15 th Varenna Conferenc on Nuclear Reaction Mechanisms

15 th Varenna Conferenc on Nuclear Reaction Mechanisms, 11 -15, June, 2018, Villa Monastero Diagnostic (99 Mo/99 m. Tc) and Therapeutic (67 Cu) Radioisotopes Produced by Neutrons from C, Be(d, n) Yasuki Nagai (QST, Tokai, Japan) Two problems in the medical RIs 1) Fragility of 99 Mo supply chain. (L. M. Filzenet al. , J. Nucl. Med. Technol. 45 (2017)) 2) New RIs are not being developed. (Appl. Radiation Isotopes (2005)). Objective: Towards sustainable production of medical RIs for domestic use Contents 1) 99 Mo/99 m. Tc 2) 67 Cu 3) Intense accelerator neutrons 4) Summary

Nuclear medicine modality The only modality that can fulfill the dream of carrying out tailored personalized medicine by way of enabling diagnosis followed 　by therapy in the same patient with the same radiopharmaceutical. {S. C. Srivastava & L. F. Mausner (2013)} Selected theragnostic radionuclide pairs: 64 Cu/67 Cu 64 Cu 67 Cu (PET) (therapy)

1) >80% diagnostic procedures: using 9 m. Tc-radiopharmaceuticals (Japan = 0. 9 millions, EU = 6 millions) 99 m. Tc 　　　 Metastasis of bone prostate cancer 1) Constant supply of 99 Mo: key issue to ensure the routine application of 99 m. Tc 2) Unscheduled shut down of research reactors producing 99 Mo: 2008 - 2009 Cause the world crisis of 99 Mo shortage. (Japan imports all 99 Mo. ) Fragility of 99 Mo supply chain: remains 　 　　　

99 Mo (99 m. Tc) Alternative production methods 　　　 The supply of Medical Radioisotopes: Report by NEA 2011 1. Reactors: 235 U(n, f)99 Mo low enriched 235 U Mo(n, )99 Mo Australia, Argentina, Brazil, USA Kazakhstan, Romania, USA 2. Accelerators: Nagai & Hatsukawa

Table ES 1: Summary of technology assessment results The supply of Medical Radioisotopes: Report by NEA 2011

99 Mo/99 m. Tc 1) 99 Mo production by 100 Mo(n, 2 n)99 Mo D-beam Accelerator Neutron Converter 100 Mo. O 3 　　　　 production Nagai & Hatsukawa: J. Phys. Soc. Japan (2009) Separation of 99 m. Tc from 100 Mo. O 3 Quality Control Tests of 99 m. Tc Problems to solve High flux of neutrons Sumitomo Heavy Industries Separation of 99 m. Tc from low-specific activity 99 Mo Collaboration with companies Chiyoda Technol 　　　　 Corporation 　　　 EU, US Pharmacopeia (since 2010) FUJIFILM RI Pharma Corporation

99 Mo yield by 100 Mo(n, 2 n) using neutrons from C(d, n) at Ed = 40 Me. V Cyclotrons at Takasaki (QST), CYRIC (Tohoku Univ. ) and FNS (JAEA) Four pellet nat. Mo. O 3 samples (25 g 4=100 g) used to measure the 99 Mo yield to test of the old neutron data including the evaluated 100 Mo(n, 2 n)99 Mo cross section. Note: Four samples different opening angle, , between the lines connecting the outer edge of the sample to the geometric centers. Results of the measured 99 Mo yield: good agreement with calculated one using the latest neutron data & evaluated cross section given in JENDL-4. 0 99 Mo 4 meas. (10 Bq) 99 Mo 4 cal. (10 Bq) Tsukada et al. , J. Phys. Soc. Japan (2018) Minatao et al. , J. Phys. Soc. Japan (2017)

Cyclotron Facility (Plan) Spec. of the cyclotron: 40 Me. V 2 m. A deuterons

99 Mo demand 99 Mo yield by using 40 Me. V 2 m. A deuterons 99 Mo yield: Enriched 100 g 100 Mo. O 3 sample, 40 Me. V 2 m. A deuterons, for 24 h irradiation 99 Mo activity reserved daily = 2. 3 TBq Calculated 99 Mo activity after starting irradiation of the 100 Mo. O 3　as a function of time. When 0. 66 TBq (18 Ci) of 99 Mo is produced daily for 6 days per week, 2. 30 TBq (63 Ci) of 99 Mo (in total) is obtained daily on average (dotted line). 99 m. Tc activity eluted from 99 Mo = 2. 3 TBq (twice a day) 99 m. Tc demand in Japan: 2. 0 TBq (at injection) Assume: 99 m. Tc radiopharmaceuticals can be delivered from a radiopharmaceutical company to people who live in the capital area within 6 h. 4. 0 TBq (at the company) 50% of the 99 Mo demand can be met by a single accelerator of 40 Me. V, 2 m. A deuterons Tsukada et al. , J. Phys. Soc. Japan (2018) Minatao et al. , J. Phys. Soc. Japan (2017)

Radionuclide purity of 99 Mo -ray spectrum of the 100 Mo. O 3 sample irradiated with neutrons (Ed = 40 Me. V) 99 Mo 99 m. Tc 97 Zr 97 Nb Radionuclide purity of 99 Mo a minimum level of radioactive wastes Minatao et al. , J. Phys. Soc. Japan (2017)

Separation of 99 m. Tc from low specific activity 99 Mo Sample Specific -activity 235 U 5, 000 Production Fission Separation method Established Milking of 99 m. Tc from 99 Mo (n, 2 n) 100 Mo 1 Challenge Al 2 O 3

Thermochromatographic Separation Method 99 m. Tc-oxide high-temp. in Mo. O 3 volatilizes at a temperature 　　　 low-temp. Mo 凝縮域 lower than that of sublimation of Mo. O 3 　　 Tc. O 4 Note: no chemical agents 　 　　 {Perrier & Segre J. Chem. Phys. (1937)} 　　 　　 　 　 　 Mo. O 3 electric furnace Tc-oxide Long standing problems to solve: Separation efficiency of 99 m. Tc from Mo. O 3 1) low, 2) diminishes markedly with repeated milking tests, and 3) decreases with a massive Mo. O 3 loaded into a furnace (ex: 25% for a 200 g sample) So far, powder Mo. O 3 and molten Mo. O 3 samples were used. {Boyd, Int. J. Appl. Radiat. Isot. 33 (1982)} 　

High separation efficiency sp of 99 m. Tc from molten Mo. O 3 Release process of 99 m. Tc from Mo. O 3 Transport of 99 m. Tc to sample surface Evaporation of 99 m. Tc-oxide from surface Molten 100 Mo 3 Powder Mo. O 3 sample D (powder)=7. 7 10 -12 cm 2/s at T = 780 C Tachimori, J. Nucl. Sci. & Tech. (1971) Molten Mo. O 3 sample Separation efficiency & diffusion coefficient for 9. 9 g Mo. O 3 with 4 mm thickness Run sp (%) D (cm 2/s) 1 95 8 10 -5 2 89 3 89 4 88 D (diffusion coeff. of 99 m. Tc) values: very large 99 m. Tc diffuses rapidly in a thick molten Mo. O 3 & subsequently released from the sample, leading to high 99 m. Tc separation effic. 2 cm thick Mo. O 3 sample can be used Nagai et al: J. Phys. Soc. Japan 83 (2014)

Quality control tests of 99 m. Tc Unites States Pharmacopeia Myocardial infarction Cerebral blood flow Kidney function Bone imaging Quality of 99 m. Tc from [(n, 2 n)-99 Mo]: comparable to that of fission-99 Mo Hashimoto et al. J. Phys. Soc. Japan 84 (2015), Nagai, Nakahara et al. , J. Phys. Soc. Japan 86 (2017)

Recovery of an expensive 100 Mo. O 3 sample So far, 93 -97 % recovery for 94 Mo. O 3. (Rösch, Novgorodov, & Qaim, Radiochim. Acta (1994)) High recovery of 99 %: achieved for a 100 Mo. O 3 sample mass of 118 g Mo. O 3 sample in Pt boat Mo. O 3 needle crystal 92 -93 % 6 -7 % 0. 6 % others = 99 % (total recovery) Kawabata et al: J. Phys. Soc. Japan 86 (2017)

2) Theragnostic radionuclide 67 Cu-labeled 　　　 radiopharmaceuticals: promising RI for Cancer therapy. emits - (E 0. 4 Me. V) & -rays (E 0. 2 Me. V), permit SPECT imag. during therapy. Low availability of 67 Cu ( 4 GBq/m in the world) limiting factor for R&D using 67 Cu An appropriate production route of 67 Cu: need to be established So far, J. Kozempel et al. , Radiochim. Acta (2012) 　　　 68 Zn(p, 2 p)67 Cu 70 30 Pupillo et al. , Nucl. Instr. Meth. B 415 (2018) 67 Zn(n, p)67 Cu Ed = 14 Spahn, Coenen & Qaim, Radiochim. Acta (2004)

2) New production route of 67 Cu by 68 Zn(n, np+d) 　　　 Estimated 67 Cu yield: 290 GBq (EOI)/(2 -days) for 68 Zn 186 g sample 　　　 Kim et al. , J. Phys. Soc. Japan (2013) Neutrons at Ed = 40 Me. V Sato et al, J. Phys. Soc. Japan, (2014)

Biodistribution of 67 Cu. Cl 2 in colorectal tumor-bearing mice Pioneering work using 64 Cu. Cl 2: Peng et al. , J. Nucl. Med. (2006) Potential agent for PET & radionuclide therapy targeting Cu transport protein Cu metabolism : important for many cancers 67 Cu. Cl 2: has not been studied High uptake of 67 Cu: observed in the tumor & in the liver &kidney, which are the major organs for copper metabolism. 67 Cu. Cl 2: a potential radionuclide agent for cancer radiotherapy. Sugo et al, J. Phys. Soc. Japan, (2017)

3) Intense accelerator neutrons 　　　 　　　 SPIRAL 2 at GANIL: 40 Me. V 5 m. A deuteron 1014 n/s produced by C(d, n) at Ed=40 Me. V S. Gales, Prog. Particle & Nuclear Physics, 2007 Carbon Rotating carbon converter: Performance of cyclotron It can withstand the high power of intense deuteron beam. K value (energy Me. V) From Mitsumoto et al. (Sumitomo)

4) Summary 1) Generation of Radioisotopes with Accelerator Neutrons by Deuterons (GRAND) provides a wide variety of RIs with a minimum level of radioactive wastes. Nagai et al. , J. Phys. Soc. Japan (2013) 2) With a single accelerator of 40 Me. V, 2 m. A deuteron beams, we showed i) 50% of 99 Mo demand in Japan can be met. ii) a large amount of 67 Cu can be produced by 68 Zn(n, np+d) 3) Proposed RI production system: compact in size, easy to operate. Used in various places for RIs production.