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National Institutes for Quantum Science and Technology (QST), formerly known as the National Institute of Radiological Sciences (NIRS), has been engaged in work on radiopharmaceutical science using cyclotrons since 1974. Eight pioneering researchers founded the basis of this field of research at NIRS, and to the present, many researchers and technicians have accumulated both scientific and technical achievements, as well as inherited the spirit of research. Besides, in recent years, we have developed production systems with AVF-930 cyclotron for various ‘non-standard’ radioisotopes applied in both diagnosis and therapy. Here, we review the past 50 years of our activities on radioisotope and radiopharmaceutical development, as well as more recent activities.

Palladium-103 is one of the most attractive radionuclides for internal radiotherapy. It is not only used as a brachytherapy seed but is also a feasible candidate for Auger electron therapy and gold-nanoparticle therapy. In this study, we propose a new method for the separation of 103Pd from a rhodium target to obtain no-carrier-added 103Pd. Rhodium powder target was irradiated under the following conditions: proton, 50 MeV, 1–3 μA, 1–4 h for the separation study; and H2 +, 24 MeV, 5 μA, 1 h to produce 103Pd. The irradiated target was pretreated using an alloying reaction between Rh and Bi on a hotplate at 500 °C. Rhodium in the chemical form of a Bi–Rh compound could then be dissolved with nitric acid and 103Pd was extracted using dimethylglyoxime as an extractant. The target rhodium was recycled using sodium tetrahydroborate (NaBH4). We obtained 103Pd with a yield of 87%. The activity of the product was 26 ± 2 MBq at the end of bombardment (EOB), and the radionuclidic purity of 103Pd was greater than 99%. The decontamination factors of rhodium and bismuth in the 103Pd product were estimated to be greater than 104 and 105, respectively. The target rhodium was recycled with a yield of 91% with a trace of bismuth (9 μg/50 mg Rh). The total separation time for 103Pd was within 3.5 h.

Fatty acid amide hydrolase (FAAH) is a key enzyme in the endocannabinoid system. N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide ([11C]DFMC) was developed as an irreversible-type positron emission tomography (PET) tracer for FAAH. Here, we attempted to noninvasively estimate rate constant k3 (rate of transfer to the specifically-bound compartment) as a direct index for FAAH in the rat brain. First, the two-tissue compartment model analysis including three parameters [K1−k3, two-tissue compartment model for the irreversible-type radiotracer (2TCMi)] in PET study with [11C]DFMC was conducted, which provided 0.21 ± 0.04 ml·cm−3·min−1 of the net uptake value (Ki), an indirect index for FAAH, in the FAAH-richest region (the cingulate cortex). Subsequently, to noninvasively estimate Ki value, the reference model analysis (Patlak graphical analysis reference model) was tried using a time-activity curve of the spinal cord. In that result, the noninvasive Ki value (KREF) was concisely estimated with high correlation (r > 0.95) to Ki values based on 2TCMi. Using estimated KREF value, we tried to obtain calculated-k3 based on previously defined equations. The calculated k3 was successfully estimated with high correlation (r = 0.95) to direct k3 in 2TCMi. Finally, the dose relationship study using calculated k3 demonstrated that in vivo ED50 value of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate, a major inhibitor of FAAH, was 66.4 µg/kg in rat brain. In conclusion, we proposed the calculated k3 as an alternative index corresponding to regional FAAH concentrations and suggested that PET with [11C]DFMC enables occupancy study for new pharmaceuticals targeting FAAH. SIGNIFICANCE STATEMENT In the present study, we proposed calculated k3 as an alternative index corresponding with fatty acid amide hydrolase concentration. By using calculated k3, in vivo ED50 of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate was successfully estimated to be 66.4 µg/kg for rats. Thus, we demonstrated the pharmacological utility of positron emission tomography with N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide.

Fatty acid amide hydrolase (FAAH) is a key enzyme in the endocannabinoid system. N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide ([11C]DFMC) was developed as an irreversible-type positron emission tomography (PET) ligand for FAAH. Here, we attempted to noninvasively estimate rate constant k3 as a direct index for FAAH in the rat brain. First, the two-tissue compartment model analysis including three parameters (K1–k3, 2TCMi) in PET study with [11C]DFMC was conducted, which provided 0.21 ± 0.04 mL·cm−3·min−1 of the net uptake value (Ki), an indirect index for FAAH, in the FAAH-richest region (the cingulate cortex). Subsequently, to noninvasively estimate Ki value, the reference model analysis (Patlak Reference, PGAREF) was tried using a time-activity curve of the spinal cord. In that result, the noninvasive Ki value (KREF) was concisely estimated with high correlation (r > 0.95) to Ki values based on 2TCMi. Using estimated KREF value, we tried to obtain calculated-k3 based on previously defined equations. The caluculated-k3 was successfully estimated with high correlation (r = 0.95) to direct k3 in 2TCMi. Finally, the dose relationship study using calculated-k3 demonstrated that in vivo ED50 value of URB597, a major inhibitor of FAAH, was 66.4 µg/kg in rat brain. In conclusion, we proposed the calculated-k3 as an alternative index corresponding to regional FAAH concentrations and suggested that PET with [11C]DFMC enables occupancy study for new pharmaceuticals targeting FAAH.

We studied the simple separation of radiosilvers from proton- or deuteron-irradiated natural palladium (natPd) targets, and successfully separated radiorhodium, radiosilver and radiopalladium using an anion-exchange resin. The yields of radiosilvers were 105Ag: 1.0 ± 0.32 MBq/μAh; 106mAg: 2.0 ± 0.64 MBq/μAh; 110mAg: 0.019 ± 0.0063 MBq/μAh (n = 4) at the end of bombardment with a total recovery rate of 98 % under the following irradiation conditions (deuteron beam energy: 20 MeV; beam current: 10 μA; irradiation time: 2.25 ± 0.50 h). We also evaluated the recycling of the palladium target.

We studied the simple separation of radiosilvers from proton- or deuteron-irradiated natural palladium (natPd) targets, and successfully separated radiorhodium, radiosilver and radiopalladium using an anion-exchange resin. The yields of radiosilvers were 105Ag: 1.0 ± 0.32 MBq/μAh; 106mAg: 2.0 ± 0.64 MBq/μAh; 110mAg: 0.019 ± 0.0063 MBq/μAh (n = 4) at the end of bombardment with a total recovery rate of 98 % under the following irradiation conditions (deuteron beam energy: 20 MeV; beam current: 10 μA; irradiation time: 2.25 ± 0.50 h). We also evaluated the recycling of the palladium target.

Copper-67 (67Cu), a feasible radionuclide for diagnosis and radiotherapy, is commercially generated from a bulk zinc (Zn) target using the 68Zn(p, 2p)67Cu and 68Zn(γ, p)67Cu nuclear reactions. Because it uses a large amount of zinc, the separation is complex – requiring a combination of three ion exchange columns – and is time-consuming (about 1 day). We developed a quick and easy separation method referred to as “double coprecipitation” using H2S gas and silver nitrate as coprecipitation agents in place of ion exchange columns. We compared this method with a conventional separation method using three ion exchange columns (AG50W-X8, AG1-X8, and Chelex-100) for a natural zinc (natZn) target irradiated by a proton beam. The product quality and the recovery rate with the new method were competitive with the conventional method, and the total operation time was reduced from 1 day to

We developed a new apparatus for the routine production of 64Cu in clinical use. The apparatus has many disposable parts that stabilize the product quality (such that there is a low deviation of the concentrations of impurity metals in the product) and reduce the work load of preparation for routine production. We also developed a new evaporator using near-infrared heaters for disposable use. We conducted a production test using the new apparatus and evaluated product quality. The product yield was 6.3 ± 0.32 GBq (end of bombardment) (N = 4), the product quality in terms of the concentrations of impurity metals (Cu2+, Ni2+, Fe3+, Zn2+, Mn2+) was as good as that usually achieved, likely on the order of parts per billion, and the preparation time was reduced from 2 days to 1 day.

Introduction Copper-67 is an attractive beta emitter for targeted radionuclide therapy. However, the availability of 67Cu limits its potential use in a wide range of applications. In this study, we propose an easy small-scale production of 67Cu using 64Ni target for a preclinical study. Methods 67Cu was produced from an electrodeposited 64Ni target via the 64Ni(α, p)67Cu-reaction with a 36 MeV alpha beam at 15 eμA (electrical microampere) conducted for 7 h. The chemical separation process of 67Cu from the 64Ni target was performed following by our routine procedure of 64Cu production using cation exchange resin, AG50W-X8, with minor modification. The target and its holder were redesigned in the preparation. Results The 67Cu product was obtained with a yield of 55 ± 10 MBq at the end of bombardment (EOB), and the yield was 527 ± 96 kBq/μAh at the EOB. The copper impurity in the product was low (0.71 ± 0.21 μg) and the product was suitable for a preclinical study. Conclusions We produced 67Cu with sufficient activity and quality for a preclinical study using a 64Ni-target. This production method also showed advantages as a routine method, i.e., shorten the processing time, reducing the radiation exposure and ready target recycling, when compared with that of a conventional Zn-target used for 67Cu production.

Copper-67 (Cu) is one of the most promising radionuclides for internal radiation therapy. Globally, several projects have recently been initiated for developing innovative approaches for the large-scale production of Cu. Encouraged by these, we performed Cu-radiolabeling of a tetrameric cyclic Arg-Gly-Asp (cRGD) peptide conjugate, cyclam-RAFT-c(-RGDfK-)4, which selectively targets αVβ3 integrin (αVβ3), the transmembrane receptor involved in tumor invasion, angiogenesis, and metastasis. We also evaluated the therapeutic potential and safety of this radiocompound.Cu, produced through the Ni(α, p)Cu reaction, was used for the radiolabeling of cyclam-RAFT-c(-RGDfK-)4 at 70°C for 10 min. The radiolabeling efficiency and product stability were assessed using reversed-phase high-performance liquid chromatography and/or thin-layer chromatography. Mice with subcutaneous αVβ3-positive U87MG-glioblastoma xenografts received a single intravenous injection of one of the following: Cu-cyclam-RAFT-c(-RGDfK-)4 (11.1 MBq), peptide control, or vehicle solution. The tumor volumes were measured, side effects were assessed in terms of body weight, routine hematology, and hepatic and renal functions, and the mouse radiation dosimetry was estimated.Cu-cyclam-RAFT-c(-RGDfK-)4 was produced with a radiochemical purity of 97.9±2.4% and a specific activity of 2.7±0.6 MBq/nmol and showed high in-vitro and in-vivo plasma stability. The administration of a single dose of Cu-cyclam-RAFT-c(-RGDfK-)4 resulted in significant tumor growth delay in comparison with that observed upon vehicle or peptide control administration, with an estimated tumor-absorbed dose of 0.712 Gy. No significant toxicity was observed in Cu-cyclam-RAFT-c(-RGDfK-)4-treated mice.Cu-cyclam-RAFT-c(-RGDfK-)4 would be a promising therapeutic agent for αVβ3 integrin-targeted internal radiotherapy.

Fatty acid amide hydrolase (FAAH) is a key enzyme in the endocannabinoid system.

Introduction Copper-64 is an attractive radionuclide for positron emission tomography and is emerging as a radiotherapeutic agent. The demand of 64 Cu with low metallic impurities has increased because of its wide applications when incorporated with antibodies, peptides, and proteins. In this study, we propose a new separation method to produce high-quality 64 Cu using a cation exchange column, as well as an automated separation system suitable for large-scale production. Methods 64 Cu was produced from an electrodeposited 64 Ni target via the 64 Ni(p,n)-reaction with a 24MeV HH+ beam at 10eμA (electrical microampere) conducted for 1–3h. The irradiated target was transported to a hot cell and disassembled remotely. 64 Cu was separated by a solvent mixture of HCl and acetone on a cation-exchange resin, AG50W-X8. The chemical purity of 64 Cu final product was evaluated using ion-chromatography coupled with a UV detector and inductively coupled plasma mass spectroscopy for quality as well as metallic impurities. Results We obtained 64 Cu in dried form at a yield of 5.2–13GBq at the end of separation, or 521±12MBq/eμAh as the final product within 2.5h of processing time. The metallic impurities were a satisfactory low level in the order of ppb. Major contaminants of Co and Ni were lower than those samples obtained by a widely accepted separation using an anion-exchange resin. Conclusion Using a cation-exchange resin and a systematic operation, we successfully reduced the contamination level of the 64 Cu product. As a straightforward separation method, which shortened the entire processing time, we obtained a satisfactory amount of high-quality 64 Cu available for routine use.

ルーチン製造の許容量と操作性向上させるべく，我々は短寿命放射性薬剤調製のための新しいエバポレーターを開発した。粗製薬剤溶液へ効率的に熱量を与えうる熱源として２つの赤外線ランプを導入した。ディスポーザブル試験管をエバポレーター容器として，上記２つのIRランプの中心に設置し，２つの排気系配管を接続した。実証試験として，塩酸とアセトンの混合溶液を含むCu-64の調製を通じ，本装置の評価と最適化を行った。本機器により，Cu-64塩化銅溶液は，試験管へ投入した初期の放射能の90％以上に相当する回収率で調製できた。乾燥に要する時間は我々の従来法と比較して劇的に短縮できた。, 第58回日本核医学会学術総会

We developed a new apparatus for the routine production of

Copper-67 is an attractive beta emitter for targeted radionuclide therapy. However, the availability ofTheWe produced

We produced 43Sc and 47Sc via the nat/44Ca(α,x)-channel using a vertical beam coupled with a ceramic target box. After activation, the powdery CaO target material was dissolved in HCl in the target box in situ and remotely recovered as a radio-Sc solution. The respective yields of 43Sc and 47Sc following isolation via a precipitation method with a typical 0.22 µm sterile filter were 54.8 MBq/µA h (1.48 mCi/µA h) and 780 kBq/µA h (21.1 µCi/µA h) at the end of separation (approximately 1.5 h from the EOB). In addition, we discuss the recycling of target Ca.

Objective: The aim of this study was to develop a method to predict a tracer's alpha-value in the human brain on the basis of animal data. The alpha-value is the ratio of the conversion rate and the back-diffusion rate (k3/k2) and is one of the critical kinetic features of the detection sensitivity of target molecule activity, such as enzyme activity, in the measurement of PET and single-photon emission computed tomography using an irreversible-type radiotracer. Method: The alpha-value in the rat brain was estimated by a simultaneous assay of the tracer uptake and the target biochemical activity using N-[14C]-methylpiperidin-4-yl acetate ([14C]MP4A) and N-[14C]-methylpiperidin-4-yl propionate ([14C]MP4P) as test tracers, both of which are metabolic trapping tracers for measurement of brain acetylcholinesterase. The alpha-value in humans was then extrapolated from the alpha-value in rats by considering the differences between the species. The predicted human alpha-values were compared with those obtained from the kinetic analyses of human PET studies using [11C]MP4A and [11C]MP4P. Result: The alpha-values in the human brain cortex were predicted to be 0.51+/-0.1 for MP4A and 0.25+/-0.05 for MP4P. These results were close to values reported in other PET studies: 0.48+/-0.1 to 0.73+/-0.2 for MP4A and 0.15+/-0.04 to 0.18+/-0.04 for MP4P. Conclusion: The alpha-value predicted by this method would be used for practical selection or development of irreversible-type radiotracers for human use.

Metabotropic glutamate receptor subtype 1 (mGluR1) is a crucial molecular target in the central nervous system disorders. 4-(18)F-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ((18)F-FITM) has been recently developed as a useful PET ligand for mGluR1 imaging in our laboratory. In this study, we aimed to measure the affinity and density of mGluR1 using PET with (18)F-FITM in rat brain under the in vivo conditions.Binding potentials (BP(ND)) and amounts of specific binding (bound ligand concentration) at equilibrium state in brain regions were noninvasively estimated using the equilibrium analysis combined with the receptor-blocked approach (EA RBA) for kinetic analysis of (18)F-FITM PET results in place of reference tissue methods. Using BP(ND) and specific binding values of rats treated with multidose ligand, we performed Scatchard analyses for in vivo measurements of mGluR1 density (maximum number of binding sites, or B(max)) and ligand affinity (dissociation constant, or K(d)) in brain regions, respectively.The pretreatment of rats with unlabeled FITM (1 mg/kg) occupied an mGluR1 binding site of (18)F-FITM by more than 99% and did not affect the input function. Hence, we used the tissue time-activity curve for receptor-blocked rats as representative of the nondisplaceable (free and nonspecific binding of radioligand) compartment. The BP(ND) based on EA RBA showed a high correlation with the BP(ND) based on invasive Logan plot graphical analysis in the thalamus, hippocampus, striatum, and cingulate cortex. The K(d) (nM) and B(max) (pmol/mL) obtained by the Scatchard analyses with the multidose ligand assays were 2.1 and 36.3, respectively, for the thalamus; 2.1 and 27.5, respectively, for the hippocampus; 1.5 and 22.2, respectively, for the striatum; and 1.5 and 20.5, respectively, for the cingulate cortex with a high confidence.Our study is the first to our knowledge to measure the in vivo affinity (K(d) and binding potential) of (18)F-FITM and mGluR1 density (B(max)) with a high correlation to in vitro values in rat brain regions. This measurement using PET with (18)F-FITM would be a useful index for research about mGluR1 functions in central nervous system disorders and development of new pharmaceuticals.

Introduction When using metabolic trapping type tracers, the tracers are not always trapped in the target tissue; i.e., some are completely trapped in the target, but others can be eliminated from the target tissue at a measurable rate. The tracers that can be eliminated are termed ‘incomplete trapping irreversible tracers'. These incomplete trapping irreversible tracers may be clinically useful when the tracer β-value, the ratio of the tracer (metabolite) elimination rate to the tracer efflux rate, is under approximately 0.1. In this study, we propose a non-input analysis for incomplete trapping irreversible tracers based on the shape analysis (Shape), a non-input analysis used for irreversible tracers. Methods A Monte Carlo simulation study based on experimental monkey data with two actual PET tracers (a complete trapping irreversible tracer [ 11 C]MP4A and an incomplete trapping irreversible tracer [ 18 F]FEP-4MA) was performed to examine the effects of the environmental error and the tracer elimination rate on the estimation of the k 3 -parameter (corresponds to metabolic rate) using Shape (original) and modified Shape (M-Shape) analysis. The simulation results were also compared with the experimental results obtained with the two PET tracers. Results When the tracer β-value was over 0.03, the M-Shape method was superior to the Shape method for the estimation of the k 3 -parameter. The simulation results were also in reasonable agreement with the experimental ones. Conclusions M-Shape can be used as the non-input analysis of incomplete trapping irreversible tracers for PET study.

Cerebral enzyme activity can be quantified using positron emission tomography (PET) in conjunction with a radiolabeled enzyme substrate. We investigated the relationship between the elimination rate (kel) of tracer metabolites from the brain and the precision of target enzyme activity estimation (k3). An initial simulation study indicated that the precision of k3 estimates was highly dependent on kel, and was characterized by several kinetic parameters including the ratio of kel and the efflux rate (k2) of authentic tracer (beta xi kel/k2). The optimal tracer condition for high sensitivity was found to be beta < 0.1. To verify the simulation results, we performed a PET study with a single monkey using two PET tracers, N-[18F]fluoroethylpiperidin-4-ylmethyl acetate ([18F]FEP-4MA) and N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A). Both of these substrate type tracers were developed for measuring cerebral acetylcholinesterase activity. There was good retention of the radioactive metabolite of [11C]MP4A in the brain (kel = 0.0036 +/- 0.0013 min− 1, beta = 0.028), whereas that of [18F]FEP-4MA was eliminated from the brain (kel = 0.012 +/- 0.0010 min− 1, beta = 0.085). A non-linear least square analysis for simultaneous estimation of all parameters showed that the precision of the k3 estimate for [18F]FEP-4MA was as high (7.4%) as that for [11C]MP4A (10%). These results indicate that tracers with metabolites that are eliminated from the brain at a slow rate (beta < 0.1) may be useful for the quantitative measurement of target enzyme activity.