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Purpose Targeted α-therapy (TAT) for prostate-specific membrane antigen (PSMA) is a promising treatment for metastatic castration-resistant prostate cancer (CRPC). Astatine is an α-emitter (half-life=7.2 h) that can be produced by a 30-MeV cyclotron. This study evaluated the treatment effect of 211At-labeled PSMA compounds in mouse xenograft models. Methods Tumor xenograft models were established by subcutaneous transplantation of human prostate cancer cells (LNCaP) in NOD/SCID mouse. [211At]PSMA1, [211At]PSMA5, or [211At]PSMA6 was administered to LNCaP xenograft mice to evaluate biodistribution at 3 and 24 h. The treatment effect was evaluated by administering [211At]PSMA1 (0.40 ± 0.07 MBq), [211At]PSMA5 (0.39 ± 0.03 MBq), or saline. Histopathological evaluation was performed for the at-risk organs at 3 and 6 weeks after administration. Results [211At]PSMA5 resulted in higher tumor retention compared to [211At]PSMA1 and [211At]PSMA6 (30.6 ± 17.8, 12.4 ± 4.8, and 19.1 ± 4.5 %ID/g at 3 h versus 40.7 ± 2.6, 8.7 ± 3.5, and 18.1 ± 2.2%ID/g at 24 h, respectively), whereas kidney excretion was superior in [211At]PSMA1 compared to [211At]PSMA5 and [211At]PSMA6. An excellent treatment effect on tumor growth was observed after [211At]PSMA5 administration. [211At]PSMA1 also showed a substantial treatment effect; however, the tumor size was relatively larger compared to that with [211At]PSMA5. In the histopathological evaluation, regenerated tubules were detected in the kidneys at 3 and 6 weeks after the administration of [211At]PSMA5. Conclusion TAT using [211At]PSMA5 resulted in excellent tumor growth suppression with minimal side effects in the normal organs. [211At]PSMA5 should be considered a new possible TAT for metastatic CRPC, and translational prospective trials are warranted.

The high in vivo stability of 2,2-dihydroxymethyl-3-[18F]fluoropropyl-2-nitroimidazole ([18F]DiFA) prompted us to evaluate neopentyl as a scaffold to prepare a radiotheranostic system with radioiodine and astatine. Three DiFA analogues with one, two, or without a hydroxyl group were synthesized. While all 125I-labeled compounds remained stable against nucleophilic substitution, only a 125I-labeled neopentyl glycol was stable against cytochrome P450 (CYP)-mediated metabolism and showed high stability against in vivo deiodination. 211At-labeled neopentyl glycol also remained stable against both nucleophilic substitution and CYP-mediated metabolism. 211At-labeled neopentyl glycol showed the biodistribution profiles similar to those of its radioiodinated counterpart in contrast to the 125I/211At-labeled benzoate pair. The urine analyses confirmed that 211At-labeled neopentyl glycol was excreted in the urine as a glucuronide conjugate with the absence of free [211At]At-. These findings indicate that neopentyl glycol would constitute a promising scaffold to prepare a radiotheranostic system with radioiodine and 211At.

Purpose Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64Cu and 225Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter (177Lu)-labelled FAPI-46 and alpha-emitter (225Ac)-labelled FAPI-46 in pancreatic cancer models. Methods PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [18F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [177Lu]FAPI-46 and [225Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [177Lu]FAPI-46 and [225Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [177Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [225Ac]FAPI-46. Tumour sizes and body weights were followed. Results [18F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [177Lu]FAPI-46 and [225Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [177Lu]FAPI-46 and [225Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [177Lu]FAPI-46 were relatively slow but lasted longer than those of [225Ac]FAPI-46. Conclusion This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly.

Objective Astatine (211At) is a promising alpha emitter as an alternative to iodine (131I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [211At]NaAt to determine the FIH dose. Methods [211At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups. Results No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [211At]NaAt. Conclusions In the extended single-dose toxicity study of [211At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.

α-Methyl-l-tyrosine (AMT) has a high affinity for the cancer-specific l-type amino acid transporter 1 (LAT1). Therefore, we established an anti-cancer therapy, with 211 At-labeled α-methyl-l-tyrosine (211 At-AAMT) as a carrier of 211 At into tumors. 211 At-AAMT had high affinity for LAT1, inhibited tumor cell growth, and induced DNA double-stranded breaks in vitro. We evaluated the accumulation of 211 At-AAMT in vivo and the role of LAT1. Treatment with 0.4 MBq/mouse 211 At-AAMT inhibited tumor growth in the PANC-1 tumor model and 1 MBq/mouse 211 At-AAMT inhibited metastasis in the lung of the B16F10 metastasis model. Our results suggested that 211 At would be useful for anti-cancer therapy and that LAT1 is suitable as a target for radionuclide therapy.

Phenylalanine derivatives, which target tumors especially through L-type amino acid transporter-1 (LAT1), have elicited considerable attention. In this study, we evaluated the treatment effect of phenylalanine labeled with the alpha emitter astatine (211At-PA) in tumor bearing mice. The C6 glioma, U-87MG, and GL261 cell lines were subjected to a cellular 211At-PA uptake analysis that included an evaluation of the uptake inhibition by the system L amino acid transporter inhibitor 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). BCH significantly inhibited para-211At-PA uptake in C6 glioma (12.2 ± 0.8%), U-87MG (27.6 ± 1.1%), and GL261 (12.6 ± 2.0%) cells compared to baseline, suggesting an uptake contribution by system L amino acid transporters. Subsequently, xenograft and allograft models were prepared by subcutaneously injecting C6 glioma (n = 12) or GL-261 cells (n = 12), respectively. C6 glioma mice received three 211At-PA doses (0.1, 0.5, or 1 MBq, n = 3/dose), while GL261 mice received one high dose (1 MBq, n = 7). 211At-PA exhibited a tumor growth suppression effect in C6 glioma models in a dose-dependent manner as well as in GL-261 models. This phenylalanine derivative labeled with astatine may be applicable as an alpha therapy that specifically targets system L amino acid transporters.

Simple Summary To enhance the therapeutic effect of 2-211At-astato-α-methyl-L-phenylalanine (2-211At-AAMP), a radiopharmaceutical for targeted alpha therapy, we evaluated the effect of probenecid loading on its biodistribution and therapeutic effect in mice. Probenecid preloading significantly delayed the clearance of 2-211At-AAMP from the blood, increasing its accumulation in tumors. Consequently, the therapeutic effect of 2-211At-AAMP markedly improved. These results indicate that 2-211At-AAMP with probenecid loading is useful for the treatment of various types of cancers. Abstract L-type amino acid transporter 1 (LAT1) might be a useful target for tumor therapy since it is highly expressed in various types of cancers. We previously developed an astatine-211 (211At)-labeled amino acid derivative, 2-211At-astato-α-methyl-L-phenylalanine (2-211At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2-211At-AAMP was insufficient, probably due to its low tumor retention. The preloading of probenecid, an organic anion transporter inhibitor, can delay the clearance of some amino acid tracers from the blood and consequently increase their accumulation in tumors. In this study, we evaluated the effect of probenecid preloading on the biodistribution and therapeutic effect of 2-211At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2-211At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2-211At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2-211At-AAMP with probenecid, and the tumor volume was significantly lower in the treatment group than in the untreated control group from day 2 to day 30 (end of the follow-up period) after treatment. These results indicate that probenecid loading could improve the therapeutic effect of 2-211At-AAMP by increasing its accumulation in tumors.

The high

Objectives: To improve the prognosis of pancreatic cancer, new imaging methods to identify tumor lesions at a size of &lt, 1 cm are urgently needed. To approach this clinical issue, we developed a new method to detect small tumor lesions in the pancreas (≥3 mm) by positron emission tomography (PET) using an intraperitoneally (ip)-administered 64Cu-labeled new anti-epidermal growth factor receptor (EGFR) antibody (encoded as NCAB001), called 64Cu-NCAB001 ipPET. Methods: NCAB001 was manufactured under cGMP conditions and labeled with 64Cu. The radiochemical and biological properties of 64Cu-NCAB001 were evaluated. Tumor uptake of an ip-administered 64Cu-NCAB001 in mice with orthotopic pancreatic tumor xPA1-DC xenografts was also evaluated. Pharmacokinetics and radiation dosimetry were examined using PET images acquired after the ip administration of 64Cu-NCAB001 into cynomolgus monkeys with pharmacologic safety monitoring. Results: Radio-chromatography, cell-binding assays, and biodistribution of 64Cu-NCAB001 in mice were identical to those of our previous data with clinically available cetuximab. Small tumor lesions in the pancreas (≥3 mm) of mice could be identified by 64Cu-NCAB001 ipPET. The ip administration of 64Cu-NCAB001 into monkeys was safely conducted using ultrasound imaging. PET images in monkeys showed that ip-administered 64Cu-NCAB001 was distributed throughout the intraperitoneal cavity for up to 6 h and cleared thereafter. Most of the radioactivity was distributed in the liver and the large intestine. The radioactivity around the pancreas became negligible 24 h after administration. The estimated human effective dose was 0.0174 mSv/MBq. Conclusion: Our data support the initiation of clinical trials of 64Cu-NCAB001 ipPET to transfer this promising tool for the early diagnosis of pancreatic cancers.

Objectives: To improve the prognosis of pancreatic cancer, new imaging methods to identify tumor lesions at a size of

Background 211At is a high-energy α-ray emitter with a relatively short half-life and a high cytotoxicity for cancer cells. Its dispersion can be imaged using clinical scanners, and it can be produced in cyclotrons without the use of nuclear fuel material. This study investigated the biodistribution and the antitumor effect of 211At-labeled gold nanoparticles (211At-AuNP) administered intratumorally. Results AuNP with a diameter of 5, 13, 30, or 120 nm that had been modified with poly (ethylene glycol) methyl ether (mPEG) thiol and labeled with 211At (211At-AuNP-S-mPEG) were incubated with tumor cells, or intratumorally administered to C6 glioma or PANC-1 pancreatic cancers subcutaneously transplanted into rodent models. Systemic and intratumoral distributions of the particles in the rodents were then evaluated using scintigraphy and autoradiography, and the changes in tumor volumes were followed for about 40 days. 211At-AuNP-S-mPEG was cytotoxic when it was internalized by the tumor cells. After intratumoral administration, 211At-AuNP-S-mPEG became localized in the tumor and did not spread to systemic organs during a time period equivalent to 6 half-lives of 211At. Tumor growth was strongly suppressed for both C6 and PANC-1 by 211At-AuNP-S-mPEG. In the C6 glioma model, the strongest antitumor effect was observed in the group treated with 211At-AuNP-S-mPEG with a diameter of 5 nm. Conclusions The intratumoral single administration of a simple nanoparticle, 211At-AuNP-S-mPEG, was shown to suppress the growth of tumor tissue strongly in a particle size-dependent manner without radiation exposure to other organs caused by systemic spread of the radionuclide. Graphic Abstract

Purpose Compared to a conventional beta-emitter 131I, an alpha-emitter 211At can have a stronger treatment effect against differentiated thyroid cancer. However, its therapeutic advantage has not been fully elucidated. Thus, here, we compared the therapeutic effect of [211At]NaAt with that of [131I]NaI. Methods In vitro observation of double-stranded breaks (DSBs) and colony formation assays were performed in K1-NIS cells. The biodistribution of [131I]NaI and [211At]NaAt was measured in K1-NIS xenograft mice at 3 and 24 h (n=12). The treatment effect was compared between [131I]NaI and [211At]NaAt in K1-NIS xenograft mice using different radioactivities for each solution (1 (n=4), 4 (n=4), and 8 MBq (n=4) of [131I]NaI and 0.4 (n=7), 0.8 (n=9), and 1.2 MBq (n=4) of [211At]NaAt).Results 211At caused more DSBs in K1-NIS cells and had a greater inhibitory effect on colony formation than 131I. In K1-NIS xenograft mice, the uptake of [131I]NaI in the thyroid gland was significantly higher than that of [211At]NaAt. In other organs and tumours, the uptake of [211At]NaAt was significantly higher than that of [131I]NaI. While both [211At]NaAt and [131I]NaI showed dose-dependent therapeutic effects, [211At]NaAt showed a stronger tumour-suppressive effect. Tumour regrowth was suppressed until 18, 25, and 46 days after 0.4, 0.8, and 1.2 MBq [211At]NaAt administration, respectively, whereas it was observed within 0–12 days after [131I]NaI administration (1, 4, and 8 MBq).Conclusions The stronger tumour-suppressive effect of [211At]NaAt solution supports the promising clinical application of [211At]NaAt therapy in patients with iodine-avid thyroid cancer refractory to [131I]NaI treatment.

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, 64Cu (half-life, 12.7 h) and 225Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) in mice with human pancreatic cancer xenografts. Methods: Male nude mice (body weight, 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, n = 12; MIA PaCa-2, n = 8). Tumor xenograft mice were investigated after the intravenous injection of 64Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of 68Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice (n = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-α-antibody. For radioligand therapy, 225Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (n = 6). Tumor size was monitored and compared with that of control mice (n = 6). Results: Dynamic imaging of 64Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of 64Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for 64Cu-FAPI-04 than for 68Ga-FAPI-04, except in the heart, and excretion in the urine was higher for 68Ga-FAPI-04 than for 64Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. 225Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. Conclusion: This proof-of-concept study showed that 64Cu-FAPI-04 and 225Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. α-therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.

Background The α-emitting radionuclide radium-223 (223Ra) is widely used for the treatment of bone metastasis in patients with castration-resistant prostate cancer. However, 223Ra decays into radon-219 (219Rn) which is a noble-gas isotope, and 219Rn may escape from patients treated with 223Ra via their respiration. In this study, we quantified the amount of 219Rn contained in the breath of patients treated with 223Ra to estimate its effect on the internal exposure dose of caregivers. Methods A total of 12 breath samples were collected using a breath collection bag from a total of six patients treated with 223RaCl2. Approximately 300 mL of exhaled breath was collected in a breath bag at 1 min and at 5 min after the start of 223RaCl2 administration. The contents of each bag were measured using an HPGe detector, and the amount of 219Rn was quantified based on the detection of the γ peak of 211Bi, which is a descendant nuclide of 219Rn, persisting in the breath bag. The effective dose to caregivers arising from the inhalation of 219Rn was estimated by referring to the scenario for the calculation of release criteria established for 131I therapy in Japan. Results A small peak for the 351-keV γ ray of 211Bi originating from the exhalation of 219Rn was observed. Using the observed γ peak of 211Bi, the average amounts of 219Rn per unit breath volume at 1 min and 5 min after the start of 223RaCl2 administration were calculated as 90 ± 56 Bq/mL and 28 ± 9 Bq/mL, respectively. The effective dose of 219Rn to caregivers was estimated to be 3.5 μSv per injection. Conclusions The amount of 219Rn in the exhaled breath of patients treated with 223RaCl2 was quantitatively calculated using breath collection bags. The internal radiation exposure of caregivers from 219Rn in the exhaled breath of patients treated with 223RaCl2 is relatively small.

211At is an α-emitter that has similar chemical properties to iodine and is used in targeted α-therapy. In the present study, we added ascorbic acid (AA) to 211At solution to increase the radiochemical purity of astatide and evaluated its efficacy against differentiated thyroid cancer, which is characterized by the expression of sodium/iodide symporter (NIS). Methods: Crude 211At solution (AA(−)) and 211At solution treated with AA (AA(+)) were prepared. Uptake by the thyroid was compared between the 2 solutions in normal male Wistar rats (n = 6). Cellular uptake in K1-NIS cells was analyzed under the AA(+) and AA(−) conditions. AA(+) was injected at 3 doses into K1-NIS xenograft mice: 1 MBq (n = 6), 0.4 MBq (n = 6), and 0.1 MBq (n = 6), and vehicle was injected into control mice (n = 6). The treatment effects were compared among the 4 groups. Results: Uptake by the thyroid was significantly enhanced in rats injected with the AA(+) as compared with those injected with AA(−). Cellular uptake analysis showed significantly increased uptake of 211At by the K1-NIS cells under the AA(+) condition as compared with the AA(−) condition. In the mouse xenograft model, the K1-NIS tumors showed significant accumulation of 211At at 3 and 24 h after administration (22.5 ± 10.4 and 12.9 ± 6.8 percentage injected dose, respectively). Tumor growth was immediately inhibited in a dose-dependent manner after administration of 211At. In the survival analysis, the 211At groups (0.1, 0.4, and 1 MBq) showed significantly better survival than the control group. Conclusion: Uptake of 211At was enhanced in differentiated thyroid cancer cells as well as the normal thyroid using 211At solution treated with AA. The method also showed dose-dependent efficacy against the K1-NIS xenografts, suggesting its potential applicability to targeted α-therapy.

Objective Astatine (211At) is a promising alpha emitter as an alternative to iodine (131I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [211At]NaAt to determine the FIH dose. Methods [211At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups. Results No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [211At]NaAt. Conclusions In the extended single-dose toxicity study of [211At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.

α‐Methyl‐l‐tyrosine (AMT) has a high affinity for the cancer‐specific l‐type amino acid transporter 1 (LAT1). Therefore, we established an anti‐cancer therapy, with 211At‐labeled α‐methyl‐l‐tyrosine (211At‐AAMT) as a carrier of 211At into tumors. 211At‐AAMT had high affinity for LAT1, inhibited tumor cell growth, and induced DNA double‐stranded breaks in vitro. We evaluated the accumulation of 211At‐AAMT in vivo and the role of LAT1. Treatment with 0.4 MBq/mouse 211At‐AAMT inhibited tumor growth in the PANC‐1 tumor model and 1 MBq/mouse 211At‐AAMT inhibited metastasis in the lung of the B16F10 metastasis model. Our results suggested that 211At would be useful for anti‐cancer therapy and that LAT1 is suitable as a target for radionuclide therapy., α‐Methyl‐l‐tyrosine (AMT) has a high affinity for the cancer‐specific l‐type amino acid transporter 1 (LAT1). Therefore, we establish an anti‐cancer therapy using 211At‐labeled α‐methyl‐l‐tyrosine (211At‐AAMT) as a carrier of 211At into tumors. 211At is useful for anti‐cancer therapy and LAT1 was suitable as a target for nuclear medicine.

X-ray and gamma-ray imaging are technologies with several applications in nuclear medicine, homeland security, and high-energy astrophysics. However, it is generally difficult to realize simultaneous wide-band imaging ranging from a few tens of keV to MeV because different interactions between photons and the detector material occur, depending on the photon energies. For instance, photoabsorption occurs below 100 keV, whereas Compton scattering dominates above a few hundreds of keV. Moreover, radioactive sources generally emit both X-ray and gamma-ray photons. In this study, we develop a “hybrid” Compton camera that can simultaneously achieve X-ray and gamma-ray imaging by combining features of “Compton” and “pinhole” cameras in a single detector system. Similar to conventional Compton cameras, the detector consists of two layers of scintillator arrays with the forward layer acting as a scatterer for high-energy photons (> 200 keV) and an active pinhole for low-energy photons ($$^{241}$$ 241 Am (60 keV) and $$^{137}$$ 137 Cs (662 keV) in the same field of view, achieving an angular resolution of 10$$^\circ $$ ∘ (FWHM) for both sources. In addition, imaging of $$^{211}$$ 211 At was conducted for the application in future nuclear medicine, particularly radionuclide therapy. The initial demonstrative images of the $$^{211}$$ 211 At phantom were reconstructed using the pinhole mode (using 79 keV) and Compton mode (using 570 keV), exhibiting significant similarities in source-position localization. We also verified that a mouse injected with 1 MBq of $$^{211}$$ 211 At can be imaged via pinhole-mode measurement in an hour.

Astatine-211 (211At) is one of the most promising radionuclides for targeted α therapy of cancers and radioiodine such as iodine-123 is useful radionuclide for diagnosis. Because astatine and iodine are the same group, halogen, the same scaffolds could be used for astatination and radioiodination to prepare radiotheranostics compounds. However, the in vivo instability of 211At-labeling agents such as 211At-benzoate limits the application of 211At to various compounds. To overcome the problem and expand the application of 211At-labeled compounds to radiotheranostics, we developed neopentyl derivatives as a novel scaffold for astatination and radioiodination. The stability and biodistribution of 211At or 125I-labeled neopentyl derivatives were compared with reference compounds radiolabeled with 125I or 211At via a conventional method using benzamide., SNMMI2020 Annual Meeting

We recently reported the dose-dependent therapeutic effect of 211At-NaAt in differentiated thyroid cancer xenograft models. In the present study, we evaluated the radiation-induced toxicity of 211At-NaAt using detailed hematological, biochemical, and histological analyses. Biodistribution of 211At-NaAt was measured in normal ICR mice (n = 12), absorbed doses in the major organs were calculated. Groups of ICR mice (n = 60) were injected with 0.1 MBq or 1 MBq of 211At-NaAt, using saline as the control group (n = 30). Body weight and food intake were followed up for 60 days. Blood cell counts and serum level of biochemical parameters were measured 3, 7, 15, 29, 60 days after injection. Histological analyses of the major organs with hematoxylin and eosin staining were performed. Biodistribution study revealed a high-absorbed dose in the thyroid gland, stomach, bladder, heart, lungs, spleen, kidneys, and testis. The 0.1 MBq group showed no abnormalities. The 1 MBq group showed decreased body weight and food intake. Histological analysis showed atrophy and fibrosis in the thyroid gland, a transient hypospermatogenesis in the testis on day 29 was found in one mouse. Hematological toxicity was mild and transient. The total cholesterol, albumin, and total protein increased with no signs of recovery, which was considered to be caused by hypothyroidism. High-dose administration of 211At-NaAt showed transient toxicity in the white blood cells and testis without severe hematological or renal toxicity, suggesting its tolerable safety as targeted alpha-therapy for differentiated thyroid cancer in the 1 MBq group.

Purpose Astatine-211 (At-211) is a promising alpha emitter for radionuclide therapy. High-resolution in vivo imaging of At-211 in small animals is needed for the development of At-211 radiopharmaceuticals. For this purpose, we developed a low-energy x-ray camera using a thin YAlO3 :Ce (YAP(Ce)) plate to image the low-energy x rays (73-87 keV) from the daughter radionuclide of At-211 (Po-211). Method We optically coupled a 38 × 38 × 1-mm YAP (Ce) plate to a position-sensitive photomultiplier (PSPMT) to develop an imaging detector. A pinhole or a parallel hole collimator was attached to the imaging detector, and the performance was measured for 60-keV gamma photons. With the developed x-ray camera, we carried out imaging of a mouse that had been administered At-211-NaAt. Results The intrinsic spatial resolution of the YAP (Ce) x-ray camera was approximately 1.2 mm FWHM, and the energy resolution was 22% FWHM. With a 5-mm-thick parallel hole collimator, the spatial resolution was 3.8 mm FWHM with a sensitivity of 8 × 10-4 at 10 mm, which is a typical distance from the surface of the collimator to a subject in mouse imaging. Using a 1-mm diameter pinhole collimator, the spatial resolution was 1.8 mm FWHM with a sensitivity of 3.5 × 10-4 at 10 mm from the collimator. In the mouse images measured by the developed x-ray camera, we could clearly observe that the At-211 accumulated in the thyroid gland and the stomach of the mouse. Conclusion We concluded that the YAP (Ce) x-ray camera is useful for in vivo imaging of At-211.

We report the first ionization potentials (IP1) of the heavy actinides, fermium (Fm, atomic number Z = 100), mendelevium (Md, Z = 101), nobelium (No, Z = 102), and lawrencium (Lr, Z = 103), determined using a method based on a surface ionization process coupled to an online mass separation technique in an atom-at-a-time regime. The measured IP1 values agree well with those predicted by state-of-the-art relativistic calculations performed alongside the present measurements. Similar to the well-established behavior for the lanthanides, the IP1 values of the heavy actinides up to No increase with filling up the 5f orbital, while that of Lr is the lowest among the actinides. These results clearly demonstrate that the 5f orbital is fully filled at No with the [Rn]5f(14)7s(2) configuration and that Lr has a weakly bound electron outside the No core. In analogy to the lanthanide series, the present results unequivocally verify that the actinide series ends with Lr.

We have studied extraction behavior of group-6 elements Mo and W to search for suitable conditions for an on-line extraction experiment of their heavier homolog, seaborgium (Sg). Batch-wise extraction of carrier-free radiotracers 93mMo and 177,179,181W were carried out from 0.10 – 8.6 M H2SO4 and 1.0 × 10−4 − 5.0 M HF/1.0 M HCl into toluene with a quaternary ammonium compound, Aliquat336. Anionic sulfate complexes of Mo and W with charge − 2 were extracted with Aliquat336 from H2SO4 solutions with concentrations of [H2SO4] > 2 M. In HF/1.0 M HCl, oxyfluoro complexes of Mo and W with charge − 1 were interpreted to be formed and extracted with Aliquat336. From these results, favorable conditions for the extraction of Sg are discussed.

L-type amino acid transporter 1 (LAT1) might be a useful target for tumor therapy, since it is highly expressed in various types of cancers. We previously developed an astatine-211 (211At)-labeled amino acid derivative, 2-[211At]-astato-α-methyl-L-phenylalanine (2-[211At]-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2-[211At]-AAMP was insufficient, probably due to its low tumor retention. The preloading of probenecid, an organic anion transporter inhibitor, can delay the clearance of some amino acid tracers from the blood and consequently increase their accumulation in tumors. In this study, we evaluated the effect of probenecid preloading on the biodistribution and therapeutic effect of 2-[211At]-AAMP in mice. In biodistribution studies, the blood radioactivity of 2-[211At]-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2-[211At-AAMP] in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2-[211At]-AAMP with probenecid, and the tumor volume was significantly lower in the treatment group than in the untreated control group from day 2 to day 30 (end of the follow-up period) after treatment. These results indicate that probenecid loading could improve the therapeutic effect of 2-[211At]-AAMP by increasing its accumulation in tumors.