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5 th International Conference on Isotopes Brussels, Belgium, 25 – 29 April 2005

5 th International Conference on Isotopes Brussels, Belgium, 25 – 29 April 2005. RECENT ACTIVITIES ON INNOVATIVE RADIONUCLIDE PRODUCTION FOR METABOLIC RADIOTHERAPY AND PET AND ON RELEVANT EXPERIMENTAL AND EVALUATED NUCLEAR DATA. Enzo Menapace

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5 th International Conference on Isotopes Brussels, Belgium, 25 – 29 April 2005

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  1. 5th International Conference on Isotopes Brussels, Belgium, 25 – 29 April 2005 RECENT ACTIVITIES ON INNOVATIVE RADIONUCLIDE PRODUCTION FOR METABOLIC RADIOTHERAPY AND PET AND ON RELEVANT EXPERIMENTAL AND EVALUATED NUCLEAR DATA Enzo Menapace ENEA,Advanced Physical Technologies, Bologna, Italy Claudio Birattari, Mauro L. Bonardi, Flavia Groppi Anna Martinotti, Sabrina Morzenti, Cristiano Zona Radiochemistry Laboratory, LASA, Universita’ degli Studiand INFN, Milano, Italy e-mail: enzo.menapace@bologna.enea.it

  2. Abstract Activities and relevant results are discussed concerning the radionuclide production for medical applications brought up in the recent years at LASA-INFN Laboratory in collaboration with ENEA, Division for Advanced Physical Technologies. In particular, measurements are discussed concerning spectrometric values with reference to radionuclidic, radiochemical and chemical purities by analytical and radioanalytical techniques. Concerning the excitation functions, relevant to the nuclear reactions involved in the radionuclide production, evaluated nuclear data are discussed as they have been produced through appropriate comparisons of present and other available and critically selected experimental values with reliable model calculations. Most significant results are presented as from recent years activities at the above Institutes. 5ICI, Brussels, Belgium

  3. Introduction • A number of initiatives on the production of innovative medical radioisotopes, both for PET and SPECT diagnostics and for therapy, have been brought up in the recent years by the present authors at INFN-LASA Laboratory and ENEA, Division for Advanced Physical Technologies, by collaborations with the Cyclotron Laboratory of JRC-Ispra (EC) referring to irradiation experiments at K=38 variable energy Cyclotron.  • Mainly scientific aspects and applications have been investigated in order to obtain high specific activity accelerator-produced radionuclides in no-carrier-added (NCA) form.   • To this aim it was necessary to optimise the irradiation parameters, determining the excitation functions of the involved nuclear reactions, and to point out selective radiochemical separations of the radioisotopes of interest. 5ICI, Brussels, Belgium

  4. Relevant examples of medicalHigh Specific Activity RadioNuclides – HSARN previously produced in NCA form, at Milano and Ispra Cyclotron Laboratories 5ICI, Brussels, Belgium

  5. Introduction • Measurements of spectrometric values and of radionuclidic, radiochemical and chemical purities, by analytical and radioanalytical techniques, have been done at LASA-INFN, as pointed out in the following. • Evaluated nuclear data have been produced at ENEA, Division for Advanced Physical Technologies through appropriate comparisons of presently investigated and critically selected experimental values with reliable model calculations, as discussed in the following. • Participation is done to international co-operation initiatives, especially to the IAEA Coordinated Research Programmes (CRPs) on nuclear data for production of medical radioisotopes.  • In the recent years up to the present, the R&D activity (as from ref.s /1/ to /6/) has been brought up or it is underway for the following NCA radionuclides, for uses in metabolic radiotherapy and PET: 5ICI, Brussels, Belgium

  6. Investigated medical radioisotopes, production reactions, emitted radiation data and applications 5ICI, Brussels, Belgium

  7. Materials and experimental methods • The irradiations were carried out at the Scanditronix MC40 cyclotron (K=38), JRC-Ispra (Varese, Italy) of the EC, that can deliver variable energy proton or alpha beams with energies up to 38 MeV and deuteron beams up to 19 MeV. • The experimental activity devoted to the At radionuclides (RNs) is discussed here as a significant example. 211At is clearly the most promising for labelling drugs and radiopharmaceutical compounds for metabolic radionuclide therapy, as:   - the half-life of 7.214 h, reasonably sufficient long for labelling organic compounds, due to the strengths of C-At, O-At and N-At bonds, which are similar to those of iodine; -  the 211At  branching of 41.80%, which is the highest among the “medium-lived” At RNs. - Although decaying by EC, the further 58.20% also leads to a emission through 211gPo. -  As a consequence the “overall”  branching of the decay of 211At is 100%. -  The energy of a particles ranges from 5 870 keV to 7 450 keV (with a raw arithmetically “averaged“ value of 6 665 MeV). 5ICI, Brussels, Belgium

  8. Materials and experimental methods • - The two main  particles of the 211At 211gPo system have an “average” range of 60 to 67 m in water (and soft animal tissues) and a nearly optimal LET of  100 - 130 eV·nm-1, which is around the maximum of the Q curve for energetic ions. • A good choice for a production method of 211At has to minimize isotopic contamination by the Po isotopes to negligible levels. • The direct production method based on the nuclear reactions 209Bi(,2n)211At seems the most satisfactory, because it can be done in a medium energy cyclotron, leading to a high yield and low contamination by the only radioisotopic impurity 210At, that can be kept at an appropriate level as internal spike. • The irradiation experiments were carried out at low beam current (50 to 250 nA), with an integrated beam charge of 100 and 450 mC, measured with an error smaller than 1-2% with a Faraday cup connected to a charge integrator. Besides, the reliability of beam charge integrator was checked by thin Cu monitor foils. 5ICI, Brussels, Belgium

  9. Materials and experimental methods • In order to produce NCA 211At/211gPo for metabolic radiotherapy, a suitable radiochemical separation of At radioisotopes from Po by-products and from the Bi target with quality control has been done, the radiochemical separation adopted being a classical “wet” method based on liquid/liquid extraction. • The g, X spectra have been measured with coaxial HPGe detectors, the a spectra with Si surface barrier or PIPS detectors, with a resolution of 27 keV (FWHM), and b spectra with a conventional liquid scintillation counting LSC and spectrometry system with a/b pulse shape analysis (PSA) discriminator. Significant results are presented in the next figures. • The radionuclidic purity of the different radiochemistry fractions produced from Bi target, 210Po impurities and the final solution were also determined accordingly. 5ICI, Brussels, Belgium

  10. HPGe g spectrum – 28.8 MeV irradiation 5ICI, Brussels, Belgium

  11. alpha spectrum after the liquid/liquid extraction: the peaks of both 211At-211gPo and 210Po are shown together (related to 32.8 MeV irradiation). alpha spectrum of the astatine fraction (extracted by the organic solvent): At product is completely extracted from the aqueous solution. alpha spectrum of the separated 210Po fraction (remained in the aqueous phase): none of the 210Po is taken into the organic solvent extraction. 5ICI, Brussels, Belgium

  12. Nuclear models and computing codes The role of the nuclear model calculations has been well recognised for the nuclear data evaluation activities in the NEA and IAEA context and a number of initiatives on the matter have been undertaken both for the validation of the computing codes with respect to measured values and for the model parameterisation and systematics aimed to reliable data calculations particularly in the case of scarce, lacking or discrepant measurements. Calculations for the involved nuclear reactions have been carried out at ENEA Division for Advanced Physical Technologies, through internal developed codes and mainly through the EMPIRE-II system (be M. Herman, IAEA-NDS, ref./8/), accounting for the major nuclear reaction mechanisms for the various competing nuclear reaction channels, including the Optical Model (OM) and the full featured Hauser-Feshbach model, with a comprehensive parameter library mainly covering nuclear masses, OM data, discrete nuclear levels, level densities and decay schemes. Particularly the Monte Carlo Pre-equilibrium approach for the investigated proton induced reactions has been successful in approximating experimental values. 5ICI, Brussels, Belgium

  13. Nuclear models and computing codes (cont.) As the determination of the nuclear level density is of the main impact on the results, the following semiempirical formula was adopted (Frisoni et al., 1997) founded on both theoretical and empirical (from the existing measurements) bases: • where: • E is the nuclear excitation energy; • P is the parity; • is the spin cutoff factor; M is the projection of the angular momentum on a given axis; Fpar takes into accont the level parity distribution. The level density parameter (the most important one) and the other parameters (a, D and b) are estimated by best approximation of:  low energy level schemes;  neutron resonance average spacings;  emission spectra with reference to the available experimental and theoretical informations. 5ICI, Brussels, Belgium

  14. Evaluations for the involved excitation functions The evaluations have been based both on selected experimental data and on nuclear model calculations. In particular, the activity has been devoted to the model parameterisation, especially concerning the nuclear discrete level structure and the level density approach in the continuum, for both target and residual nuclei. The excitation functions were evaluated for the production reactions of radionuclides as from the above table scheme. Most recent evaluations concerned (a,2n) and (a,3n) reactions on 209Bi target for the production of 211At and 210At, and the radioisotope production reactions 186W(p,n)186gRe and 103Rh(d,2n)103Pd and 226Ra(p,2n)225Ac. The research was especially aimed to investigate the production optimal conditions, relevant to future Cyclotron irradiations experiments by proton and deuteron beams.  A satisfactory agreement has been found between the theoretical results and the existing experimental values as shown in the figures reported in the following. 5ICI, Brussels, Belgium

  15. In this work, special care is devoted to the discussion of the results for the production of the: 211At, 210At, 186gRe and 103Pd radionuclides by the above reaction routes. For the other radionuclides, the relevant results, as from ref.s /1/ , /2/, /3/, /4/ and /5/, are reviewed hereafter. 5ICI, Brussels, Belgium

  16. Relevant comments (I) • The cumulative excitation functions are presented for the production of 64Cu and 66Ga by nuclear reactions on natural zinc target in the energy range up to 19 MeV, such as (d,axn) reactions for 64Cu, (d,2p) reaction for 64Cu production and (d,xn) reactions for 66Ga production; • the experimental values, obtained from the analyses of the above mentioned irradiation experiments, are consistently compared with the model calculations (full lines) for 64Cu and 66Ga production reactions in the incident energy intervals from the thresholds up to 19 MeV. 5ICI, Brussels, Belgium

  17. ENERGY THRESHOLDS FOR THE MAIN NUCLEAR REACTIONS INDUCED BY DEUTERON BEAMS ON ZINC TARGET OF NATURAL ISOTOPIC COMPOSITION Natural Zn (%): 64Zn 48.6, 66Zn 26.9, 67Zn 4.1, 68Zn 18.8, 70Zn 0.6 5ICI, Brussels, Belgium

  18. COMPARISON BETWEEN EXPERIMENTAL AND CALCULATED CROSS-SECTIONS 5ICI, Brussels, Belgium

  19. HPGe SPECTRUM OF A DEUTERON IRRADIATED ZINC TARGET (Pb absorbers 3mm + b+ annihilators 2x7 mm) Cu-64 (Cu-61) Ga-66Ga-67 Zn-65Zn-69m 5ICI, Brussels, Belgium

  20. THIN-TARGET YIELDS OF CU-64 AND CU-61 vs. “AVERAGE” DEUTERON ENERGY IN THE THIN TARGETS 5ICI, Brussels, Belgium

  21. EXPERIMENTAL AND INTEGRATED THICK-TARGET YIELD at the EOIBfor Zn(d,X) nuclear reactions at 19 MeVbeam energy: 19 ± 0.2 MeV; beam current: 100 nA; irradiation time: 30 min; target thickness: 730 mm (total energy absorption + 10 %) 1 MBq.C-1 = 3.6/37 Ci. A-1.h-1 5ICI, Brussels, Belgium

  22. radionuclidic purity • radiochemical purity • specific activity • chemical purity Scheme of Radiochemistry and Q.C. for N.C.A. radio-Cu and radio-Ga separation from irradiated zinc target 5ICI, Brussels, Belgium

  23. Characteristics of 225Ac T1/2 = 10 d Generator of 203Bi (T1/2 = 45 min) 203Bi labeled tumor seeking compounds are already in clinical experimentation (Phase I) for lymphoma therapy Production of 225Ac Decay of 229Th Cyclotron activation via 226Ra(p,2n)225Ac Cyclotron used: FzK Karlsruhe 5ICI, Brussels, Belgium

  24. Relevant comments (II) • For the 226Ra(p,2n) reaction cross section, the Institute for Transuranium Elements (ITU) of the JRC in collaboration with the cyclotron of the Forschungszentrum Karlsruhe, Germany, has demonstrated the feasibility of the production of 225Ac in a cyclotron based on the reaction 226Ra(p,2n)225Ac. The excitation function of this reaction was determined by irradiation of a series of identical Ra-targets containing 12.5 µg 226Ra. • The experimental cross section values presented at 2004 Cyclotron Conference in Tokio, as from ref. /9/, are shown in the next figure in comparison with model calculations using theEMPIRE-II code. • Those first published experimental values appear to be in good agreement with the model calculations. Maximum yields of 225Ac are shown at incident proton energies around 16.8 MeV. 5ICI, Brussels, Belgium

  25. Production of 225Ac via (p,2n) reaction on 226Ra target 5ICI, Brussels, Belgium

  26. Production of 225Ac via (p,2n) reaction on 226Ra target 5ICI, Brussels, Belgium

  27. Relevant comments (III) • For the excitation functions of the (p,n) reactions on 186W target for the production of 186gRe in the incident energy interval up to 20 MeV, the experimental valuesfrom the literature are compared with the theoretical ones (full lines) obtained through the EMPIRE-II code. Particularly the Monte Carlo Pre-equilibrium approach has been successful in approximating the experimental values; • the discussion on possible systematic errors appears to be desirable in order to solve the present experimental discrepancies; • this production method can provide NCA186gRe as an alternative route to the CA production utilizing a reactor neutron field via (n,g) reaction on enriched 185Re target. 5ICI, Brussels, Belgium

  28. Production of 186Re via (p,n) reaction on 186W target 5ICI, Brussels, Belgium

  29. Relevant comments (IV) • Concerning the 103Rh(d,2n)103Pd reaction route for producing an highly relevant radioisotope for local therapy treatments, two data sets from one experimental work have been considered, concerning respectively: - detected X-rays in the energy interval from 5 to 20.2 MeV; - detected week gamma-rays in the energy interval from 8.7 to 20.2 MeV. • In the following figure  the comparison of theoretical model calculations with the experimental values shows a satisfactory agreement, taking into account the experimental uncertainties. 5ICI, Brussels, Belgium

  30. Production of 103Pd via (d,2n) reaction on 103Rh target 5ICI, Brussels, Belgium

  31. Relevant comments (V) • Experimental cross section data have been selected for (a,2n) and (a,3n) reactions on 209Bi target for the production of 211At and 210At respectively, in the incident energy interval from 20 MeV to 50 MeV; • those experimental values are compared with model calculations ones (full line) obtained utilising the EMPIRE-II code; • the thick target yield value obtained by integration of the theoretical curve, from 28.8 down to 20 MeV, is 9234 MBq·C-1, in comparison with the experimental value equal to 8085 ± 176MBq·C-1 for the total energy absorption, as obtained at LASA-INFN from a preliminary irradiation: the discrepancy of about 12.4% appears to be reasonable with regard to the present experimental conditions. 5ICI, Brussels, Belgium

  32. Production of 211At via (a,2n) reaction on 209Bi target 5ICI, Brussels, Belgium

  33. Production of 210At via (a,3n) reaction on 209Bi target 5ICI, Brussels, Belgium

  34. REFERENCES • C. Birattari, M. L. Bonardi, F. Groppi, L. Gini, C. Mainardi, A. Ghioni, G. Ballarini, E. Menapace, K. Abbas, U. Holzwarth, M.F. Stroosnijder, J. Radioan. Nucl. Chem., 257 (2003) 229-241, Proceeding of 4th International Conference on Isotopes, Cape Town, South Africa - 2002. • E. Menapace, C. Birattari, M.L. Bonardi, F. Groppi, Rad. Phys. Chem.,71 (2004) 943-945. • F. Groppi, M. Bonardi, C. Birattari, L. Gini, C. Mainardi, E. Menapace, K. Abbas, U. Holzwarth, R.M.F. Stroosnijder, NIM-B, 213C (2004) 373-377. • M.L. Bonardi, F. Groppi, H.S.C. Mainardi, V.M. Kokhanyuk, E.V. Lapshina, M.V. Mebel, B.L. Zhuikov, J. Radioanal. Nucl. Chem., 264-1 (2005). • E. Menapace, C. Birattari, M.L. Bonardi, F. Groppi, S. Morzenti, C. Zona, Proc. of Intern. Conf. on Nuclear Data for Science and Technology., Santa Fe, USA (2004), American Institute of Physics, in press • F. Groppi, M.L. Bonardi, C. Birattari, E. Menapace, K. Abbas, U. Holzwarth, A. Alfarano, S. Morzenti, C. Zona, Z.B. Alfassi, Appl. Rad. Isot. (2005) in press. • A.Hermanne, F. Tarkanyi, S. Takàcs, Z. Szucs, Yu. N. Shubin, A. I. Dityuk, Appl. Rad. Isot. (2005) in press. • M. Herman, EMPIRE-II Statistical model code for nuclear reaction calculations (version 2.18), distributed by the IAEA Nuclear Data Section. • K. Abbas, A. Alfarano, Z. Alfassi, C. Apostolidis, C. Birattari, M. Bonardi, N. Gibson, F. Groppi, U. Holzwarth, E. Menapace, A. Morgenstern, S. Morzenti, H. Stamm, Development in alpha emitting radioisotope production at the Joint Research Centre (JRC) of the European Commission, Contr. Paper to the 17th Internat. Conf. on Cyclotrons and their Applications, Tokyo, Japan, October 2004. 5ICI, Brussels, Belgium

  35. REFERENCES • M. Bonardi, “The contribution to nuclear data for medical radioisotope production from the Milan Cyclotron Laboratory”, IAEA Consultants’s Meeting on “Nuclear Data Requirements for Medical Radioisotope Production”, Tokyo, Apr 1987 (Invited), INDC(NDS)-195/GZ, IAEA, Vienna, Austria, 1988, pp. 98-112. • D. Basile, C. Birattari, M. Bonardi, L. Goetz, E. Sabbioni, A. Salomone, Int. J. Appl. Rad. Isot., 32, 403-410 (1981). • E. Acerbi, C. Birattari, M. Bonardi, C. De Martinis, A. Salomone, Int. J. Appl. Rad. Isot., 32, 465-475 (1981). • M. Crippa, E. Gadioli, P. Vergani, G. Ciavola, C. Marchetta, M. Bonardi, Zeits. f. Phys. A, Hadrons and Nuclei, 350 (2), 121-129 (1994). • M. Bello, C. Bovati, A. Di Filippo, T.G. Stevens, S.H. Connell, J.P.F. Sellschop, S.J. Mills, F.M. Nortier, G.F. Steyn, C. Marchetta, C. Birattari, M. Bonardi, F. Groppi, Phys. Rev. C, 54 (6), 3051-3055 (1996). • M. Bonardi, C. Birattari, M. Gallorini, F. Groppi, D. Arginelli, L. Gini, J. Radioanal. Nucl. Chem., 236, 159-164 (1998). • F. Groppi, M. Bonardi, C. Birattari, M. Gallorini, L. Gini, J. Radioanal. Nucl. Chem., 249, 289-293 (2001). • C. Birattari, M. Bonardi, L. Gini, F. Groppi, E. Menapace, J. Nucl. Sci. Technol., Suppl. 2, 1302-1305 (2002). 5ICI, Brussels, Belgium

  36. REFERENCES • F. Groppi, C. Birattari, M. Bonardi, H.S. Mainardi, E. Menapace, “A Method For Simultaneous Deuteron-Cyclotron Production Of NCA 64Cu And 66Ga, 67Ga For Application In PET Diagnostics And Metabolic Therapy Of Tumors”, Int. Conf. Isotopic Nucl. Anal. Techn. Health Environ., Vienna 10-13 June 2003, IAEA-CN- 103/108, CD-Rom10 pages. • E. Menapace, “Trends and progresses on nuclear data activities and international cooperation, according to the IAEA-International Nuclear Data Committee” (Invited), Int. Conf. Nucl. Data for Science and Technology Conference Proceeding, Gatlinburg, TN, 1994, pp. 18-24. • N. Shigeta, H. Matsuoka, A. Osa, M. Koizumi, M. Izumo, K. Kobayashi, K. Hashimoto, T. Sekine, R.M. Lambrecht, J. Radioanal. Nucl. Chem., 205, 85-92 (1996). • F.W. Pement, and R.L. Wolke, Nucl. Phys., 86, 429 (1966). • S.J. Nassiff, and H. Munzel, Radiochim. Acta, 19(3), 97 (1973). • T. Zhenlan, Z. Fuying, Q. Huiyuan, W. Gong Qing, Chin. J. Nucl. Phys. (in chinese), 3(3), 242, (1981). • E.L. Kelly, E. Segrè, Phys. Rev,. 75(7), 999-1005 (1949). • W.J. Ramler, J. Winf, D.J. Henderson, J.R. Huizenga, Phys. Rev. 114(1), (1959) 154-162. • R.M. Lambrecht, S. Mirzadeh, Int. J. Appl. Radiat. Isot. 36(6), 443-450 (1985).. • M. Frisoni, E. Menapace, A. Musumeci, E. Spezi, M. Vaccari, “Nuclear Data For Medical Applications of Accelerators and Related Shielding Aspects”, Topical Meeting Nucl. Appl. Acc. Technol. Conf. Proceedings, Albuquerque, NM, USA, 1997, pp. 190-197. 5ICI, Brussels, Belgium

  37. THANK YOU FOR YOUR KIND ATTENTION 5ICI, Brussels, Belgium

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