Journal of Radioanalytical Nuclear Chemistry manuscript No. (will be inserted by the editor) Investigation of production routes for the 161Ho Auger-electron emitting radiolanthanide, a candidate for therapy F. T´ark´anyi · F. Ditr´oi · A. Hermanne · S. Tak´acs · A.V. Ignatyuk 3 1 0 2 Received:2012-11-13/Accepted:2012-12-19 n a J Abstract Theradiolanthanide161Ho(2.48h)isapro- internalirradiation[2,3,4,5,6].Differentroutesexistto 0 mising Auger-electron emitter for internal radiother- produce 161Ho with particle accelerators. One route is 3 apy that can be produced with particle accelerators. α- or 3He- particle irradiation of 159Tb relying on the ] The excitation functions of the natDy(p,xn)161Ho and 159Tb(α,2n)161Hoand159Tb(3He,n)161Horeactions.An- h natDy(d,x)161Horeactionsweremeasuredupto40and other route is the irradiation of dysprosium targets us- p - 50 MeV respectively by using the stacked foil activa- ingprotonsviathe161Dy(p,n),162Dy(p,2n)ordeuterons d tion method and -ray spectrometry. The experimental via 160Dy(d,n) and 161Dy(d,2n) reactions. When using e m data were compared with results of the TALYS code the 159Tb(α,2n)161Ho, 162Dy(p,2n) or 161Dy(d,2n) re- available in the TENDL 2011 library [1]. The main pa- actions processes, emission of one neutron also takes . s rameters of different production routes are discussed. place resulting in simultaneous production of 162Ho, c i which is a radionuclide impurity. This radionuclide has s Keywords medical radioisotopes · therapeutical a short half-life ground state 162gHo (15 min, Iπ = 1+) y isotopes · proton and deuteron irradiation · 161Ho · h and a longer-lived isomeric state (67.0 min, Iπ = 6−). 162mHo p From the point of view of 161Ho production, the con- [ taminationwiththelonger-livedexcitedstatehassome 1 importance at the beginning after EOB, which will be v 1 Introduction reduced by the waiting time. The decay through inter- 6 nal transition of 162mHo is followed only by low energy 7 Theradiolanthanide161HoisanAuger-electronemitter 1 low intensity γ-ray emission,but the38% electroncap- having also low energy photons in high abundance. It 7 turedecayresultsinstronghighenergyγ-lines(seeTa- . is very suitable for internal radiotherapy of small tu- ble 1). The cross-sections of the 159Tb(α,2n)161Ho re- 1 mors because of the low energy electrons emitted. The 0 action was investigated by several authors (see in com- 3 short range of Auger electrons however requires that parisonofproductionroutes).Althoughthebasiccross- 1 labeled compounds approach the cell nucleus. It is also section data are still missing the proton induced reac- v: interestingaslow-energynarrow-bandX-raysourcefor tionwasalsowasusedforpracticalproduction[5].The i X deuteroninducedreactionwasnotusedyetforthepro- F.Ditr´oiF.T´ark´anyi· S.Taka´cs r Institute of Nuclear Research of the Hungarian Academy of duction and no cross-section data were published. We a Sciences decided to investigate the excitation functions of the Tel.:+36-52-509251 proton and deuteron routes experimentally. Naturally Fax: +36-52-416181 occurring dysprosium is composed of 7 stable isotopes E-mail:[email protected] (156Dy - 0.06%, 158Dy - 0.10%, 160Dy - 2.34%, 161Dy A.Hermanne - 18.9%, 162Dy - 25.5%, 163Dy - 24.9% and 164Dy - Cyclotron Laboratory, Vrije Universiteit Brussel (VUB), Brussels,Belgium 28.2%). Taking into account that many of these sta- bleDyisotopeshavealargermassnumberthan161Ho, A.V.Ignatyuk InstituteofPhysicsandPowerEngineering(IPPE),Obninsk thedirectexperimentalinvestigationofthe161Dy(p,n), 249020,Russia 161Dy(d,2n)or160Dy(d,n)reactions,androutesleading 2 F.T´ark´anyietal. Table 1 Main experimental parameters Reaction natDy(p,x) natDy(d,x) Incidentparticle Proton Deuteron Method Stackedfoil Stackedfoil Targetandthickness natDy foil, 100.59 natDy foil, 100.59 µm µm Numberoftargetfoils 15 15 Accelerator CGR 560 cyclotron Cyclone 90 cyclotron of Vrije Universiteit of the Universit Brussels Catholique in City- placeLouvain la Neuve(LLN) Primaryenergy 36MeV 50MeV Irradiationtime 71min 30min Beamcurrent 61nA 120nA Monitor reaction, natTi(p,x)48V reac- 27Al(d,x)24Na reac- [recommendedvalues] tion[12] tion[12] Monitor target and natTi,10.9µm natAl,26.96µm thickness detector HpGe HpGe γ-spectra measure- 3series 3series ments Coolingtimes 1.5h,20h,80h 4h,20h,120h to possibly disturbing activation products, should re- Fig. 1 The simultaneously measured monitor reactions for determinationofprotonbeamenergyandintensity quire highly enriched targets. A second possibility is to usenaturaltargetsandtouseresultsoftheoreticalcal- culations to separate the contributions of the different target isotopes. This supposes an accurate predictivity Table 2 Main parameters of data evaluation (with of the calculations and a method to check the reliabil- references) ity has to be implemented. We adopted this approach γ-spectrumevaluation Genie2000,Forgamma [13,14] by making measurement of production cross-section of Determinationofbeamin- Faradaycup(preliminary) [15] tensity Fitted monitor reaction 161Ho on natDy target with protons and deuterons and (final) Decaydata NUDAT2.6 [16] by comparing our experimental data with the predic- ReactionQ-values Q-valuecalculator [17] Determinationofbeamen- Andersen(preliminary) [18] tions of the theoretical model codes. In case of good ergy Fitted monitor reaction [8] (final) agreement we can then compare the different charged Uncertaintyofenergy cumulativeeffectsofpossi- [19] bleuncertainties particle production routes using theoretical results val- Cross-sections Isotopiccrosssection [[20] Uncertainty of cross- Sum in quadrature of all [19] idated by integral experiment. sections individualcontributions Yield Physicalyield [20] 2 Experimental and data evaluation calculations. The numerical data important for further The general characteristics and procedures for irradia- dataevaluationarecollectedinTables4and5.Inboth tion, activity assessment and data evaluation (includ- casesthetheoreticalresultsreproduceexceptionallywell ing estimation of uncertainties) were similar as in our the shape of the measured excitation functions, but an manyearlierworks[7,8,9,10,11].Themainexperimen- overestimation over the whole energy range is seen for tal parameters for the present study including the cho- the natDy(p,xn)161,162mHo and natDy(d,xn)161Ho re- sen monitor reactions [12] are summarized in Table 1. actions. In case of the natDy(d,xn)162mHo the agree- Themainmethodsusedindataevaluationandtheused ment of the maximum is acceptable. The numerical decaydata[8,13,14,15,16,17,18,19,20]arecollectedin values of theoretical results by a factor of 0.7 in case of Table 2 and Table 3. The excitation function of simul- xDy(p,xn)161,162mHoandof0.55incaseofxDy(d,xn)161- taneously measured proton and deuteron monitor re- Ho should be multiplied as a rough estimation. There actions and comparison with recommended values are is no normalization for xDy(d,xn)162mHo reaction. For shown in Fig. 1. further discussion we have normalized the theoretical cross-sections of the contributing reactions involved in 3 Results 161Ho production with these factors. The comparison of the normalized TENDL 2011 cross-sections of the 3.1 Cross-sections 161Dy(p,n)161Ho and the 162Dy(p,2n)161Ho reactions andthe162Dy(p,n)162mHoimpurityreactionareshown ThemeasuredexcitationfunctionsfornatDy(p,xn)161,162m-inFig.4andofthe160Dy(d,n)161Ho,the161Dy(d,2n)161- Ho and natDy(d,xn)161,162mHo are shown in Figs 2-3 Ho reactions and the 161Dy(d,n)162mHo impurity reac- and 5-6 in comparison with the results of the model tion is presented in Fig 7. Investigationofproductionroutesforthe 161HoAuger-electronemittingradiolanthanide,acandidate fortherapy 3 Table3 Decaycharacteristicsofthe161Hoand162Ho and Q-values of reactions for their productions) Nuclide Half- Eγ(keV) Iγ(%) Contributing Q-value life reaction (keV) 161Ho 2.48h 77.42 1.9 161Dy(p,n) -1640.64 ε:100% 103.05 103.05 162Dy(p,2n) -9837.63 7/2- 157.26 0.49 163Dy(p,3n) -16108.65 175.42 0.43 164Dy(p,4n) -23766.77 160Dy(d,n) 2589.18 161Dy(d,2n) -3865.2 162Dy(d,3n) -12062.2 163Dy(d,4n) --1285393931..2313 164Dy(d,5n) 162mHo 67.0m 184.99 23.94 162Dy(p,n) -3027.91 IT:62% 282.86 10.27 163Dy(p,2n) -9298.92 ε:38% 937.17 10.44 164Dy(p,3n) -16957.05 6- 1220.04 23.7 105.87keV 161Dy(d,n) 2944.51 162Dy(d,2n) -5252.48 163Dy(d,3n) -11523.49 164Dy(d,4n) -19181.61 162gHo 15.0m 80.7 8.0 162Dy(p,n) -2922.04 ε1:+100% 1319.75 3.82 116634DDyy((pp,,23nn)) --91169835.10.518 Fig. 3 Experimental cross-sections of the natDy(p,xn)162mHo reaction in comparison with the 161Dy(d,n) 3050.38 resultsofmodelcalculationsin TENDL2011 162Dy(d,2n) -5146.61 163Dy(d,3n) -11417.62 164Dy(d,4n) -19075.74 Fig.4 Experimentalcross-sectionsofthenatDy(d,xn)161Ho reactionincomparisonwiththeresultsofmodelcalculations Fig.2 Experimentalcross-sectionsofthenatDy(p,xn)161Ho inTENDL2011 reactionincomparisonwiththeresultsofmodelcalculations inTENDL2011 Table 4 Measured cross-sections of the natDy(p,x)161,162mHo reactions 161Ho 162mHo E σ ±δσ σ ±δσ MeV mb mb 35.3 253.5 34.8 34.7 5.7 33.8 246.2 35.6 46.9 5.9 32.3 293.4 39.0 55.6 7.3 30.8 285.5 38.1 82.6 10.2 29.2 265.0 35.2 103.4 11.5 27.5 214.8 33.2 113.6 14.6 25.7 239.8 32.2 114.6 13.1 23.8 239.2 34.1 118.6 13.4 21.9 248.9 28.1 111.1 12.3 19.7 226.1 25.5 93.0 10.4 17.4 178.8 20.6 80.8 9.0 14.8 156.1 21.1 73.0 8.0 11.9 122.3 14.1 49.0 5.4 8.2 39.2 5.8 15.3 1.7 4.3 5.7 1.7 0.8 0.1 Fig. 5 Experimental cross-sections of the natDy(d,xn)162mHo reaction in comparison with the resultsofmodelcalculationsin TENDL2011 4 F.T´ark´anyietal. Table 5 Measured cross-sections of the natDy(d,x)161,162mHo reactions 161Ho 162mHo E σ ±δσ σ ±δσ MeV mb mb 48.6 219.9 26.6 66.7 9.0 46.5 222.2 26.9 75.2 10.0 44.4 242.0 28.1 94.4 11.2 42.3 295.2 33.1 93.9 10.8 40.0 274.8 31.3 106.1 12.5 37.6 301.0 33.7 143.2 15.7 35.1 265.8 29.8 166.8 18.4 32.5 277.7 31.3 192.5 21.1 29.8 295.1 33.1 189.9 20.8 26.8 250.9 28.3 172.8 19.0 23.6 234.9 26.3 147.5 16.3 20.0 181.0 20.5 126.1 13.9 16.0 127.5 14.7 91.7 10.1 11.0 45.0 5.5 36.6 4.2 Fig. 7 Comparison of the cross-sections of the 160Dy(d,n)161Ho and the 161Dy(d,2n)161Ho reactions and the 161Dy(d,n)162mHo impurity reaction in TENDL 2011 Fig. 6 Comparison of the cross-sections of the 161Dy(p,n)161Ho and the 162Dy(p,2n)161Ho reactions and the 162Dy(p,n)162mHo impurity reaction in TENDL 2011 Fig. 8 Integral yields of the natDy(p,xn)161Ho, natDy(p,xn)162mHo, natDy(d,xn)162mHo and 3.2 Integral yields natDy(d,xn)162mHoreactions The integral yields calculated on the basis of the nor- 4 Comparison of production routes on different malizedTENDL2011cross-sectionsforthenatDy(p,xn)- target materials 161Ho,natDy(p,xn)162mHo,natDy(d,xn)162mHoandnat- Dy(d,xn)162mHoproductionreactionsareshowninFig. The main parameters of the selected low and medium 8.Thecalculatedintegralyieldrepresentssocalledphys- energy reactions that can lead to production of 161Ho ical yield i.e. yield obtained in a short irradiation [19]. on different target materials are collected in Table 6. ThenatDy(p,xn)161Hoyieldsarecomparedwiththeex- The excitation functions of the proton and deuteron perimental data of Stephens [5]. The value calculated routes are shown in Figs. 2-3 and Fig 4-5. Mukher- by the Stephens’ result for 11.6 MeV proton bombard- jee [21] and Bonesso [22] reported earlier experimental ment is significantly lower than our result, but it can cross-section data on 159Tb(α,2n)161Ho and Mukher- be caused by the fact that the irradiation time was jee [21] and Singh [23] on total cross-section of and not published in that paper. Comparing the saturation 159Tb(α,2n)162Ho. The 162mHo/162gHo isomeric ratio activities, which are 1.8 GBq by Stephens (after 3.6 was measured by Tulinov [24], Baskova [25]. No exper- hours) and 1.89 GBq in our measurement/calculation, imental data were found for the 159Tb(3He,n)161Ho re- the agreement can be considered as good. action. The experimental data from literature and the Investigationofproductionroutesforthe 161HoAuger-electronemittingradiolanthanide,acandidate fortherapy 5 theoreticalexcitationfunctionsofthe159Tb(α,2n)161Ho and 159Tb(α,n)162mHo reactions are shown in Fig. 9 and10respectively.Thetheoreticalexcitationfunctions of the 159Tb(α,2n)161Ho and 159Tb(,n)162mHo and the 159Tb(3He,n)161Ho reactions are compared in Fig. 11. From the excitation functions of the above mentioned reactions the following conclusions can be drawn: – The production yields for the 162Dy(p,2n) is the highest followed by the 161Dy(d,2n), 159Tb(α,2n) and 161Dy(p,n) – No162mHoimpurityisproducedwhenusingof159Tb- (3He,n), 161Dy(p,n) and the 160Dy(d,n) reactions. Among them the 161Dy(p,n) reaction has the high- est cross-section ( max 260 mb) followed by the 160Dy(d,n) reaction( max 60 mb) and the less pro- Fig. 9 Experimental and theoretical cross-sections of the ductive 159Tb(3He,n) ( max 1 mb) 159Tb(α,2n)161Horeaction – The element Tb is monoisotopic, relatively cheap and recovery is practically not necessary – In case of proton and deuteron induced reactions highly enriched 160, 161 or 162 Dy targets are re- quired – The production cross-sections of the 162mHo from 169Tb(α,n), 161Dy(d,n) and 162Dy(d,n) are low – The impurity level depends on the selected energy range.Theratioofthesaturationyieldsofthemain reactionandofcompetingimpurityreactionisshown inFig.12asafunctionofenergy.Intheproduction energy range the ratio is lower than 3 – Thehalf-lifeof162mHoisthreetimesshorter,there- fore by using a short irradiation, the activity im- puritylevelwillreach3%.Butbyusingirradiations lastingtwohalf-lifeof161Hoandtakingintoaccount 1 hour needed for the chemical separation and the Fig. 10 Experimental and theoretical cross-sections of the labelingprocesstheimpuritylevelof162mHowillbe 159Tb(α,2n)162mHoreaction reduced to 1% by decay. radionuclide impurity level of the last two reactions however is significant. No enriched target material is 5 Summary and conclusions necessary in case of 159Tb(α,2n) (Tb is monoisotopic) but it requires accelerators having medium energy al- The principal aim of this work was an investigation of pha particles. The 159Tb(3He,n) and 160Dy(d,n) reac- the production possibility of the radiotherapy related tionshaveverylowcross-sections,andacceleratorsdis- 161Ho. We present first experimental cross-sections for posing of 3He beam are rare and the 3He irradiation natDy(p,xn)161Ho,natDy(p,xn)162mHo,natDy(d,x)161Ho without recovery of 3He gas is expensive. On the basis and natDy(d,x)162mHo up to 40 and 50 MeV incident of the production yields, the impurity levels and the particle energies respectively. The TENDL 2011 the- requirements of the medical application the 161Dy(p,n) oretical data predict well the shape of the excitation reaction is the production method of best choice. functions but overestimate the absolute values with a nearly constant factor in the whole energy range. The comparison of the different production routes shows Acknowledgements Thisworkwasperformedintheframe of the HAS-FWO Vlaanderen (Hungary-Belgium) project. thatforproductionof161Howithhighradionuclidepu- Theauthorsacknowledgethesupportoftheresearchproject ritythe161Dy(p,n)161Ho,162Dy(p,2n)and161Dy(d,2n) andoftherespectiveinstitutionsinprovidingthebeamtime reactionsgivethehighestproductionyields.The162mHo andexperimentalfacilities. 6 F.T´ark´anyietal. Table 6 Summary of the production parameters for selected reactions Reaction Q-value Impurity reac- Optimal 161Ho Impurity Optimal 161Ho Impurity tion energyrange thick tar- level energyrange thick tar- level (MeV) getyield (%) at low impu- getyield (%) (GBq/C) rity (GBq/C) (MeV) 159Tb(α,2n)161Ho -16053.93 159Tb(α,n)162mHo 35-19 165 6 30-23 107 2.8 159Tb(3He,n)161Ho 4523.7 no 30-15 0 161Dy(p,n)161Ho -1640.64 no 15-8 132 0 162Dy(p,2n)161Ho -9837.63 162Dy(p,n)162mHo 30-12 1459 8.5 22-15 868 4.6 160Dy(d,n)161Ho 2589.18 no 15-7 34 0 161Dy(d,2n)161Ho -3865.2 161Dy(d,n)162mHo 30-16 1454 1.8 28-20 955 1.5 4. M.Neves,A.Kling,A.Oliveira,JournalofRadioanalyt- icalandNuclear Chemistry 266(3),377(2005) 5. B.J.Stephens,161ho+iudr:optimizedphotonactivation therapy. Ph.D.thesis(2010) 6. B.J.Stephens,M.H.Mendenhall,AppliedRadiationand Isotopes 68(10),1928(2010) 7. 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