Optimizing the pharmacokinetics of an 211At-labeled RGD peptide with an albumin-binding moiety via the administration of an albumin-binding inhibitor.

PURPOSE: A probe for targeted alpha therapy (TAT) using the RGD peptide (Ga-DOTA-K([211At]APBA)-c(RGDfK) ([211At]1)) with albumin-binding moiety (ABM) was recently developed. [211At]1 highly accumulated in tumors and significantly inhibited tumor growth in U-87 MG tumor-bearing mice. However, high [211At]1 retention in blood may cause critical adverse events, such as hematotoxicity. Therefore, we attempted to accelerate the blood clearance of [211At]1 by competitively inhibiting the binding of [211At]1 to albumin to modulate the pharmacokinetics of the former. METHODS: To evaluate the effects of albumin-binding inhibitors in normal mice, sodium 4-(4-iodophenyl)butanoate at 2, 5, or 10 molar equivalents of blood albumin was administered at 1-h postinjection of [211At]1. The biodistribution of [211At]1, SPECT/CT imaging of [67Ga]Ga-DOTA-K(IPBA)-c(RGDfK) ([67Ga]2), and the therapeutic effects of [211At]1 were compared with or without IPBA administration in U-87 MG tumor-bearing mice. RESULTS: Blood radioactivity of [211At]1 was decreased in a dose-dependent manner with IPBA in normal mice. In U-87 MG tumor-bearing mice, the blood radioactivity and accumulation in nontarget tissues of [211At]1 were decreased by IPBA. Meanwhile, tumor [211At]1 accumulation was not changed at 3-h postinjection of IPBA. In SPECT/CT imaging of [67Ga]2, IPBA administration dramatically decreased radioactivity in nontarget tissues, and only tumor tissue was visualized. In therapeutic experiments, [211At]1 with IPBA injected-group significantly inhibited tumor growth compared to the control group. CONCLUSION: IPBA administration (as an albumin-binding inhibitor) could modulate the pharmacokinetics and enhance the therapeutic effects of [211At]1.

Recent advances in the development of 225Ac- and 211At-labeled radioligands for radiotheranostics.

Radiotheranostics utilizes a set of radioligands incorporating diagnostic or therapeutic radionuclides to achieve both diagnosis and therapy. Imaging probes using diagnostic radionuclides have been used for systemic cancer imaging. Integration of therapeutic radionuclides into the imaging probes serves as potent agents for radionuclide therapy. Among them, targeted alpha therapy (TAT) is a promising next-generation cancer therapy. The α-particles emitted by the radioligands used in TAT result in a high linear energy transfer over a short range, inducing substantial damage to nearby cells surrounding the binding site. Therefore, the key to successful cancer treatment with minimal side effects by TAT depends on the selective delivery of radioligands to their targets. Recently, TAT agents targeting biomolecules highly expressed in various cancer cells, such as sodium/iodide symporter, norepinephrine transporter, somatostatin receptor, αvß3 integrin, prostate-specific membrane antigen, fibroblast-activation protein, and human epidermal growth factor receptor 2 have been developed and have made remarkable progress toward clinical application. In this review, we focus on two radionuclides, 225Ac and 211At, which are expected to have a wide range of applications in TAT. We also introduce recent fundamental and clinical studies of radiopharmaceuticals labeled with these radionuclides.

Synthesis and Evaluation of Radiogallium Labeled Bone-Imaging Probes Using Oligo-γ-Carboxy Glutamic Acid Peptides as Carriers to Bone.

We investigated the importance of the carboxy group density in bone affinity during the development of peptide-based bone-seeking radiopharmaceuticals and carriers. Oligo-γ-carboxy glutamic acid peptides [(Gla)n] with higher carboxy group density than oligo-glutamic acid peptides [(Glu)n] and oligo-aspartic acid peptides [(Asp)n] were chosen. Using the radiogallium chelator N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC), we synthesized [67Ga]Ga-HBED-CC-(Gla)n (n = 1, 2, 5, 8, 11, or 14) with high yields. Hydroxyapatite-binding assays, biodistribution, and SPECT imaging showed higher affinity and bone accumulation for [67Ga]Ga-HBED-CC-(Gla)n compared to [67Ga]Ga-HBED-CC-(Glu)n. Notably, [67Ga]Ga-HBED-CC-(Gla)8 and [67Ga]Ga-HBED-CC-(Gla)11 exhibited superior bone accumulation and rapid blood clearance. SPECT/CT imaging with [67Ga]Ga-HBED-CC-(Gla)8 exclusively visualized the bone tissue. These findings support the potential use of [67Ga]Ga-HBED-CC-(Gla)n as excellent bone-imaging PET probes, suggesting (Gla)n peptides are superior bone-seeking carriers.

Development of probes for radiotheranostics with albumin binding moiety to increase the therapeutic effects of astatine-211 (211At).

PURPOSE: We have developed probes for multiradionuclides radiotheranostics using RGD peptide ([67Ga]Ga-DOTA-c[RGDf(4-I)K] ([67Ga]1) and Ga-DOTA-[211At]c[RGDf(4-At)K] ([211At]2)) for clinical applications. The introduction of an albumin binding moiety (ABM), such as 4-(4-iodophenyl)-butyric acid (IPBA), that has high affinity with the blood albumin and prolongs the circulation half-life can improve the pharmacokinetics of drugs. To perform more effective targeted alpha therapy (TAT), we designed and synthesized Ga-DOTA-K([211At]APBA)-c(RGDfK) ([211At]5) with 4-(4-astatophenyl)-butyric acid (APBA), which has an astato group instead of an iodo group in IPBA. We evaluated whether APBA functions as ABM and [211At]5 is effective for TAT. In addition, we prepared 67Ga-labeled RGD peptide without ABM, [67Ga]Ga-DOTA-K-c(RGDfK) ([67Ga]3), and 125I-labeled RGD peptide with ABM, Ga-DOTA-K([125I]IPBA)-c(RGDfK) ([125I]4), to compare with [211At]5. METHODS: Biodistribution experiments of [67Ga]3 without ABM, [125I]4 and [211At]5 with ABM were conducted in normal mice and U-87 MG tumor-bearing mice. In addition, two doses of [211At]5 (370 or 925 kBq) were administered to U-87 MG tumor-bearing mice to confirm the therapeutic effects. RESULTS: The blood retention of [125I]4 and [211At]5 was remarkably increased compared to [67Ga]3. Also, [125I]4 and [211At]5 showed similar biodistribution and significantly greater tumor accumulation and retention compared to [67Ga]3. In addition, [211At]5 inhibited tumor growth in a dose-dependent manner. CONCLUSION: The functionality of APBA as ABM like IPBA, and the usefulness of [211At]5 as the radionuclide therapy agent for TAT was revealed.

Trends in amount of use to upper limb function in patients with subacute stroke: a cross-sectional study using segmental regression analysis.

BACKGROUND: Hemiparesis affects approximately 33-80% of patients with stroke, and a quarter of these individuals experience difficulty with the voluntary use of their paretic upper limb for performing activities of daily living within five years of stroke onset. Therefore, assessing upper limb functionality and use after a stroke is crucial. The Fugl-Meyer Assessment (FMA) and the Motor Activity Log (MAL) are the two most widely used methods for assessing post-stroke paretic upper limb. While previous research has shown a strong correlation between the FMA of Upper Extremity (FMA-UE) and the MAL scores, to date, no study has investigated the differences in the characteristics and trends of upper extremity usage frequency in the FMA-UE. This study aimed to statistically categorize the FMA-UE scores using segmental regression analysis and identify disparities in the trends of paretic upper extremity utilization frequency in MAL. METHODS: Patients with first-episode subacute stroke were chosen for the cohort study. The primary assessments used were FMA-UE and MAL Amount of Use (MAL-A); age, gender, and time since onset served as secondary assessments. Segmental regression analysis was used, with FMA-UE as the independent variable and MAL-A as the dependent variable. R2 values were calculated using linear and polynomial regression on binary values, and the coefficients of determination were compared using segmental regression analysis. RESULTS: The study included 203 participants with a mean age of 70.1 ± 13.1 years; 113 were male and 90 female. The mean time since onset was 29.2 ± 14.8 days, the mean FMA-UE score was 43.6 ± 22.3 points, and the mean MAL-A score was 2.3 ± 2.0 points. The segmental regression analysis revealed that the inflection point for FMA-UE was 45.3 points, and the slope of the regression line underwent a transformation before and after the inflection point. CONCLUSIONS: This study indicates that the trend in the amount of use of paretic upper limb utilization changes around inflection point 45 in the FMA-UE. These findings could be useful for designing rehabilitation strategies to improve paretic upper limb utilization by increasing exercise duration in patients with subacute stroke.

Eye movement training and gaze analysis for a patient with binocular diplopia after traumatic brain injury: a case report.

BACKGROUND: Patients with traumatic brain injury often develop sequelae such as eye movement disorders, including diplopia. Eye movement training is effective in diplopia management. However, few longitudinal follow-up studies have been conducted from the subacute disease stage, owing to the complexity of methods for quantifying diplopia. CASE PRESENTATION: The patient is a 30-year-old Japanese man who presented with diplopia and underwent eye movement training for approximately 4 weeks. The angle of diplopia, distance of abduction of the eye, gaze analysis, and self-assessment of diplopia using Holmes' diplopia questionnaire were evaluated. The degree of diplopia increased from 12° to 40° on the right side. The distance of eye abduction increased from 10.4 to 12.8 mm. The self-assessment score improved from 76 to 12 points. Analysis of gaze transition revealed a reduction in the error between the target and gaze. CONCLUSION: Eye movement training was successful in ameliorating the symptoms of diplopia in the patient with binocular diplopia. Furthermore, for patients with diplopia symptoms, it was suggested that the oculomotor approach to eye movement training should not only focus on the direction of the diplopia but also on the direction opposite to the diplopia (the weak side).

Astatine-211-labeled aza-vesamicol derivatives as sigma receptor ligands for targeted alpha therapy.

INTRODUCTION: As sigma receptors are abundantly expressed on different types of cancer cells, several radiolabeled sigma receptor ligands have been developed for cancer imaging and therapy. Previously, we synthesized and evaluated radioiodinated aza-vesamicol derivatives, [125I]pIC3NV, [125I]mIC2N5V, and [125I]mIC3N5V. They accumulated in tumors, and [125I]mIC2N5V and [125I]mIC3N5V showed higher tumor to non-target tissue ratios than [125I]pIC3NV. Therefore, we synthesized and evaluated the corresponding 211At-labeled compounds, [211At]mAtC2N5V and [211At]mAtC3N5V, for targeted alpha therapy (TAT). METHODS: [211At]mAtC2N5V and [211At]mAtC3N5V were prepared by the standard method of electrophilic astatodestannylation of the corresponding trimethylstannyl precursors. Cellular uptake experiments, and biodistribution experiments and therapeutic experiments in tumor-bearing mice were performed. RESULTS: The radiochemical yields of [211At]mAtC2N5V and [211At]mAtC3N5V were 45.5 ± 14.4% and 56.9 ± 13.8%, respectively. After HPLC purification, their radiochemical purities were over 95%. [211At]mAtC2N5V and [211At]mAtC3N5V showed high uptake in DU-145 cells. They demonstrated high accumulation in tumors (6.9 ± 1.4%injected dose/g and 5.1 ± 1.4%injected dose/g at 1 h, respectively) and similar biodistribution tendencies compared with the corresponding 125I-labeled compounds. A single injection of [211At]mAtC2N5V (0.48 MBq) or [211At]mAtC3N5V (0.48 MBq) significantly inhibited tumor growth. CONCLUSION: These results indicated that [211At]mAtC2N5V and [211At]mAtC3N5V could be potential candidates for TAT.

Preparation and Evaluation of Thermosensitive Liposomes Encapsulating I-125-Labeled Doxorubicin Derivatives for Auger Electron Therapy.

Auger electrons (AEs) are very low-energy electrons emitted by radionuclides such as I-125 (125I). This energy is deposited across a small distance (<0.5 µm), resulting in high linear energy transfer that is potent for causing lethal damage to cancer cells. Thus, AE-emitting radiotherapeutic agents have great potential for cancer treatment. In this study, thermosensitive liposomes (TSLs) encapsulating 125I-labeled doxorubicin (DOX) derivatives were developed for Auger electron therapy, targeting the DNA of cancer cells. A radioiodinated DOX derivative [125I]5 highly accumulated in the nuclei of cancer cells and showed potent cytotoxicity against Colon 26 cancer cells by AEs. Subsequently, [125I]5 was loaded into the TSLs with high encapsulation efficiency. Potent release of [125I]5 from TSLs was achieved with heating, whereas a decreased release was observed without heating. Furthermore, TSLs encapsulating [125I]5 showed a high uptake in the nuclei at 42 °C for 1 h. We supposed that [125I]5 was released by heating at 42 °C and accumulated in the nuclei in the cells. These results suggest that the combination of TSLs encapsulating [125I]5 and hyperthermia is an effective cancer therapy.

Effects of Vibration-Based Generation of Timing of Tactile Perception on Upper Limb Function After Stroke: A Case Study.

Sensorimotor dysfunction of the fingers and hands hinders the recovery of motor function post-stroke. Generally, hemiplegic patients are unable to properly control the dynamic friction generated between their fingers and objects during hand/finger muscle activity. In addition to sensory information, a sense of agency generated by the temporal synchronization of sensory prediction and sensory feedback is required to control this dynamic friction. In the present study, we utilized a novel rehabilitation device that transmits real-time fingertip contact information to a transducer in a case of stroke hemiplegia with sensorimotor deficits and stagnated hand/finger motor performance. Post-intervention, the patient's upper extremity motor function score (FMA-UE), which had previously been in a state of arrested recovery, improved from 51/66 to 61/66, especially in the wrist joints. Excessive grip force during object grasping and frequency of falling objects was notably decreased post-intervention. We believe that rehabilitation tasks using perceptual generation via transducer will be a new tool for the rehabilitation of post-stroke hand/finger sensorimotor deficits.

RGD Peptide-Conjugated Dodecaborate with the Ga-DOTA Complex: A Preliminary Study for the Development of Theranostic Agents for Boron Neutron Capture Therapy and Its Companion Diagnostics.

A boron neutron capture therapy (BNCT) system, using boron-10-introduced agents coupled with companion diagnostics, is anticipated as a promising cancer theranostic. Thus, this study aimed to synthesize and evaluate a probe closo-dodecaborate-(Ga-DOTA)-c(RGDfK) (16) [Ga = gallium, DOTA =1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, and c(RGDfK) = cyclo(arginine-glycine-aspartate-d-phenylalanine-lysine] containing closo-dodecaborate ([B12H12]2-) as a boron cluster, a [67Ga]Ga-DOTA derivative for nuclear medicine imaging, and an RGD peptide for tumor targeting. Moreover, we prepared a radioiodinated probe [125I]17 in which I-125 is introduced into a closo-dodecaborate moiety of 16. [67Ga]16 and [125I]17 showed high stability and high uptake in cancer cells in vitro. Biodistribution experiments in tumor-bearing mice revealed similar biodistribution patterns between [67Ga]16 and [125I]17, such as a high uptake in the tumor and a low uptake in other non-target tissues. Meanwhile, [125I]17 exhibited higher accumulation in most tissues, including the tumor, than [67Ga]16, probably because of higher albumin binding. The higher the [125I]17 accumulation in the tumor, the more desirable it is for BNCT, with the possibility that the iodo-closo-dodecaborate site may work as an albumin binder.

Synthesis and evaluation of radiolabeled porphyrin derivatives for cancer diagnoses and their nonradioactive counterparts for photodynamic therapy.

Radioiodinated porphyrin derivatives and the corresponding nonradioactive iodine introduced compounds, [125I]I-TPPOH ([125I]3), [125I]I-l-tyrosine-TPP ([125I]9), I-TPPOH (3), and I-l-tyrosine-TPP (9) were designed, synthesized, and evaluated by in vitro and in vivo experiments. In cytotoxicity assays, 3 and 9 exhibited significant cytotoxicity under light conditions but did not show significant cytotoxicity without light irradiation. Biodistribution experiments with [125I]3 and [125I]9 showed similar distribution patterns with high retention in tumors. In photodynamic therapeutic (PDT) experiments, 3 and 9 at a dose of 13.6 µmol kg-1 weight with 50 W single light irradiation onto the tumor area significantly inhibited tumor growth. These results indicate that the iodinated porphyrin derivatives [123/natI]3 and [123/natI]9 are promising cancer theranostic agents.

Borealin-Derived Peptides as Survivin-Targeting Cancer Imaging and Therapeutic Agents.

Survivin is overexpressed in most cancer cells but is rarely expressed in normal adult tissues. It is associated with poor prognosis and resistance to radiation therapy and chemotherapy. In this study, we designed and synthesized borealin-derived small peptides (Bor peptides) to function as survivin-targeting agents for the diagnosis and treatment of cancers. These peptides exhibited binding affinities for recombinant human survivin (Kd = 49.6-193 nM), with Bor65-75 showing the highest affinity (Kd = 49.6 nM). Fluorescence images of fluorescein isothiocyanate-labeled Bor65-75 showed its co-localization with survivin expression in the human pancreatic cancer cell line, MIA PaCa-2. In the WST-1 assay, cell penetrable nona-d-arginine-conjugated Bor65-75 (r9-Bor65-75) inhibited the growth of MIA PaCa-2 cells and MDA-MB-231 cells (89 and 88% inhibition at 10 µM, respectively), whereas it had almost no effect on the human mammary epithelial cell line, MCF-10A, that inherently does not have high survivin expression. Flow cytometry with annexin V and propidium iodide staining revealed that r9-Bor65-75 induced apoptosis in MIA PaCa-2 cells in a dose-dependent manner. An increase in cleaved poly ADP-ribose polymerase protein expression was observed in MIA PaCa-2 cells exposed to r9-Bor65-75 by western blotting, suggesting that r9-Bor65-75 inhibits cell proliferation by inducing apoptosis. In vivo, r9-Bor65-75 significantly suppressed tumor growth in MIA PaCa-2 xenograft mice, without any marked weight loss. Hence, Bor peptides are promising candidates for the development of cancer imaging and anticancer agents targeting survivin.

Synthesis and evaluation of a multifunctional probe with a high affinity for prostate-specific membrane antigen (PSMA) and bone.

Prostate cancer frequently metastasizes to the bone. Because patients with bone metastases suffer from skeletal-related events, the diagnosis and treatment of bone metastases in the early stage are important. In this study, to improve the sensitivity of detecting bone metastases in patients with prostate cancer, we designed, synthesized, and evaluated a multifunctional radiotracer, [67Ga]Ga-D11-PSMA-617 ([67Ga]3), with an undeca-aspartic acid as a bone-seeking moiety between [67Ga]Ga-DOTA and a prostate-specific membrane antigen (PSMA) ligand based on the lysine-urea-glutamate motif. [67Ga]3 showed a high affinity for hydroxyapatite and high uptake in PSMA-positive LNCaP cells. Moreover, in biodistribution experiments using tumor-bearing mice, [67Ga]3 exhibited high accumulation in the bone and PSMA-positive tumor although the accumulation of [67Ga]3 in the PSMA-positive tumor was lower than that of [67Ga]Ga-PSMA-617. This study provides valuable information for developing radiotheranostic probes combining multiple carriers with different mechanisms.

Development of tumor-targeting aza-vesamicol derivatives with high affinity for sigma receptors for cancer theranostics.

As sigma receptors are highly expressed on various cancer cells, radiolabeled sigma receptor ligands have been developed as imaging and therapeutic probes for cancer. Previously, we synthesized and evaluated a radioiodinated vesamicol derivative, 2-(4-[125I](4-iodophenyl)piperidine)cyclohexanol ((+)-[125I]pIV), and a radioiodinated aza-vesamicol derivative, trans-2-(4-(3-[125I](4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([125I]2), as sigma-1 receptor-targeting probes. In order to obtain sigma receptor-targeting probes with superior biodistribution characteristics, we firstly synthesized twelve bromine-containing aza-vesamicol derivatives and evaluated their affinity for sigma receptors. One such derivative exhibited high selectivity for the sigma-1 receptor and another exhibited high affinity for both the sigma-1 and sigma-2 receptors. Thus, their halogen-substituted iodine- and radioiodine-containing compounds were prepared. The 125I-labeled compounds exhibited high uptake in tumor and lower uptake in non-target tissues than the two previously developed and evaluated 125I-labeled sigma receptor-targeting probes, [125I]pIV and [125I]2. Therefore, these novel radioiodine-labeled compounds should be promising as sigma receptor-targeting probes.

Synthesis and Biological Evaluation of Novel 2-(Benzofuran-2-yl)-chromone Derivatives for In Vivo Imaging of Prion Deposits in the Brain.

Prion diseases are fatal neurodegenerative disorders caused by the deposition of scrapie prion protein aggregates (PrPSc) in the brain. We previously reported that styrylchromone (SC) and benzofuran (BF) derivatives have potential as imaging probes for PrPSc. To further improve their properties, we designed and synthesized 2-(benzofuran-2-yl)-chromone (BFC) derivatives hybridized with SC and BF backbones as novel single-photon emission computed tomography probes for the detection of cerebral PrPSc deposits. Recombinant mouse prion protein (rMoPrP) aggregates and mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice were used to evaluate the binding properties of BFC derivatives to PrPSc. The BFC derivatives exhibited high binding affinities (equilibrium dissociation constant [Kd] = 22.6-47.7 nM) for rMoPrP aggregates. All BFC derivatives showed remarkable selectivity against amyloid beta aggregates. Fluorescence microscopy confirmed that the fluorescence signals of the BFC derivatives corresponded to the antibody-positive deposits of PrPSc in mBSE-infected mouse brains. Among the BFC derivatives, [125I]BFC-OMe and [125I]BFC-NH2 exhibited high brain uptake and favorable washout from the mouse brain. In vitro autoradiography demonstrated that the distribution of [125I]BFC-OMe in the brain tissues of mBSE-infected mice was colocalized with PrPSc deposits. Taken together, BFC derivatives appear to be promising prion imaging probes.

Development and evaluation of a theranostic probe with RGD peptide introduced platinum complex to enable tumor-specific accumulation.

Cisplatin (CDDP) has been widely used for chemotherapy. However, it has several unfavorable side effects due to its low tumor selectivity. In this study, we designed, synthesized, and evaluated Pt(IV)-[c(RGDyK)]2 (9), in which two molecules of an RGD peptide are introduced as a carrier molecule to cancer into oxoplatin, a Pt(IV) prodrug of CDDP, to enhance cancer selectivity. Furthermore, we prepared and evaluated Pt(IV)-[c(RGDyK)]{[125I]c[RGDy(3-I)K]} ([125I]10) for a preliminary step of nuclear medicine imaging and theranostics. Compound 9 inhibited cell growth in the cell viability assay and, [125I]10 was highly accumulated in tumor tissues (1 h: 3.53 ± 0.53 %ID/g) in the biodistribution study. These results indicate that implementing RGD peptides into oxoplatin enabled tumor-specific accumulation, and combining [123/124I]10 and 9 for diagnostic imaging and therapy could be useful for cancer theranostics.

Synthesis and Characterization of Hydroxyethylamino- and Pyridyl-Substituted 2-Vinyl Chromone Derivatives for Detection of Cerebral Abnormal Prion Protein Deposits.

Prion diseases are fatal neurodegenerative diseases characterized by the deposition of abnormal prion protein aggregates (PrPSc) in the brain. In this study, we developed hydroxyethylamino-substituted styrylchromone (SC) and 2-(2-(pyridin-3-yl)vinyl)-4H-chromen-4-one (VPC) derivatives for single-photon emission computed tomography (SPECT) imaging of PrPSc deposits in the brain. The binding affinity of these compounds was evaluated using recombinant mouse prion protein (rMoPrP) aggregates, which resulted in the inhibition constant (Ki) value of 61.5 and 88.0 nM for hydroxyethyl derivative, (E)-2-(4-((2-hydroxyethyl)amino)styryl)-6-iodo-4H-chromen-4-one (SC-NHEtOH) and (E)-2-(4-((2-hydroxyethyl)(methyl)amino)styryl)-6-iodo-4H-chromen-4-one (SC-NMeEtOH), respectively. However, none of the VPC derivatives showed binding affinity for the rMoPrP aggregates. Fluorescent imaging demonstrated that the accumulation pattern of SC-NHEtOH matched with the presence of PrPSc in the brain slices from mouse-adapted bovine spongiform encephalopathy-infected mice. A biodistribution study of normal mice indicated low initial brain uptake of [125I]SC-NHEtOH (0.88% injected dose/g (% ID/g) at 2 min) despite favorable washout from the brain (0.26% ID/g, at 180 min) was displayed. [125I]SC-NHEtOH exhibited binding affinities to both artificial prion aggregates as well as prion deposits in the brain. However, significant improvement in the binding affinity for PrPSc and blood-brain barrier permeability is necessary for the development of successful in vivo imaging probes for the detection of cerebral PrPSc in the brain.

Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib.

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for treating non-small-cell lung cancer (NSCLC) with EGFR mutations. Genetic testing is required to detect the mutation for selecting patients who can use osimertinib. Here, we report an attempt to develop nuclear imaging probes that detect the EGFR mutations. We designed and synthesized I-osimertinib and Br-osimertinib with a radioactive or nonradioactive halogen atom at an indole ring in osimertinib and evaluated them. In vitro assays suggested that both I-osimertinib and Br-osimertinib exhibit a specifically high activity toward NSCLC with EGFR L858R/T790M mutations. In biodistribution experiments, the accumulation of both [125I]I-osimertinib and [77Br]Br-osimertinib in tumors with mutations was significantly higher than that in blood and muscle. However, these osimertinib derivatives showed a significantly higher accumulation in lungs than in tumors. Therefore, for detecting the mutations in lung cancer, further structural modifications of the probes are required.

Transcranial direct electrical stimulation for hand function in a stroke patient with severe upper limb paralysis due to lenticulostriate artery occlusion: a case report.

BACKGROUND: Transcranial direct current stimulation, a therapeutic modality to modulate the excitability of injured and uninjured brain hemispheres in stroke patients, is expected to be effective in treating upper limb paralysis. We describe the use of transcranial direct current stimulation to improve the function and frequency of use of the paralyzed hand of a patient with lenticulostriate artery occlusion. CASE PRESENTATION: A Japanese man in his fifties developed a left internal hindfoot perforator branch infarction owing to lenticulostriate artery occlusion, and presented with severe right upper and lower limb paralysis. Multiple interventions for the paralyzed hand, primarily robot therapy, did not noticeably change his hand function or frequency of use in daily life. Therefore, transcranial direct current stimulation was used in combination with upper limb functional exercises for 20 minutes a day, five times a week, for 6 weeks. Consequently, scores for the hand items of the Fugl-Meyer Assessment of the upper extremities improved, and pain and subluxation around the shoulder joint were reduced. Furthermore, the frequency of use and the quality of movement of the paralyzed hand were improved. CONCLUSIONS: Upper limb functional training and transcranial direct current stimulation improved the function and frequency of use of the paralyzed hand in a stroke patient with severe upper limb paralysis, suggesting that this combined intervention could effectively improve hand function in patients with severe upper limb paralysis.

Synthesis and Evaluation of a Dimeric RGD Peptide as a Preliminary Study for Radiotheranostics with Radiohalogens.

We recently developed 125I- and 211At-labeled monomer RGD peptides using a novel radiolabeling method. Both labeled peptides showed high accumulation in the tumor and exhibited similar biodistribution, demonstrating their usefulness for radiotheranostics. This study applied the labeling method to a dimer RGD peptide with the aim of gaining higher accumulation in tumor tissues based on improved affinity with αvß3 integrin. We synthesized an iodine-introduced dimer RGD peptide, E[c(RGDfK)] (6), and an 125/131I-labeled dimer RGD peptide, E[c(RGDfK)]{[125/131I]c[RGDf(4-I)K]} ([125/131I]6), and evaluated them as a preliminary step to the synthesis of an 211At-labeled dimer RGD peptide. The affinity of 6 for αvß3 integrin was higher than that of a monomer RGD peptide. In the biodistribution experiment at 4 h postinjection, the accumulation of [125I]6 (4.12 ± 0.42% ID/g) in the tumor was significantly increased compared with that of 125I-labeled monomer RGD peptide (2.93 ± 0.08% ID/g). Moreover, the accumulation of [125I]6 in the tumor was greatly inhibited by co-injection of an excess RGD peptide. However, a single injection of [131I]6 (11.1 MBq) did not inhibit tumor growth in tumor-bearing mice. We expect that the labeling method for targeted alpha therapy with 211At using a dimer RGD peptide could prove useful in future clinical applications.