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The cell-type continuous electromagnetic radiation system is a demonstration device capable of generating high-power millimeter electromagnetic waves of a specific wavelength and observing their effects on living organisms. It irradiates a biological sample placed in a 30 × 30 × 50 cm3 cell with electromagnetic waves in the 3.15-mm-wavelength region (with an output of ≥1 W) and analyzes the temperature change of the sample. A vacuum electronic device-based coupled-cavity backward-wave oscillator converts the electron energy of the electron beam into radiofrequency (RF) energy and radiates it to the target through an antenna, increasing the temperature through the absorption of RF energy in the skin. The system causes pain and ultimately reduces combat power. A cell-type continuous electromagnetic radiation system consisting of four parts—an electromagnetic-wave generator, a high-voltage power supply, a test cell, and a system controller—generates an RF signal of ≥1 W in a continuous waveform at a 95-GHz center frequency, as well as a chemical solution with a dielectric constant similar to that of the skin of a living organism. An increase of 5 °C lasting approximately 10 s was confirmed through an experiment.

Background: The goal of this article was to investigate the feasibility of 64Cu labeling in prostate-specific membrane antigen imaging and therapy (PSMA I&T) for PSMA positron emission tomography (...

The aim of this work was to evaluate Gd-FC705, a prostate-specific membrane antigen (PSMA)-targeted MRI contrast agent. The r

Background Immunotherapy with clodronate-encapsulated liposomes, which induce macrophage depletion, has been studied extensively. However, previously reported liposomal formulation-based drugs (Clodrosome® and m-Clodrosome®) are limited by their inconsistent size and therapeutic efficacy. Thus, we aimed to achieve consistent therapeutic effects by effectively depleting macrophages with uniform-sized liposomes.Results We developed four types of click chemistry-based liposome nanoplatforms that were uniformly sized and encapsulated with clodronate, for effective macrophage depletion, followed by conjugation with Man-N3 and radiolabeling. Functionalization with Man-N3 improves the specific targeting of M2 macrophages, and radioisotope labeling enables in vivo imaging of the liposome nanoplatforms. The functionalized liposome nanoplatforms are stable under physiological conditions. The difference in the biodistribution of the four liposome nanoplatforms in vivo were recorded using positron emission tomography imaging. Among the four platforms, the clodronate-encapsulated mannosylated liposome effectively depleted M2 macrophages in the normal liver and tumor microenvironment ex vivo compared to that by Clodrosome® and m-Clodrosome®.Conclusion The newly-developed liposome nanoplatform, with finely tuned size control, high in vivo stability, and excellent ex vivo M2 macrophage targeting and depletion effects, is a promising macrophage-depleting agent.

We developed a novel therapeutic radioligand, [177Lu]1h, with an albumin binding motif and evaluated it in a prostate-specific membrane antigen (PSMA)-expressing tumor xenograft mouse model. Fourteen PSMA target candidates were synthesized, and binding affinity was evaluated with an in vitro competitive binding assay. First, four compound candidates were selected depending on binding affinity results. Next, we selected four compounds ([68Ga]1e, [68Ga]1g, [68Ga]1h, and [68Ga]1k) were screened for tumor targeting efficiency by micro–positron emission tomography/computed tomography (micro-PET/CT) imaging. Finally, [177Lu]1h compound was evaluated the tumor targeting efficiency and therapeutic efficiency by micro–single-photon emission computed tomography/computed tomography (micro-SPECT/CT), biodistribution, and radiotherapy studies. Estimated human effective dose was calculated by biodistribution data. Compound 1h showed a high binding affinity (Ki value = 4.08 ± 0.08 nmol/L), and [177Lu]1h showed extended blood circulation (1 hour = 10.32 ± 0.31, 6 hours = 2.68 ± 1.07%ID/g) compared to [177Lu]PSMA-617 (1 h = 0.17 ± 0.10%ID/g). [177Lu]1h was excreted via the renal pathway and showed high tumor uptake (24.43 ± 3.36%ID/g) after 1 hour, which increased over 72 hours (72 hours = 51.39 ± 9.26%ID/g). Mice treated with 4 and 6 MBq of [177Lu]1h showed a median survival rate of >61 days. In particular, all mice treated with 6 MBq of [177Lu]1h survived for the entire monitoring period. The estimated human effective dose of [177Lu]1h was 0.07 ± 0.01 and 0.03 ± 0.00 mSv/MBq in total body and kidney, respectively. The current study indicates that [177Lu]1h has the potential for further investigation of metastatic castration-resistant prostate cancer (mCRPC) therapy in clinical trials.

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

A number of researchers in Korea have tried to set-up the production of radionuclides and develop new radiopharmaceuticals for several decades. Thanks to their 60-year endeavor to advance the field of radiopharmaceutical sciences, now we have a lot of research units and facilities in Korea. Still, there are huge number of issues to be solved in radiopharmaceutical sciences; however, our efforts will be continued to develop new radiopharmaceuticals and to apply the new radiopharmaceuticals into nuclear medicine field.

We developed a novel therapeutic radioligand, [177Lu]1h, with an albumin binding motif and evaluated it in a prostate-specific membrane antigen (PSMA)-expressing tumor xenograft mouse model. Fourteen PSMA target candidates were synthesized, and binding affinity was evaluated with an in vitro competitive binding assay. First, four compound candidates were selected depending on binding affinity results. Next, we selected four compounds ([68Ga]1e, [68Ga]1g, [68Ga]1h, and [68Ga]1k) were screened for tumor targeting efficiency by micro–positron emission tomography/computed tomography (micro-PET/CT) imaging. Finally, [177Lu]1h compound was evaluated the tumor targeting efficiency and therapeutic efficiency by micro–single-photon emission computed tomography/computed tomography (micro-SPECT/CT), biodistribution, and radiotherapy studies. Estimated human effective dose was calculated by biodistribution data. Compound 1h showed a high binding affinity (Ki value = 4.08 ± 0.08 nmol/L), and [177Lu]1h showed extended blood circulation (1 hour = 10.32 ± 0.31, 6 hours = 2.68 ± 1.07%ID/g) compared to [177Lu]PSMA-617 (1 h = 0.17 ± 0.10%ID/g). [177Lu]1h was excreted via the renal pathway and showed high tumor uptake (24.43 ± 3.36%ID/g) after 1 hour, which increased over 72 hours (72 hours = 51.39 ± 9.26%ID/g). Mice treated with 4 and 6 MBq of [177Lu]1h showed a median survival rate of >61 days. In particular, all mice treated with 6 MBq of [177Lu]1h survived for the entire monitoring period. The estimated human effective dose of [177Lu]1h was 0.07 ± 0.01 and 0.03 ± 0.00 mSv/MBq in total body and kidney, respectively. The current study indicates that [177Lu]1h has the potential for further investigation of metastatic castration-resistant prostate cancer (mCRPC) therapy in clinical trials.

Early diagnosis of radiation-induced pulmonary fibrosis (RIPF) in lung cancer patients after radiation therapy is important. A gastrin-releasing peptide receptor (GRPR) mediates the inflammation and fibrosis after irradiation in mice lungs. Previously, our group synthesized a GRPR-targeted positron emission tomography (PET) imaging probe, [

64Cu-DOTA-rituximab PET/CT was performed on a 62-year-old and a 71-year-old men diagnosed with B-cell non-Hodgkin lymphoma. Compared with 18F-FDG PET/CT, lesions could be detected more sensitively, and it was confirmed that there was no discernible 64Cu-DOTA-rituximab uptake in the tumor other than lymphoma. 64Cu-DOTA-rituximab PET/CT could be a powerful tool for the diagnosis and monitoring treatment response of lymphoma because of imaging the CD20 expression.

Boron neutron capture therapy (BNCT) is a precision treatment technology that ideally damages only boron-accumulating cells. The effectiveness of BNCT depends on the amount of boron in the tumor cells and the concentration ratio between normal and tumor tissues. Therefore, for successful brain-tumor treatment using BNCT, it is essential to develop a drug with high blood-brain barrier (BBB) permeability and high tumor accumulation. The benzothiazole-based boron complex 4-(benzo[

Immuno-positron emission tomography (immuno-PET) is a rapidly growing imaging technique in which antibodies are radiolabeled to monitor their in vivo behavior in real time. However, effecting the c...

The prolonged blood circulation of the radiolabeled antibody conjugates is problematic when using immuno-PET imaging due to the increased radiation exposure and longer hospitalization required until sufficient contrast develops. In contrast to the prevailing belief that PEGylation prolongs blood retention time, we observed that a PEGylated antibody with a short PEG8 linker cleared much faster from the blood while maintaining tumor uptake compared to its non-PEGylated counterpart. Breast tumors were clearly visualized with a very high tumor-to-background ratio as early as 24 h after injection in immuno-positron emission tomography (PET) imaging.

Background The purpose of this study was to evaluate both the biodistribution and safety of 64Cu-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-Trastuzumab, a novel 64Cu-labeled positron emission tomography (PET) tracer for human epidermal growth factor receptor 2 (HER2) in patients with breast cancer. Methods PET images at 1, 24, and 48 h after 296 MBq of 64Cu-NOTA-Trastuzumab injection were obtained from seven patients with breast cancer. Both the primary tumors’ and metastatic lesions’ maximum standardized uptake value (SUVmax) was evaluated. The mean SUVmax (SUVmean) was evaluated in the other organs, including the blood pool, liver, kidney, muscle, spleen, bladder, and the lungs, as well as the bones. Moreover, the internal radiation dosimetry was calculated using the OLINDA/EXM software. Safety was assessed based on feedback regarding adverse reactions and safety-related issues within 1 month after 64Cu-NOTA-Trastuzumab administration. Results 64Cu-NOTA-Trastuzumab PET images showed that the overall SUVmean values in each organ negatively correlated with time. The liver’s average SUVmean values were measured at 5.3 ± 0.7, 4.8 ± 0.6, and 4.4 ± 0.5 on 1 h, 24 h, and 48 h after injection, respectively. The average SUVmean blood values were measured at 13.1 ± 0.9, 9.1 ± 1.2, and 7.1 ± 1.9 on 1 h, 24 h, and 48 h after injection, respectively. The SUVmax of HER2-positive tumors was relatively higher than HER2-negative tumors (8.6 ± 5.1 and 5.2 ± 2.8 on 48 h after injection, respectively). Tumor-to-background ratios were higher in the HER2-positive tumors than in the HER2-negative tumors. No adverse events related to 64Cu-NOTA-Trastuzumab were reported. The calculated effective dose with a 296 MBq injection of 64Cu-NOTA-Trastuzumab was 2.96 mSv. The highest absorbed dose was observed in the liver (0.076 mGy/MBq), followed by the spleen (0.063 mGy/MBq), kidney (0.044 mGy/MBq), and heart wall (0.044 mGy/MBq). Conclusions 64Cu-NOTA-Trastuzumab showed a specific uptake at the HER2-expressing tumors, thus making it a feasible and safe monitoring tool of HER2 tumor status in patients with breast cancer. Trial registration CRIS, KCT0002790. Registered 02 February 2018, https://cris.nih.go.kr

We have compared the similarity of the in vivo distribution of the prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging agents [18F]DCFPyL, [68Ga]ludotadipep, and [68Ga]PSMA-11. This study is designed for a further selection of a PSMA-targeted PET imaging agent for the therapeutic evaluation of [177Lu]ludotadipep, our previously developed prostate-specific membrane antigen (PSMA)-targeted prostate cancer therapeutic radiopharmaceutical. In vitro cell uptake was performed to evaluate the affinity to PSMA using PSMA + PC3-PIP, and PSMA − PC3-flu was used for the study. MicroPET/CT 60 min dynamic imaging and biodistribution were performed at 1, 2, and 4 h after injection. Autoradiography and immunohistochemistry were performed to evaluate the PSMA + tumor target efficiency. In the microPET/CT image, [68Ga]PSMA-11 showed the highest uptake in the kidney among all three compounds. [18F]DCFPyL and [68Ga]PSMA-11 showed similar patterns of in vivo biodistribution and high tumor targeting efficiency, similar to those of [68Ga]ludotadipep. All three agents showed high uptake in tumor tissue on autoradiography, and PSMA expression was confirmed by immunohistochemistry. Thus, [18F]DCFPyL or [68Ga]PSMA-11 can be used as a PET imaging agent to monitor [177Lu]ludotadipep therapy in prostate cancer patients.

Hydrogen sulfide (Hsub2/subS) plays important roles in brain pathophysiology. However, nuclear imaging probes for the in vivo detection of brain Hsub2/subS in living animals have not been developed. Here, we report the first nuclear imaging probe that enables in vivo imaging of endogenous Hsub2/subS in the brain of live mice.Utilizing a bis(thiosemicarbazone) backbone, a fluorescent ATSM-FITC conjugate was synthesized. Its copper complex, Cu(ATSM-FITC) was thoroughly tested as a biosensor for Hsub2/subS. The same ATSM-FITC ligand was quantitatively labeled with [sup64/supCu]CuClsub2/subto obtain a radioactive [sup64/supCu][Cu(ATSM-FITC)] imaging probe. Biodistribution and positron emission tomography (PET) imaging studies were performed in healthy mice and neuroinflammation models.The Cu(ATSM-FITC) complex reacts instantly with Hsub2/subS to release CuS and becomes fluorescent. It showed excellent reactivity, sensitivity, and selectivity to Hsub2/subS. Endogenous Hsub2/subS levels in living cells were successfully detected by fluorescence microscopy. Exceptionally high brain uptake of [sup64/supCu][Cu(ATSM-FITC)] (gt; 9% ID/g) was observed in biodistribution and PET imaging studies. Subtle changes in brain Hsub2/subS concentrations in live mice were accurately detected by quantitative PET imaging. Due to its dual modality feature, increased Hsub2/subS levels in neuroinflammation models were characterized at the subcellular level by fluorescence imaging and at the whole-body scale by PET imaging.Our biosensor can be readily utilized to study brain Hsub2/subS function in live animal models and shows great potential as a novel imaging agent for diagnosing brain diseases.

Photodynamic therapy (PDT) is an effective cancer treatment option, but it suffers from penetration limit of light, making it available only for superficial and endoscopically accessible cancers. Recently, there have been reports that Cerenkov luminescence originated from radioisotopes can be utilized as an excitation source for PDT without external light illumination. Here, cancer-selective agents, i.e., (1) clinically available 5-aminolevulinic acid (5-ALA), which promotes cancer metabolism-specific accumulation of protoporphyrin IX (PpIX), and (2)

To build a proton beam accelerator that can be applied to a boron neutron capture therapy system based on an electrostatic accelerator, a high-voltage direct-current (DC) power supply system equivalent to the generation of neutrons should be provided. The symmetrical Cockcroft-Walton voltage multiplier method is suitable for stable acceleration of the proton beam in the tandem electrostatic accelerator in this system. Before the second step-up with the Cockcroft-Walton circuit, the design of the inverter is prioritized by preponderantly considering the first voltage and resonance frequency. Moreover, the optimized stacking number is determined with consideration of the ripple voltage, voltage drop, average output voltage, and fundamental harmonics, and a design is performed to set related parameter values to be stable in the flat-top region of the voltage. A high-voltage DC power supply system of 1.2 MV/45 mA is needed for a stable terminal energy of 2.4 MeV/20 mA. Such a design can be optimized by securing reliable data using a simulation tool on the basis of theoretical calculations. This will become a formidable touchstone in manufacturing technology based on acquiring practical know-how for setting up a tandem electrostatic accelerator-based boron neutron capture therapy system in the future.

Background Prostate-specific membrane antigen (PSMA) is increasingly recognized as an excellent target for prostate cancer imaging and therapy. Finding compounds with a high target-to-nontarget ratio are an important challenge in the development of positron emission tomography (PET) imaging agents. In this study, we attempted to find a suitable compound from a simply-synthesized compound library. Method 18 F-labeling was achieved in a two-step synthesis consisting of [18 F]fluorination of azido sulfonates followed by copper(I)-catalyzed click ligation. In vitro binding experiment and in vivo studies were carried out using isogenic PSMA+ PC3-PIP and PSMA- PC3-flu cells and 22RV1 cells. [125 I]MIP-1095 was used to measure the binding affinities of compounds through a competitive binding assay, and [18 F]DCFPyL was used for a comparative assessment of compounds. Radiation dosimetry data were obtained using OLINDA/EXM software. Results Nine novel PSMA ligands were synthesized by the combination of three azido compounds and three terminal acetylene-containing Glu-urea-Lys compounds. Among them, compound 6f having a pyridine moiety showed a high binding affinity of 6.51 ± 0.19 nM (Ki ). 18 F-labeled compounds were obtained at moderate yields within 70 to 75 minutes (including high-performance liquid chromatography purification). Compound [18 F]6c had the lowest log P of -2.693. MicroPET/computed tomography (CT) images were acquired from 22RV1 cell xenograft mice after injecting [18 F]6c, [18 F]6f, and [18 F]6i. Additional microPET/CT experiments of [18 F]6c and [18 F]6f were performed using PSMA+ PC3-PIP and PSMA- PC3-flu cell-bearing mice. [18 F]6c was selected for further studies because it was found to have high uptake in tumors and rapid renal clearance, resulting in great tumor-to-nontumor ratios and distinct tumor images with very low background activity. Human dosimetry estimation of [18 F]6c using OLINDA/EXM software was calculated, resulting in an effective dose of 4.35 × 10-3 mSv/MBq. Conclusions [18 F]6c showed significant tumor uptake, a high tumor-to-nontumor ratio, and good radiation dosimetry results, suggesting further development as a potential diagnostic PET agent for prostate cancer.

To evaluate the biodistribution of [18F]Florastamin, a novel 18F-labelled positron emission tomography (PET) tracer for prostate-specific membrane antigen (PSMA) for the diagnosis of prostate cancer. PET was performed for five healthy controls and 10 patients with prostate cancer at 0, 10, 30, 70, and 120 mins after injecting 370 MBq of [18F]Florastamin. The maximum standardised uptake value (SUVmax) was evaluated in the primary tumour. The mean SUVmax (SUVmean) was evaluated in normal organs. Furthermore, the residence time was evaluated by assessing radioactivity in each organ. The internal radiation dosimetry was calculated using the OLINDA/EXM software. The SUVmax in primary tumours increased with time. A favourable tumour to background ratio was also observed over time. Multiple lymph nodes and bone metastases were also evaluated and showed a similar pattern to SUVmax in the primary tumour. In one patient, a tiny lymph node metastasis was identified using [18F]Florastamin PET, which was not observed using other modalities, and was histologically confirmed. The highest absorbed dose was observed in the kidney (0.062 ± 0.015 mGy/MBq), followed by the bladder (0.032 ± 0.013 mGy/MBq), liver (0.022 ± 0.006 mGy/MBq), and salivary gland (0.018 ± 0.006 mGy/MBq). The effective dose with a 370 MBq injection of [18F]Florastamin was 1.81 mSv. No adverse events related to [18F]Florastamin were reported. We identified a novel PSMA-targeted PET ligand, [18F]Florastamin, for imaging prostate cancer. [18F]Florastamin showed a high SUVmax and relatively high tumour to background ratio in both primary tumour and metastatic lesions, which suggests its high sensitivity to detect tumours without any adverse events. KCT0003924 registered at https://cris.nih.go.kr/ .

Neuroinflammation in Parkinson’s disease (PD) is known to play a pivotal role in progression to neuronal degeneration. It has been reported that colony-stimulation factor 1 receptor (CSF-1R) inhibition can effectively deplete microglia. However, its therapeutic efficacy in PD is unclear still now. To elucidate this issue, we examined the contribution of microglial depletion to PD by behavioral testing, positron emission tomography (PET) imaging, and immunoassays in sham, PD, and microglial depletion PD model (PLX3397 was administered to PD groups, with n = 6 in each group). The microglial depletion in PD model showed improved sensory motor function and depressive-like behavior. NeuroPET revealed that PLX3397 treatment resulted in partial recovery of striatal neuro-inflammatory functions (binding values of [18F]DPA-174 for PD, 1.47 ± 0.12, p 0.05). Western blotting for microglia showed similar changes. Microglial depletion has inflammation-related therapeutic effects, which have beneficial effects on motor and nonmotor symptoms of PD.

Background: Trans-splicing ribozymes (TSR) are useful anticancer agents targeting cancer-specific transcripts and replacing the RNA to induce anticancer gene expression specifically and selectively...

Developmental complex trauma is strongly associated with various psychiatric disorders in adulthood. Multiple lines of evidence have demonstrated that the amygdala-mPFC circuit regulates emotion and plays an important role in stress reactions. However, most studies on developmental trauma have mainly focused on neurological aspects in biological, behavioral, and structural changes with regard to a single stressor. In the present study, after applying complex stressors to the developmental phase, we would like to elucidate the functional changes in amygdala-mPFC circuit in the dopaminergic and serotonergic systems in the adult brain. Here, maternal separation and restraint stress were used to generate the trauma. The results showed that the body weights and corticosterone levels of animals exposed to developmental trauma decreased when compared to controls. In the neuroendocrine aspect, trauma leads to changes in proinflammatory cytokines, resulting in a decrease in IL-β and an increase in TNF-α. In the neuroPET studies, the developmental trauma group displayed a reduction in serotonergic and dopaminergic PET uptake in the amygdala and mPFC. Collectively, our results indicate that developmental trauma weakens the serotonergic and dopaminergic systems in the amygdala-mPFC circuit.

Immuno-positron emission tomography (immuno-PET) is a rapidly growing imaging technique in which antibodies are radiolabeled to monitor their in vivo behavior in real time. However, effecting the controlled conjugation of a chelate-bearing radioactive atom to a bulky antibody without affecting its immunoreactivity at a specific site is always challenging. The in vivo stability of the radiolabeled chelate is also a key issue for successful tumor imaging. To address these points, a facile ultra-stable radiolabeling platform is developed by using the propylene cross-bridged chelator (PCB-TE2A-alkyne), which can be instantly functionalized with various groups via the click reaction, thus enabling specific conjugation with antibodies as per choice. The PCB-TE2A-tetrazine derivative is selected to demonstrate the proposed strategy. The antibody trastuzumab is functionalized with the

The major pathologies of Alzheimer's disease (AD) are amyloid plaques and hyperphosphorylated tau. The deposition of amyloid plaques leads to synaptic dysfunction, neuronal cell death, and cognitive impairment. Among the neurotransmitters, glutamate is the most abundant in the mammalian brain and plays an important role in synaptic plasticity. With respect to synaptic transmission, metabotropic glutamate receptor 5 (mGluR5) is highly affected by amyloid pathology. However, the neuropathologic changes in the protein expression of mGluR5 in AD remain unclear. Therefore, to elucidate the alteration in mGluR5 expression with the progression of AD, we performed serial behavioral tests, longitudinal imaging studies, and histopathological immunoassay for both 5xFAD (n = 14) mice and age-matched wild-type mice (n = 14). The 5xFAD mice started showing severe hyperactivity and memory impairment from 7 months of age. In addition, mGluR5 positron emission tomography revealed that while the binding values in the wild-type mice were similar over time, those in 5xFAD mice fluctuated from 5 months of age. Furthermore, the 5xFAD mice presented a 35% decrease in the binding values of their cortical and subcortical areas at 9 months of age compared with those at 3 months of age. Magnetic resonance spectroscopy and histopathological studies showed similar changes. In conclusion, mGluR5 availability changes with age, and mGluR5 positron emission tomography could successfully detect this synaptic change in the 5xFAD mice.