) and184gRe (4.6 � 10ÿ2%) and no 187W and 183Ta could bedetected. In terms of the activity of 65Zn from the65Cu ( p,2n ) 65Zn monitor reaction, the experimental

thick-target yield of 186Re at the end of bombardmentwas determined to be 529 mCi/mA h, by summing theradioactivity of 186Re in the target solution and in the

residue left from the ®ltration. This value is in goodagreement (within the limits of experimental errors)with the calculations, done on the basis of the energy

windows of incident deuteron and the excitation func-tion reported by Nassi� et al. (1973). In addition, theexperimental thick-target yield of 187W was calculatedto be 1.3 mCi/mA h, which is reasonable because the

maximum cross section of the 186W(d,p ) 187W reactionwas as high as 204 mb.1

To summarize, production of no-carrier-added 186Re

was achieved for the ®rst time via the 186W(d,2n )186Re reaction. Because of the high experimental thick-target yield, the 186W(d, 2n ) 186Re reaction may be

more suitable for preparation of no-carrier-added186Re for medical application, if the deuteron beamsare available.

Acknowledgements

The authors would like to thank Mr. Bufa Zhang,Prof. Shuanghui Shi and their colleagues for their tech-nical assistance during the irradiations. This work wassupported, in part, by the National Nature Science

Foundation of China.

References

Fulmer, C.B., Williams, I.R., 1970. Excitation functions for

radioactive nuclides produced by deuteron-induced reac-

tions in copper. Nuclear Physics A155, 43.

Breitz, H.B., Weiden, P.L., Vandergeyden, J.-L., Appelbaum,

J.W., Bjorn, M.J., Fer, M.F., Wolf, S.B., Ratli�, B.A.,

Seiler, C.A., Foisie, D.C., Fisher, D.R., Schro�, R.W.,

Fig. 1. Elution curves of 186Re, 187W, and 183Ta from the acid

alumina column (# adsorbing solution).

1 The cross sections for the 186W(d,p ) 187W reaction were

reported by a literature published in Chinese in 1981. The

maximum value and its position of the cross section were 204

mb and at 13.2 MeV, respectively.

X. Zhang et al. / Applied Radiation and Isotopes 54 (2001) 89±92 91

Fritzberg, A.R., Abrams, P.G., 1992. Clinical experience

with rhenium-186-labeled monoclonal antibodies for radio-

immunotherapy: results of phase I trials. J. Nucl. Med. 33,

1099.

Nassi�, S.J., MuÈ nzel, H., 1973. Cross sections for the reac-

tions 66Zn(d,n )67Ga, 52Cr(d,2n )52gMn and186W(d,2n )186Re. Radiochimica Acta 19, 97.

Pement, F.W., Wolke, R., 1966. Compound-statistical fea-

tures of deuteron-induced reactions (II). The compound

nucleus and stripping-evaporation mechanisms in ( p,2n )

Reactions. Nuclear Physics 86, 429.

Shigeta, N., Matsuoka, H., Osa, A., Koizumi, M.,

Kobayashi, K., Hashimoto, K., Sekine, T., Lambrecht,

R.M., 1996. Production method of no-carrier-added 186Re.

Journal of Radioanalytical and Nuclear Chemistry,

Articles 205, 85.

Zhang, X., Li, W., Fang, K., He, W., Sheng, R., Ying, D.,

Hu, W., 1999. Excitation functions for natW( p,xn )181±186Re reactions and production of no-carrier-added186Re via 186W( p,n )186Re reaction. Radiochimica Acta 86,

11.

Ziegler, J.F., Biersack, J.P., Littmark, U., 1985. The Stopping

and Ranges of Ions in Matter. Pergamon, New York.

X. Zhang et al. / Applied Radiation and Isotopes 54 (2001) 89±9292