Novel synthesis of 11 C-labeled imidazolines via Pd(0)-mediated 11 C-carbomethoxylation using [11 C]CO and arylborons.

A labeling technique was developed for the imidazoline I2 receptor ligand 2-(3-fluoro-tolyl)-4, 5-dihydro-1H-imidazole (FTIMD) using Pd(0)-mediated 11 C-carbomethoxylation with [11 C]CO, followed by imidazoline ring formation with ethylenediamine-trimethylaluminium (EDA-AlMe3 ). To achieve this, [11 C]CO was passed through a methanol (MeOH) solution containing 3-fluoro-4-methylphenylboronic acid (1), palladium (II) acetate (Pd [OAc]2 ), triphenylphosphine (PPh3 ), and p-benzoquinone (PBQ). The mixture was then heated at 65°C for 5 min. EDA was introduced into the reaction mixture, and MeOH was completely evaporated at temperatures exceeding 100°C. The dried reaction mixture was combined with an EDA-AlMe (1:1) toluene solution and heated at 145°C for 10 min. Portions of the reaction mixture were analyzed through high-performance liquid chromatography, resulting in [11 C]FTIMD with 26% (n = 2) decay-corrected radiochemical yield (RCY). This method could be utilized for various arylborons to produce [2-11 C]imidazolines 4a-h with RCYs ranging from low to moderate. Notably, [2-11 C]benazoline was obtained with a moderate RCY of 65%. The proposed technique serves as an alternative to the Grignard method, which uses [11 C]CO to generate a [2-11 C]-labeled imidazoline ring.

Novel Auger-Electron-Emitting 191Pt-Labeled Pyrrole-Imidazole Polyamide Targeting MYCN Increases Cytotoxicity and Cytosolic dsDNA Granules in MYCN-Amplified Neuroblastoma.

Auger electrons can cause nanoscale physiochemical damage to specific DNA sites that play a key role in cancer cell survival. Radio-Pt is a promising Auger-electron source for damaging DNA efficiently because of its ability to bind to DNA. Considering that the cancer genome is maintained under abnormal gene amplification and expression, here, we developed a novel 191Pt-labeled agent based on pyrrole-imidazole polyamide (PIP), targeting the oncogene MYCN amplified in human neuroblastoma, and investigated its targeting ability and damaging effects. A conjugate of MYCN-targeting PIP and Cys-(Arg)3-coumarin was labeled with 191Pt via Cys (191Pt-MYCN-PIP) with a radiochemical purity of >99%. The binding potential of 191Pt-MYCN-PIP was evaluated via the gel electrophoretic mobility shift assay, suggesting that the radioagent bound to the DNA including the target sequence of the MYCN gene. In vitro assays using human neuroblastoma cells showed that 191Pt-MYCN-PIP bound to DNA efficiently and caused DNA damage, decreasing MYCN gene expression and MYCN signals in in situ hybridization analysis, as well as cell viability, especially in MYCN-amplified Kelly cells. 191Pt-MYCN-PIP also induced a substantial increase in cytosolic dsDNA granules and generated proinflammatory cytokines, IFN-α/ß, in Kelly cells. Tumor uptake of intravenously injected 191Pt-MYCN-PIP was low and its delivery to tumors should be improved for therapeutic application. The present results provided a potential strategy, targeting the key oncogenes for cancer survival for Auger electron therapy.

A 211At-labelled mGluR1 inhibitor induces cancer senescence to elicit long-lasting anti-tumor efficacy.

Metabotropic glutamate receptor 1 (mGluR1), a key mediator of glutamatergic signaling, is frequently overexpressed in tumor cells and is an attractive drug target for most cancers. Here, we present a targeted radiopharmaceutical therapy strategy that antagonistically recognizes mGluR1 and eradicates mGluR1+ human tumors by harnessing a small-molecule alpha (α)-emitting radiopharmaceutical, 211At-AITM. A single dose of 211At-AITM (2.96 MBq) in mGluR1+ cancers exhibits long-lasting in vivo antitumor efficacy across seven subtypes of four of the most common tumors, namely, breast cancer, pancreatic cancer, melanoma, and colon cancers, with little toxicity. Moreover, complete regression of mGluR1+ breast cancer and pancreatic cancer is observed in approximate 50% of tumor-bearing mice. Mechanistically, the functions of 211At-AITM are uncovered in downregulating mGluR1 oncoprotein and inducing senescence of tumor cells with a reprogrammed senescence-associated secretory phenotype. Our findings suggest α-radiopharmaceutical therapy with 211At-AITM can be a useful strategy for mGluR1+ pan-cancers, regardless of their tissue of origin.

Dynamic imaging analysis reveals Auger electron-emitting radio-cisplatin induces DNA damage depending on the cell cycle.

Auger electrons can induce nanoscale physiochemical damage to DNA. The present study reports a sequential and systematic evaluation of the relationship between DNA damage such as double-strand breaks (DSBs) and the cell cycle for the Auger electron-emitting agent radiolabeled cisplatin with DNA binding ability. For dynamic imaging analysis, we used U2OS-derived cancer cells expressing two fluorescent fusion proteins: tumor-suppressor p53 binding protein 1 with a green fluorescent protein (53BP1-EGFP) and proliferating cell nuclear antigen with a red fluorescent protein (PCNA-DsRed). Time-lapse images of the cells were quantitatively analyzed using the ImageJ software with the deepImageJ plugin and the Google Colaboratory platform. From the middle-to-late G1 phase, around the G1-to-S phase transition, we found increased 53BP1 foci in cells treated with the radio-cisplatin. The radio-cisplatin caused significantly more DSBs than the nonradioactive cisplatin and saline in the G1 phase but not in the other phases. These results indicate that Auger electron-induced DNA damage, including DSBs, depends on the cell cycle. The G1 phase, which is associated with low DNA repair capacity and high radiosensitivity, is a promising target; thus, combining radiolabeled cisplatin with agents that arrest cells in the G1 phase could improve the DNA-damaging effect of Auger electrons and their therapeutic efficacy.

Precise quantitative evaluation of pharmacokinetics of cisplatin using a radio-platinum tracer in tumor-bearing mice.

OBJECTIVE: The platinum-based antineoplastic drug cisplatin is commonly used for chemotherapy in clinics. This work aims to demonstrate a radio-platinum tracer is useful for precisely quantifying small amounts of platinum in pharmacokinetics studies. METHODS: A cisplatin radiotracer (radio-cisplatin) was synthesized, and a comprehensive evaluation of cisplatin over 7 days after its intravenous injection into nude mice bearing a subcutaneous lung tumor (H460) was conducted. RESULTS: A biphasic retention curve in the whole body and blood was observed [ T1/2 (α) = 1.14 h, T1/2 (ß) = 5.33 days for the whole body, and T1/2 (α) = 23.9 min, T1/2 (ß) = 4.72 days for blood]. The blood concentration decreased within 1 day after injection. Most of the intact cisplatin was excreted via the kidneys in the early time points, and a small part was distributed in tissues including tumors. The plasma protein binding rate of cisplatin increased rapidly after injection, and the protein-bound cisplatin remained in the blood longer than intact cisplatin. The peak uptake in H460 tumors was 4.7% injected dose per gram at 15 min after injection, and the area under the curve (AUC 0-7 days ) was approximately one-half to one-third of the AUC 0-7 days in the kidneys, liver, and bone, where some toxicity is observed in humans. CONCLUSION: The radio-platinum tracer revealed the highly quantitative biodistribution of cisplatin, providing insights into the properties of cisplatin, including its adverse effects. The tracer enables a precise evaluation of pharmacokinetics for platinum-based drugs with high sensitivity.

Development of Novel 191Pt-Labeled Hoechst33258: 191Pt Is More Suitable than 111In for Targeting DNA.

This study aims to establish new labeling methods for no-carrier-added radio-Pt (191Pt) and to evaluate the in vitro properties of 191Pt-labeled agents compared with those of agents labeled with the common emitter 111In. 191Pt was complexed with the DNA-targeting dye Hoechst33258 via diethylenetriaminepentaacetic acid (DTPA) or the sulfur-containing amino acid cysteine (Cys). The intranuclear fractions of 191Pt- and 111In-labeled Hoechst33258 were comparable, indicating that the labeling for 191Pt via DTPA or Cys and the labeling for 111In via DTPA worked equally well. 191Pt showed a DNA-binding/cellular uptake ratio of more than 1 order of magnitude greater than that of 111In. [191Pt]Pt-Hoechst33258 labeled via Cys showed a higher cellular uptake than that labeled via DTPA, resulting in a very high DNA-binding fraction of [191Pt]Pt-Cys-Hoechst33258 and extensive DNA damage. Our labeling methods of radio-Pt, especially via Cys, promote the development of radio-Pt-based agents for use in Auger electron therapy targeting DNA.

Cyclotron production of 225Ac from an electroplated 226Ra target.

PURPOSE: We demonstrate cyclotron production of high-quality 225Ac using an electroplated 226Ra target. METHODS: 226Ra was extracted from legacy Ra sources using a chelating resin. Subsequent ion-exchange purification gave pure 226Ra with a certain amount of carrier Ba. The radium target was prepared by electroplating. We successfully deposited about 37 MBq of 226Ra on a target box. Maximum activation was achieved using 15.6 MeV protons on the target at 20 µA for 5 h. Two functional resins with various concentrations of nitric acid purified 225Ac and recovered 226Ra. Cooling the intermediate 225Ac for 2-3 weeks decayed the major byproduct of 226Ac and increased the radionuclidic purity of 225Ac. Repeating the same separation protocol provided high-quality 225Ac. RESULTS: We obtained 225Ac at a yield of about 2.4 MBq at the end of bombardment (EOB), and the subsequent initial purification gave 1.7 MBq of 225Ac with 226Ac/225Ac ratio of < 3% at 4 days from EOB. Additional cooling time coupled with the separation procedure (secondary purification) effectively increased the 225Ac (4n + 1 series) radionuclidic purity up to 99 + %. The recovered 225Ac had a similar identification to commercially available 225Ac originating from a 229Th/225Ac generator. CONCLUSION: This procedure, which involves the 226Ra(p,2n)225Ac reaction and the appropriate purification, has the potential to be a major alternative pathway for 225Ac production because it can be performed in any facility with a compact cyclotron to address the increasing demand for 225Ac.

Synthesis of no-carrier-added [188, 189, 191Pt]cisplatin from a cyclotron produced 188, 189, 191PtCl42- complex.

We developed a novel method for production of no-carrier-added (n.c.a.) [188, 189, 191Pt]PtIICl42- from an Ir target material, and then synthesized n.c.a. [*Pt]cis-[PtIICl2(NH3)2] ([*Pt]cisplatin) from [*Pt]PtIICl42-. [*Pt]PtIICl42- was prepared as a synthetic precursor of n.c.a. *Pt complex by a combination of resin extraction and anion-exchange chromatography after the selective reduction of IrIVCl62- with ascorbic acid. The ligand-substitution reaction of Cl with NH3 was promoted by treating n.c.a. [*Pt]PtIICl42- with excess NH3 and heating the reaction mixture, and n.c.a. [*Pt]cisplatin was successfully produced without employing precipitation routes. After this treatment, [*Pt]cisplatin was isolated through preparative HPLC with a radiochemical purity of 99 + % at the end of synthesis (EOS).

In Vitro Evaluation of No-Carrier-Added Radiolabeled Cisplatin ([189, 191Pt]cisplatin) Emitting Auger Electrons.

Due to their short-range (2-500 nm), Auger electrons (Auger e-) have the potential to induce nano-scale physiochemical damage to biomolecules. Although DNA is the primary target of Auger e-, it remains challenging to maximize the interaction between Auger e- and DNA. To assess the DNA-damaging effect of Auger e- released as close as possible to DNA without chemical damage, we radio-synthesized no-carrier-added (n.c.a.) [189, 191Pt]cisplatin and evaluated both its in vitro properties and DNA-damaging effect. Cellular uptake, intracellular distribution, and DNA binding were investigated, and DNA double-strand breaks (DSBs) were evaluated by immunofluorescence staining of γH2AX and gel electrophoresis of plasmid DNA. Approximately 20% of intracellular radio-Pt was in a nucleus, and about 2% of intra-nucleus radio-Pt bound to DNA, although uptake of n.c.a. radio-cisplatin was low (0.6% incubated dose after 25-h incubation), resulting in the frequency of cells with γH2AX foci was low (1%). Nevertheless, some cells treated with radio-cisplatin had γH2AX aggregates unlike non-radioactive cisplatin. These findings suggest n.c.a. radio-cisplatin binding to DNA causes severe DSBs by the release of Auger e- very close to DNA without chemical damage by carriers. Efficient radio-drug delivery to DNA is necessary for successful clinical application of Auger e-.

Utility of 211At-Trastuzumab for the Treatment of Metastatic Gastric Cancer in the Liver: Evaluation of a Preclinical α-Radioimmunotherapy Approach in a Clinically Relevant Mouse Model.

A liver metastasis from a primary gastric cancer (LMGC) is relatively common and results in an extremely poor prognosis due to a lack of effective therapeutics. We here demonstrate in a clinically relevant mouse model that an α-particle radioimmunotherapy approach with 211At-labeled trastuzumab has efficacy against LMGCs that are positive for human epidermal growth factor receptor 2 (HER2). Methods:211At was produced in a cyclotron via a 209Bi (α,2n) 211At reaction. 211At-trastuzumab was subsequently generated using a single-step labeling method. NCI-N87 cells (HER2-positive human gastric cancer cells) carrying a luciferase gene were intrasplenically transplanted into severe combined immunodeficiency mice to generate an HER2-positive LMGC model. A biodistribution study was then conducted through the intravenous injection of 211At-trastuzumab (1 MBq) into these LMGC xenograft mice. In parallel with this experimental therapy, phosphate-buffered saline, intact trastuzumab, or 211At-nonspecific human IgG (1 MBq) was injected into control groups. The therapeutic efficacy was evaluated by monitoring tumor changes by chemiluminescence imaging. Body weights, white blood cell counts, and serum markers of tissue damage were monitored at regular intervals. Microdosimetry using a CR-39 plastic detector was also performed. Results: The biodistribution analysis revealed an increased uptake of 211At-trastuzumab in the metastasized tumors that reached approximately 12% of the injected dose per gram of tissue (%ID/g) at 24 h. In contrast, its uptake to the surrounding liver was about 4 %ID/g. The LMGCs in the mouse model reduced dramatically at 1 wk after the single systemic injection of 211At-trastuzumab. No recurrences were observed in 6 of 8 mice treated with this single injection, and their survival time was significantly prolonged compared with the control groups, including the animals treated with 211At-nonspecific antibodies. No severe toxicities or abnormalities in terms of body weight, white blood cell number, liver function, or kidney parameters were observed in the 211At-trastuzumab group. Microdosimetric studies further revealed that 211At-trastuzumab had been delivered at an 11.5-fold higher dose to the LMGC lesions than to the normal liver. Conclusion: α-radioimmunotherapy with 211At-trastuzumab has considerable potential as an effective and safe therapeutic option for LMGC.

Cyclotron production of no carrier added 186gRe radionuclide for theranostic applications.

186gRe (T1/2 = 3.7183 d, E(ß-)mean = 346.7 keV, I(ß-)mean = 92.59%), a mixed beta and γ-emitter shows great potential for use in theranostic applications. The dominant 185Re(n,γ) route, via use of a nuclear reactor, provides 186gRe in carrier added form with low specific activity, while cyclotrons offer no carrier-added (NCA) high specific activity production of 186gRe. However, to be able to select the best possible nuclear reaction and to optimize the production route via the use of a cyclotron, information on the excitation function for the reaction of interest as well as for the competing reactions is necessary. Accordingly, we have conducted a detailed study of the excitation functions for natW(d, x) reactions in seeking optimized parameters for the NCA production of 186gRe. Noting a discrepancy among the experimental data, we made an evaluation of the available literature, finally selecting optimum parameters for the production of 186gRe via the 186W(d,2n)186Re reaction. These beam parameters were then used for batch production of 186gRe by irradiating an enriched 186W metallic powder target, followed by a subsequent automated chemical separation process. The preliminary results show 98.1% radionuclidic purity of 186gRe at 8 h subsequent to the End of Bombardment (EOB), offering the potential for use in clinical applications.

6-[124I]Iodo-9-pentylpurine for Imaging the Activity of the Sodium Iodide Symporter in the Brain.

Iodide homeostasis and thyroid hormone metabolism in the brain are potentially related to changes in the activity of the sodium iodide symporter (NIS). No radiotracers are currently available for imaging brain NIS activity. Here, we synthesized 6-[124I]iodo-9-pentylpurine that can noninvasively measure iodide efflux from the brain and showed that the efflux rate of [124I]I- in NIS knockout mice was 84% lower than that of wild-type mice. Thus, 6-[124I]iodo-9-pentylpurine would be useful for imaging brain NIS activity.

131I-IITM and 211At-AITM: Two Novel Small-Molecule Radiopharmaceuticals Targeting Oncoprotein Metabotropic Glutamate Receptor 1.

Targeted radionuclide therapy (TRT) targeting oncoproteins facilitates the delivery of therapeutic radionuclides to tumor tissues with high precision. Herein, we developed 2 new radiopharmaceuticals, 4-131I-iodo- and 4-211At-astato-N-[4-(6-(isopropylamino)pyridine-4-yl)-1,3-thiazol-2-yl]-N-methylbenzamide (131I-IITM and 211At-AITM), targeting the ectopic metabotropic glutamate receptor 1 (mGluR1) in melanomas for TRT studies. Methods:131I-IITM and 211At-AITM were synthesized by reacting a stannyl precursor with 131I-NaI and 211At in the presence of an oxidizing agent. The therapeutic efficacy and safety of the 2 radiopharmaceuticals were investigated using mGluR1-expressing B16F10 melanoma cells and melanoma-bearing mice. Results:131I-IITM and 211At-AITM were obtained with a radiochemical purity of greater than 99% and radiochemical yields of 42.7% ± 10.4% and 45.7% ± 6.5%, respectively, based on the total radioactivity of used radionuclides. 131I-IITM and 211At-AITM exhibited a maximum uptake of 4.66% ± 0.70 and 7.68% ± 0.71 percentage injected dose per gram (%ID/g) in the targeted melanomas, respectively, and were rapidly cleared from nontarget organs after intravenous injection. Both agents markedly inhibited melanoma growth compared with the controls (61.00% and 95.68%, respectively). In the melanoma model, considerably greater therapeutic efficacy with negligible toxicity was observed using 211At-AITM. Conclusion: The nontoxic radiopharmaceuticals 131I-IITM and 211At-AITM are useful high-precision TRT agents that can be used to target the oncoprotein mGluR1 for melanoma therapy.

PIN FORMED 2 Modulates the Transport of Arsenite in Arabidopsis thaliana.

Arsenic contamination is a major environmental issue, as it may lead to serious health hazard. The reduced trivalent form of inorganic arsenic, arsenite, is in general more toxic to plants compared with the fully oxidized pentavalent arsenate. The uptake of arsenite in plants has been shown to be mediated through a large subfamily of plant aquaglyceroporins, nodulin 26-like intrinsic proteins (NIPs). However, the efflux mechanisms, as well as the mechanism of arsenite-induced root growth inhibition, remain poorly understood. Using molecular physiology, synchrotron imaging, and root transport assay approaches, we show that the cellular transport of trivalent arsenicals in Arabidopsis thaliana is strongly modulated by PIN FORMED 2 (PIN2) auxin efflux transporter. Root transport assay using radioactive arsenite, X-ray fluorescence imaging (XFI) coupled with X-ray absorption spectroscopy (XAS), and inductively coupled plasma mass spectrometry analysis revealed that pin2 plants accumulate higher concentrations of arsenite in roots compared with the wild-type. At the cellular level, arsenite specifically targets intracellular sorting of PIN2 and thereby alters the cellular auxin homeostasis. Consistently, loss of PIN2 function results in arsenite hypersensitivity in roots. XFI coupled with XAS further revealed that loss of PIN2 function results in specific accumulation of arsenical species, but not the other metals such as iron, zinc, or calcium in the root tip. Collectively, these results suggest that PIN2 likely functions as an arsenite efflux transporter for the distribution of arsenical species in planta.

Preclinical Evaluation of the Acute Radiotoxicity of the α-Emitting Molecular-Targeted Therapeutic Agent 211At-MABG for the Treatment of Malignant Pheochromocytoma in Normal Mice.

The α-emitter 211At-labeled meta-astatobenzylguanidine (211At-MABG) has a strong antitumor effect on pheochromocytoma xenograft tumors and holds great promise as a new therapeutic option for malignant pheochromocytoma. To evaluate the acute radiation-related toxicity of 211At-MABG, we conducted biodistribution and dosimetry studies of 211At-MABG in ICR mice to estimate the doses absorbed by organs. We determined the maximum tolerated doses (MTD) of 211At-MABG on the basis of body weight loss and assessed the acute radiation-related toxicity induced by MTD administration on the basis of organ weights, histologic features, hematologic indices, and biochemical indices. The biodistribution and dosimetry studies of α-emitting 211At-MABG revealed high doses absorbed by most organs except the brain in ICR mice. The administration of 1.1, 2.2, and 3.3 MBq of 211At-MABG induced transient body weight loss, and 4.4 MBq of 211At-MABG induced unrecoverable body weight loss; thus, the MTD was 3.3 MBq for ICR mice. Although by day 5 the administration of 3.3 MBq had induced some radiation-related toxicity symptoms-such as body weight loss and leucopenia, which are generally observed in radiation therapy including ß--emitting radiopharmaceuticals-the mice had recovered by day 28. We observed no unexpected severe toxicity in ICR mice despite the high absorbed doses in most organs, especially the thyroid, heart, stomach, and adrenal glands. Our findings suggest that therapeutic treatments with appropriate doses of 211At-MABG estimated by dosimetry in each patient could be tolerated, although lower doses may initially be necessary to ensure patient safety in the first-in-human study.

Production of 191Pt from an iridium target by vertical beam irradiation and simultaneous alkali fusion.

We have developed a new method for producing 191Pt from an iridium target. Alkali fusion of iridium was successfully performed using a vertical beam irradiation method and a mixed target of Ir and Na2O2, which resulted in easy dissolution of the irradiated iridium target. A trace amount of PtⅣCl62- was isolated from bulk IrⅣCl62- by solvent extraction and anion exchange chromatography. The production yield of 191Pt was 7.1 ±â€¯0.4 (MBq/µA h, EOB) by proton irradiation at 30 MeV. The radioplatinum product (n.c.a.) was prepared at a radiochemical purity of 97% for PtⅣCl62-, and 95% for PtⅡCl42-, respectively.

Development of a remote purification apparatus with disposable evaporator for the routine production of high-quality 64Cu for clinical use.

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 ±â€¯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.

Targeted cancer cell ablation in mice by an α-particle-emitting astatine-211-labeled antibody against major histocompatibility complex class I chain-related protein A and B.

Major histocompatibility complex class I chain-related protein A and B (MICA/B) are ligands of the immune receptor, natural-killer group 2 member D. MICA/B expression is often found in several types of cancer but is restricted in normal tissues. Here, we show that an α-particle emitting astatine-211 (211At)-labeled antibody targeting MICA/B (211At-anti MICA/B Ab) efficiently ablates cancer cells in vitro and in vivo. We generated 211At-anti MICA/B Ab, an anti-MICA/B antibody conjugated with a highly cytotoxic α-particle emitting radionuclide 211At. 211At-anti MICA/B Ab binds to human osteosarcoma SaOS2 and U2OS cells that exhibit high levels of MICA/B expression and efficiently kills those cells in vitro. Biodistribution analysis using xenograft mouse models of HCT116 p53-/- positive for MICA/B expression, showed increased 211At in the xenografts for up to 22 h after injection as time proceeded. A single dose of 211At-anti MICA/B Ab (1 MBq) showed significant reduction in the tumor growth rate of HCT116 p53-/- xenografts compared to 211At-labeled mouse IgG (1 MBq) at 21 days after injection. No body weight loss and erythrocytopenia was evident in mice that received 211At-anti MICA/B. Leukocytopenia and thrombocytopenia were observed within a week after 211At-anti MICA/B injection, but counts of red blood cells and platelets were recovered to control levels at about 3-4 weeks after injection. Taken together, these data strongly demonstrate that targeted α-particle therapy using 211At-anti-MICA/B Ab emitting highly cytotoxic α-particles is a potential new therapeutic option for several types of cancer.

α-particle therapy for synovial sarcoma in the mouse using an astatine-211-labeled antibody against frizzled homolog 10.

Synovial sarcoma (SS) is a rare yet refractory soft-tissue sarcoma that predominantly affects young adults. We show in a mouse model that radioimmunotherapy (RIT) with an α-particle emitting anti-Frizzled homolog 10 (FZD10) antibody, synthesized using the α-emitter radionuclide astatine-211 (211 At-OTSA101), suppresses the growth of SS xenografts more efficiently than the corresponding ß-particle emitting anti-FZD10 antibody conjugated with the ß-emitter yettrium-90 (90 Y-OTSA101). In biodistribution analysis, 211 At was increased in the SS xenografts but decreased in other tissues up to 1 day after injection as time proceeded, albeit with a relatively higher uptake in the stomach. Single 211 At-OTSA101 doses of 25 and 50 µCi significantly suppressed SS tumor growth in vivo, whereas a 50-µCi dose of 90 Y-OTSA101 was needed to achieve this. Importantly, 50 µCi of 211 At-OTSA101 suppressed tumor growth immediately after injection, whereas this effect required several days in the case of 90 Y-OTSA101. Both radiolabeled antibodies at the 50-µCi dosage level significantly prolonged survival. Histopathologically, severe cellular damage accompanied by massive cell death was evident in the SS xenografts at even 1 day after the 211 At-OTSA101 injection, but these effects were relatively milder with 90 Y-OTSA101 at the same timepoint, even though the absorbed doses were comparable (3.3 and 3.0 Gy, respectively). We conclude that α-particle RIT with 211 At-OTSA101 is a potential new therapeutic option for SS.

Small-scale production of 67Cu for a preclinical study via the 64Ni(α, p)67Cu channel.

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 ±â€¯10 MBq at the end of bombardment (EOB), and the yield was 527 ±â€¯96 kBq/µAh at the EOB. The copper impurity in the product was low (0.71 ±â€¯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.