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The biological properties of deltic guanidinium derivatives such as target affinity, biodistribution, and metabolic stability have been studied for the first time, and the result suggested that deltic guanidinium could be a unique bioisostere of guanidinium.

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, [

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.

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-[(125)I](4-iodophenyl)piperidine)cyclohexanol ((+)-[(125)I]pIV), and a radioiodinated aza-vesamicol derivative, trans-2-(4-(3-[(125)I](4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([(125)I]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 (125)I-labeled compounds exhibited high uptake in tumor and lower uptake in non-target tissues than the two previously developed and evaluated (125)I-labeled sigma receptor-targeting probes, [(125)I]pIV and [(125)I]2. Therefore, these novel radioiodine-labeled compounds should be promising as sigma receptor-targeting probes.

Herein, we present the common structural features of a family of semiconducting molecular donor–acceptor (DA) compounds based on alkylated fused-ring thieno-acenes. Crystal structure analyses were conducted for 22 DA compounds of variously substituted benzothieno[3,2-b][1]benzothiophenes (BTBTs), unsubstituted dithieno[3,2-b:2’,3’-d]thiophene, and unsubstituted benzo[1,2-b:4,5-b’]dithiophene as donors, which were combined with 7,7,8,8-tetracyanoquinodimethane (TCNQ) and its fluorinated derivatives (FmTCNQ, m = 0, 1, 2, 4) as acceptors. Fourteen DA compounds of (substituted BTBT)(TCNQ derivative) formed isomorphous layered molecular packing, where the intermolecular stacking arrangements between the planar skeletons of BTBT and TCNQ were common to each other, and the various substituents played supplementary roles. Density functional theory calculations were conducted to investigate the intermolecular forces between π-electron cores along the DA stacks. Dispersion interactions were the dominant intermolecular attraction, showing weak stacking position dependence, while the short-range orbit–orbit interaction was always repulsive, irrespective of stacking. An important finding is that the orbit–orbit interaction has a relatively strong position dependence and leads to common structural features in the DA compounds. We discuss the origin of the isostructural nature of molecular DA compounds, which is crucial in searching for and exploring unique combinations of molecules with superior semiconducting characteristics., Journal of Materials Chemistry C, 10(43), pp.16471-16479; 2022

Weyl semimetals show unique physical properties exemplified by the colossal anomalous Hall effect, arising from exotic quasiparticles called Weyl fermions emerging around the Weyl nodes. Manipulating these topologically protected Weyl nodes is anticipated to play a leading role towards the on-demand control of quantum properties in Weyl semimetals. We demonstrate non-volatile chirality switching in a ferromagnetic Weyl semimetal Co3Sn2S2 via all-optical magnetization reversal. When excited by circularly polarized mid-infrared light pulses, the sign reversal of the anomalous Hall conductivity stemming from the Berry curvature is observed, manifesting the switching of the chirality of the Weyl nodes accompanying with the magnetization reversal. Magneto-optical imaging measurements reveal that the mechanism of the magnetization/chirality switching is attributed to the helicity-dependent deterministic magnetization associated with the magnetic circular dichroism.

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

Angiogenesis is an important process facilitating the healing process after myocardial infarction. 125I-RGD imaging may be a promising candidate to image angiogenesis but may also detect inflammation. Left coronary artery was occluded for 30 min, followed by reperfusion in a rat model (n = 31). One, 3, 7 and 14 days, 1 and 2 months later, Triple-tracer autoradiography was performed. 125I-RGD (1.5 MBq) and 201Tl (15 MBq) were injected at 80 and 10 min before sacrifice. Left coronary artery was reoccluded and 99mTc-MIBI (150–180 MBq) was injected 1 min before sacrifice to verify the area at risk. Angiogenesis and macrophage infiltration were evaluated by immunohistochemical analysis with anti-alpha-smooth muscle actin and anti-CD68, respectively. 125I-RGD uptake ratio in the area at risk was weak at day 3 (1.23 ± 0.23 but increased markedly and peaked at day 7 (2.27 ± 0.37) followed by a gradual reduction until 1 and 2 months later (1.93 ± 0.16 at 1 month, 1.58 ± 0.15 at 2 month). In the immunohistochemical analysis, copious staining of anti-CD68 cells was observed, with anti-SMA cells stained only minimally at day 3. The number of anti-CD68 cells was decreased significantly at day 7 but largely absent at 1 month. Anti-SMA positive cells peaked at day 7 and reduced gradually until 1 month. Myocardial 125I-RGD uptake reflects angiogenesis rather than inflammation after myocardial infarction.

金沢大学疾患モデル総合研究センター, Background: This study chronologically evaluated the expression of the intensity and distribution of the sigma-1 receptor (σ1R) demonstrated by radiolabeled 2-[4-(2-iodophenyl)piperidino]cyclopentanol (OI5V) in a rat model of myocardial ischemia and reperfusion. Methods and Results: The left coronary artery was occluded for 30 min, followed by reperfusion. Dual-tracer autoradiography with 125I-OI5V and 99 mTc-MIBI was performed to assess the spatiotemporal changes in 125I-OI5V uptake (n=5-6). Significant and peaked 125I-OI5V uptake in the ischemic area was observed at 3 days after reperfusion, and the 125I-OI5V uptake ratio of ischemic area to normally perfused left ventricular area decreased gradually from 3 to 28 days (mean value ± SD; 0.90±0.12 at 1 day, 1.89±0.19 at 3 days, 1.52±0.17 at 7 days, 1.34±0.13 at 14 days, and 1.16±0.14 at 28 days, respectively). Triple-tracer autoradiography with 125I-OI5V, 99 mTc-MIBI, and 201TlCl was performed to evaluate 125I-OI5V uptake in the ischemic area in relation to the residual perfusion at 7 days (n=4). The 125I-OI5V uptake ratio of the non-salvaged area was higher compared to that of the salvaged area in the ischemic area. 123I-OI5V and 99 mTc-MIBI SPECT/CT was performed 3 days after reperfusion (n=3), and the in vivo images showed clear uptake of 123I-OI5V in the perfusion defect area. Conclusions: The present study confirmed the spatiotemporal expression pattern of σ1R expression. Non-invasive σ1R imaging with 123I or 125I-OI5V was feasible to monitor the expression of σ1R after myocardial ischemia and reperfusion. © 2021 Japanese Circulation Society. All rights reserved.

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 (

Probes for radiotheranostics could be produced by introducing radionuclides with similar chemical characteristics into the same precursors. We recently developed an 211At-labeled RGD peptide and a corresponding radioiodine-labeled RGD peptide. Both labeled peptides accumulated in large quantities in the tumor with similar biodistribution, demonstrating their usefulness for radiotheranostics. In this study, we hypothesized that probes for radiotheranostics combined with multiradionuclides, such as 68Ga and 211At, have useful clinical applications. New radiolabeled RGD peptide probes were synthesized via a molecular design approach, with two labeling sites for metal and halogen. These probes were evaluated in biodistribution experiments using tumor-bearing mice. [67Ga]Ga-DOTA-c[RGDf(4-I)K] ([67Ga]4), Ga-DOTA-[125I]c[RGDf(4-I)K] ([125I]4), and Ga-DOTA-[211At]c[RGDf(4-At)K] ([211At]7) showed similar biodistribution, with high and equivalent accumulation in tumors. These results indicate the usefulness of these probes in radiotheranostics with multiradionuclides, such as a radiometal and a radiohalogen, and they could contribute to a personalized medicine regimen.

Prion diseases are fatal neurodegenerative disorders caused by 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 co-localized with PrPSc deposits. Taken together, BFC derivatives appear to be promising prion imaging probes., ACS Infectious Diseases, 8(9), pp. 1869-1882; 2022

The prepared radiolabeled porphyrin derivatives showed high accumulation in tumor tissues and good phototoxicities indicating their potential for cancer theranostics.

We investigated the characteristics of radio-iodinated 2-[4-(2-iodophenyl)piperidino]cyclopentanol (OI5V) as a single photon emission computed tomography (SPECT) ligand for mapping sigma-1 receptor (σ-1R), which plays an important role in stress remission in many organs. OI5V was synthesized from o-bromobenzaldehyde in three steps. OI5V was evaluated for its affinity to VAChT, σ-1 and σ-2 receptor by in vitro competitive binding assays using rat tissues and radioligands, [3H]vesamicol, ( +)-[3H]pentazocine and [3H]DTG, respectively. [125/123I]OI5V was prepared from o-trimethylstannyl-cyclopentanevesamicol (OT5V) by the iododestannylation reaction under no-carrier-added conditions. In vivo biodistribution study of [125I]OI5V in blood, brain regions and major organs of rats was performed at 2, 10, 30 and 60 min post-injection. In vivo blocking study and ex vivo autoradiography were performed to assess the binding selectivity of [125I]OI5V for σ-1 receptor. SPECT-CT imaging study was performed using [123I]OI5V. OI5V demonstrated high selective binding affinity for σ-1R in vitro. In the biodistribution study, the blood–brain barrier (BBB) permeability of [125I]OI5V was high and the accumulation of [125I]OI5V in the rat cortex at 2 min post-injection exceeded 2.00%ID/g. In the in vivo blocking study, the accumulation of [125I]OI5V in the brain was significantly blocked by co-administration of 0.5 μmol of SA4503 and 1.0 μmol of pentazocine. Ex vivo autoradiography revealed that the regional brain accumulation of [125I]OI5V was similar to σ-1R-rich regions of the rat brain. SPECT images of [123I]OI5V in the rat brain reflected the distribution of sigma receptors in the brain. This study confirmed that [125/123I]OI5V selectively binds σ-1R in the rat brain in vivo. [123I]OI5V was suggested to be useful as a σ-1R ligand for SPECT.

Colchicine has been used as an anti-inflammatory agent and may be cardioprotective after acute myocardial infarction (AMI). We investigated how colchicine administration after AMI affects the myocardial inflammatory response using 14C-methionine and subsequent ventricular remodeling using single-photon emission computed tomography (SPECT) in a rat model of AMI. The left coronary artery (LCA) was occluded for 30 min followed by reperfusion. 14C-methionine was injected at 20 min before sacrifice. The LCA was re-occluded at 1 min before sacrifice and 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) was injected. Colchicine was administered intraperitoneally from day 1 to the day before 14C-methionine injection. Dual-tracer autoradiography of the left ventricular short-axis slices was performed. The methionine uptake ratio in an ischemic area was calculated. 99mTc-MIBI gated SPECT assessed end-diastolic volume (EDV), end-systolic volume (ESV) and left ventricular ejection fraction (LVEF). On Cluster of Differentiation 68 with 4′,6-diamidino-2-phenylindole (CD68/DAPI) staining the positive myocardial cell percentage in an ischemic area was calculated. In control rats, 14C-methionine uptake ratios on day 3 and 7 were 1.87 ± 0.15 and 1.39 ± 0.12, respectively. With colchicine, the uptake was reduced on days 3 (1.56 ± 0.26, p = 0.042) and 7 (1.23 ± 0.10, p = 0.030). Colchicine treated rats showed smaller EDV, ESV, and higher LVEF compared with control rats. At 8 weeks, those in control rats were 864 ± 115 μL, 620 ± 100 μL, 28.4 ± 2.5%, and in colchicine rats 665 ± 75 μL, 390 ± 97 μL, 42.2 ± 8.5% (p = 0.012, 0.0061, 0.0083), respectively. In control rats, CD68/DAPI positive myocardial cell percentages on days 3 and 7 were 38.4 ± 1.9% and 24.0 ± 2.4%, respectively. With colchicine, the percentages were reduced significantly on both days 3 (31.5 ± 2.0%, p

In this study, we determined whether the 201Tl (thallium-201)-based olfactory imaging is affected if olfactory sensory neurons received reduced pre-synaptic inhibition signals from dopaminergic interneurons in the olfactory bulb in vivo. The thallium-201 migration rate to the olfactory bulb and the number of action potentials of olfactory sensory neurons were assessed 3 h following left side nasal administration of rotenone, a mitochondrial respiratory chain complex I inhibitor that decreases the number of dopaminergic interneurons without damaging the olfactory sensory neurons in the olfactory bulb, in mice (6–7 animals per group). The migration rate of thallium-201 to the olfactory bulb was significantly increased following intranasal administration of thallium-201 and rotenone (10 μg rotenone, p = 0.0012; 20 μg rotenone, p = 0.0012), compared with that in control mice. The number of action potentials was significantly reduced in the olfactory sensory neurons in the rotenone treated side of 20 μg rotenone-treated mice, compared with that in control mice (p = 0.0029). The migration rate of thallium-201 to the olfactory bulb assessed with SPECT-CT was significantly increased in rats 24 h after the left intranasal administration of thallium-201 and 100 μg rotenone, compared with that in control rats (p = 0.008, 5 rats per group). Our results suggest that thallium-201 migration to the olfactory bulb is increased in intact olfactory sensory neurons with reduced pre-synaptic inhibition from dopaminergic interneurons in olfactory bulb glomeruli.

Objectives Acridone alkaloids from Citrus and their derivatives show various kinds of biological activity. However, the anticancer activities of dimeric acridone alkaloids with unique structures and the molecular mechanism of these effects are poorly understood. Methods We investigated the cytotoxicity effects of dimeric acridone alkaloids isolated from Marsh grapefruit on human myeloid leukaemia HL-60 cells. Key findings Of the six dimeric acridone alkaloids tested, citbismine-E, the most potent, dose- and time-dependently decreased HL-60 cell viability by inducing apoptosis. The treatment of HL-60 cells with citbismine-E yielded a significant increase in levels of intracellular reactive oxygen species (ROS). Citbismine-E lowered the mitochondrial membrane potential and increased the activities of caspase-9 and -3. In addition, citbismine-E-induced apoptosis, decrease in mitochondrial membrane potential and caspase activation were significantly alleviated by pretreatment of the cells with antioxidant N-acetylcysteine (NAC). Citbismine-E induced intrinsic caspase-dependent apoptosis through ROS-mediated c-Jun N-terminal kinase activation. Citbismine-E-induced production of oxidative stress biomarkers, malondialdehyde and 8-hydroxy-2′-deoxyguanosine was also attenuated by pretreatment with NAC. Conclusions Citbismine-E is a powerful cytotoxic agent against HL-60 cells that acts by inducing mitochondrial dysfunction-mediated apoptosis through ROS-dependent JNK activation. Citbismine-E also induced oxidative stress damage via ROS-mediated lipid peroxidation and DNA damage in HL-60 cells.

There are various diagnostic and therapeutic agents for prostate cancer using bombesin (BBN) derivatives, but astatine-211 (211At)-labeled BBN derivatives have yet to be studied. This study presented a preliminary evaluation of 211At-labeled BBN derivative. Several nonradioactive iodine-introduced BBN derivatives (IB-BBNs) with different linkers were synthesized and their binding affinities measured. Because IB-3 exhibited a comparable affinity to native BBN, [211At]AB-3 was synthesized and the radiochemical yields of [211At]AB-3 was 28.2 ± 2.4%, with a radiochemical purity of >90%. The stability studies and cell internalization/externalization experiments were performed. [211At]AB-3 was taken up by cells and internalized; however, radioactivity effluxed from cells over time. In addition, the biodistribution of [211At]AB-3, with and without excess amounts of BBN, were evaluated in PC-3 tumor-bearing mice. Despite poor stability in murine plasma, [211At]AB-3 accumulated in tumor tissue (4.05 ± 0.73%ID/g) in PC-3 tumor-bearing mice, which was inhibited by excess native BBN (2.56 ± 0.24%ID/g). Accumulated radioactivity in various organs is probably due to free 211At. Peptide degradation in murine plasma and radioactivity efflux from cells are areas of improvement. The development of 211At-labeled BBN derivatives requires modifying the BBN sequence and preventing deastatination.

Porphyrins coordinated with platinum(II) chemotherapeutic drugs are attractive for the development of photosensitizers for photodynamic therapy (PDT) of cancer. In this paper, inorganic and metal-organic nanocomposites were synthesized with cascade-responsive imaging and photochemical synergistic effects. After endo/lysosomal escape, the outer metal-organic frameworks were degraded, leading to the release of an excellent photosensitizer (tetrapyridylporphyrin, PtTPyP). Subsequently, doxorubicin (DOX), inserted in the adenosine triphosphate (ATP) aptamer-functionalized gold nanoparticles, was released under the stimulation of endogenous ATP, synergistically enhancing cancer treatment. Fluorescence imaging allowed tracking of PtTPyP and DOX for real-time detection and on-demand therapy. This strategy endowed the nanocomposites with stability, responsiveness, effectiveness, and ease of synthesis, namely, sTREE strategy. Accordingly, our demonstration provided a promising and smart nanocarrier for imaging and drug delivery.

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., Chemical and Pharmaceutical Bulletin, 70(3), pp. 211-219; 2022

Auger electrons (AEs) are very low-energy electrons emitted by radionuclides such as I-125 (125I). This energy is deposited across a small distance (

BACKGROUND Methionine uptake after myocardial infarction has been proven to reflect myocardial inflammation. The effect of postconditioning on the post-infarction inflammatory process, however, remains to be elucidated.Methods and Results:In control (n=22) and postconditioning rats (n=23), the left coronary artery was occluded for 30 min, followed by reperfusion for 1, 3, 7, and 14 days. Postconditioning was performed immediately following the reperfusion. 14C-methinine (0.74 MBq) and 201Tl (14.8 MBq) were injected 20 and 10 min prior to sacrifice, respectively. One minute before sacrifice, 150-180 MBq of 99 mTc-MIBI was injected immediately following the re-occlusion of the left coronary artery to verify the area at risk, and left ventricular triple-tracer autoradiography was performed. To examine the ventricular remodeling, echocardiography was performed 2 months after reperfusion in both groups (n=6 each). In the control rats, the methionine uptake ratios on days 1, 3, 7, and 14 were 0.74±0.12, 1.85±0.16, 1.48±0.10, 1.25±0.04, respectively. With postconditioning, methionine uptake was similar on day 3 (1.90±0.21), but was lower on day 7 (1.23±0.22, P

A novel tetracationic porphyrin-platinum(II) conjugate was synthesized and characterized. This complex, 4Pt(dach)ClTPyP, showed reasonable water solubility, lack of aggregation, and high singlet ox...

“Radiotheranostics” is a term used in nuclear medicine to refer to the use of radioisotope (RI)-labeled agents to perform simultaneous imaging and therapy of a target lesion. A radiotheranostics system uses radiolanthanides as diagnostic and therapeutic RIs. In this review, we discuss radiotheranostics with radiolanthanides, focusing on the design, development strategies, and medical applications of radiolanthanide-labeled probes. We also discuss the potential and future uses of radiolanthanides in radiotheranostics.

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)]

Angiogenesis is an important process facilitating the healing process after myocardial infarction.Left coronary artery was occluded for 30 min, followed by reperfusion in a rat model (n = 31). One, 3, 7 and 14 days, 1 and 2 months later, Triple-tracer autoradiography was performed.Myocardial

Colchicine has been used as an anti-inflammatory agent and may be cardioprotective after acute myocardial infarction (AMI). We investigated how colchicine administration after AMI affects the myocardial inflammatory response usingThe left coronary artery (LCA) was occluded for 30 min followed by reperfusion.In control rats,Short-term colchicine treatment after AMI attenuated the post-AMI inflammatory response and subsequent ventricular remodeling and dysfunction.

We investigated the characteristics of radio-iodinated 2-[4-(2-iodophenyl)piperidino]cyclopentanol (OI5V) as a single photon emission computed tomography (SPECT) ligand for mapping sigma-1 receptor (σ-1R), which plays an important role in stress remission in many organs.OI5V was synthesized from o-bromobenzaldehyde in three steps. OI5V was evaluated for its affinity to VAChT, σ-1 and σ-2 receptor by in vitro competitive binding assays using rat tissues and radioligands, [OI5V demonstrated high selective binding affinity for σ-1R in vitro. In the biodistribution study, the blood-brain barrier (BBB) permeability of [This study confirmed that [

金沢大学疾患モデル総合研究センター, [223Ra]RaCl2 is the first alpha-particle emitting radiopharmaceutical to be used for castration-resistant prostate cancer patients with bone metastases because of its excellent therapeutic effects. [223Ra]RaCl2 is excreted via the intestine into feces, and some is absorbed from the intestine into the blood, which may be undesirable in terms of the exposure to radiation. Recently, we showed that a complex of myo-inositol-hexakisphosphate (InsP6) with zinc is a useful decorporation agent against radiostrontium. In this study, we hypothesized that Zn-InsP6 could bind to not only strontium but also to radium, and could inhibit the absorption of radium from the intestine. In in vitro binding experiments, Zn-InsP6 showed a high binding affinity for radium. In in vivo biodistribution experiments by intravenous injection of [223Ra]RaCl2 after treatment of Zn-InsP6, mice treated with Zn-InsP6 showed significantly lower bone accumulation of radioactivity (34.82 ± 1.83%Dose/g) than the mice in the non-treatment control group (40.30 ± 2.78%Dose/g) at 48h postinjection. These results indicate that Zn-InsP6 bound radium in the intestine and inhibited the absorption of radium into the blood. Therefore, the insoluble Zn-InsP6 complex has high potential to decrease the side effects of [223Ra]RaCl2. © 2020, The Author(s).

To develop a PET imaging agent to visualize brain cholinergic neurons and synaptic changes caused by Alzheimer's disease, (-)- and (+)-o-[11 C]methyl-trans-decalinvesamicol ([11 C]OMDV) were isolated and investigated for differences in not only their binding affinity and selectivity to vesicular acetylcholine transporter (VAChT), but also their in vivo activities. [11 C]OMDV has a high binding affinity for VAChT both in vitro and in vivo. Racemic OMDV and o-trimethylstannyl-trans-decalinvesamicol (OTDV), which are precursors for synthesis of [11 C]OMDV, were separated into (-)-optical isomers ((-)-OMDV and (-)-OTDV) and (+)-optical isomers ((+)-OMDV and (+)-OTDV) by HPLC. In the in vitro binding assay, (-)-OMDV(7.2 nM) showed eight times higher binding affinity (Ki) to VAChT than that of (+)-OMDV(57.5 nM). In the biodistribution study, the blood-brain barrier permeability of both enantiomers ((-)-[11 C]OMDV and (+)-[11 C]OMDV) was similarly high (about 1.0%ID/g) at 2 min post-injection. However, (+)-[11 C]OMDV clearance from the brain was faster than (-)-[11 C]OMDV. In the in vivo blocking study, accumulation of (-)-[11 C]OMDV in the cortex was markedly decreased (approximately 30% of control) by coadministration of vesamicol, and brain uptake of (-)-[11 C]OMDV was not significantly altered by coadministration of (+)-pentazocine or (+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP). PET-CT imaging revealed inhibition of the rat brain uptake of (-)-[11 C]OMDV by coadministration of vesamicol. In conclusion, (-)-[11 C]OMDV, which is an enantiomer of OMDV, selectively binds to VAChT with high affinity in the rat brain in vivo. (-)-[11 C]OMDV may be utilized as a potential PET ligand for studying presynaptic cholinergic neurons in the brain.

Rociletinib (CO-1686), a 2,4-diaminopyrimidine derivative, is a highly potent tyrosine kinase inhibitor (TKI) that acts on epidermal growth factor receptor (EGFR) with L858R/T790M mutations. We supposed radioiodinated CO-1686 would function as a useful tool for monitoring EGFR L858R/T790M mutations. To aid in patient selection before therapy with EGFR-TKIs, this study aimed to develop a 125I-labeled derivative of CO-1686, N-{3-[(2-{[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino}-5-(trifluoromethyl)pyrimidine-4-yl] amino}-5-([125I]iodophenyl)acrylamide ([125I]ICO1686) and evaluate its selectivity toward EGFR L858R/T790M. Radiosynthesis was performed by iododestannylation of the corresponding tributylstannyl precursor with [125I]NaI and N-chlorosuccinimide. The selectivity of the tracer for detecting EGFR L858R/T790M was evaluated using three relevant non-small cell lung cancer (NSCLC) cell lines&mdash, H1975, H3255 and H441 overexpressing the dual mutation EGFR L858R/T790M, active mutant EGFR L858R and wild-type EGFR, respectively. The nonradioactive ICO1686 and the precursor compound were successfully synthesized. A novel radiolabeled probe, [125I]ICO1686, was prepared with high radiochemical yield (77%) and purity (&gt, 99%). ICO1686 exhibited high cytotoxicity toward H1975 (IC50 0.20 &plusmn, 0.05 &mu, M) and H3255 (IC50 0.50 &plusmn, 0.21 &mu, M), which is comparable to that of CO-1686. In contrast, the cytotoxicity of ICO1686 toward H441 was 10-fold lower than that toward H1975. In the cell uptake study, the radioactivity uptake of [125I]ICO1686 in H1975 was 101.52% dose/mg, whereas the uptakes in H3255 and H441 were 33.52 and 8.95% dose/mg, respectively. The uptake of [125I]ICO1686 in H1975 was greatly reduced to 45.61% dose/mg protein by treatment with excess CO-1686. In vivo biodistribution study of the radiotracer found that its accumulation in H1975 tumor (1.77 &plusmn, 0.43% ID/g) was comparable to that in H3255 tumor (1.63 &plusmn, 0.23% ID/g) and the accumulation in H1975 tumor was not reduced by pretreatment with an excess dose of CO-1686. Although this radiotracer exhibited highly specific in vitro uptake in target cancer cells, structural modification is required to improve in vivo biodistribution.

Several malignant tumors and fibrotic diseases are associated with PDGFRβ overexpression and excessive signaling, making this receptor attractive for molecular targeting and imaging approaches. A series of benzo[d]imidazole-quinoline derivatives were designed and synthesized to develop radioiodinated compounds as PDGFRβ-specific imaging probes. The structure activity relationship (SAR) evaluation of the designed compounds was performed. Among them, 2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (5a) and 4-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (5d) exhibited a relatively high PDGFRβ-TK inhibitory potency, whereas iodinated 5a derivative 5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (8) exhibited a superior inhibitory potency as PDGFRβ inhibitor than iodinated 5d derivative 4-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (11). Furthermore, [125I]8 and [125I]11 were synthesized and evaluated for PDGFRβ radioligand ability, both in vitro and in vivo. Cellular uptake experiments showed that [125I]8 had a higher uptake in BxPC3-luc cells as PDGFRβ-positive cells than [125I]11. Incubation of [125I]8 after pretreatment of PDGFRβ ligands significantly reduced the uptake of [125I]8. In biodistribution experiments using tumor-bearing mice, [125I]8 accumulation in the tumor 1 h postinjection was higher than that of the benzo[d]imidazol-quinoline derivative [125I]IIQP, used in our previous research. These results indicate that [125I]8 could be a promising PDGFRβ imaging agent. Although its clinical application requires further structural modifications, the results obtained in this research may be useful for the development of PDGFRβ-specific radioligands.

To develop a PET imaging agent to visualize brain cholinergic neurons and synaptic changes caused by Alzheimer's disease, (-)- and (+)-o-[

The new palladium(II) complex, [Pd(bpy)(AtC3)]2+, where bpy = 2,2′-bipyridine and AtC3 = N-(9-anthracenylmethyl)-1,3-propanediamine, was synthesized and characterized. The crystal structure of [Pd(...

Epigenetic deregulation plays an essential role in colorectal cancer progression. Bromodomains are epigenetic “readers” of histone acetylation. Bromodomain-containing protein 4 (BRD4) plays a pivotal role in transcriptional regulation and is a feasible drug target in cancer cells. Disease-specific elevation of nucleoporin, a component of the nuclear pore complex (NPC), is a determinant of cancer malignancy, but BRD4-driven changes of NPC composition remain poorly understood. Here, we developed novel aminocyclopropenones and investigated their biological effects on cancer cell growth and BRD4 functions. Among 21 compounds developed here, we identified aminocyclopropenone 1n (ACP-1n) with the strongest inhibitory effects on the growth of the cancer cell line HCT116. ACP-1n blocked BRD4 functions by preventing its phase separation ability both in vitro and in vivo, attenuating the expression levels of BRD4-driven MYC. Notably, ACP-1n significantly reduced the nuclear size with concomitant suppression of the level of the NPC protein nucleoporin NUP210. Furthermore, NUP210 is in a BRD4-dependent manner and silencing of NUP210 was sufficient to decrease nucleus size and cellular growth. In conclusion, our findings highlighted an aminocyclopropenone compound as a novel therapeutic drug blocking BRD4 assembly, thereby preventing BRD4-driven oncogenic functions in cancer cells. This study facilitates the development of the next generation of effective and potent inhibitors of epigenetic bromodomains and extra-terminal (BET) protein family.

Platinum antitumour agents, containing aromatic rings, which are used for targeting DNA in effective therapies for the treatment of cancer. We have synthesized the title metallocomplex with an aromatic ligand and determined its crystal structure. In many cases, complexes of platinum and other metals have a symmetrical structure. In contrast, the platinum(II) complex with pyridine and N-(9-anthracenylmethyl)-1,2-ethanediamine as ligands (systematic name: cis-{N-[(anthracen-9-yl)methyl]ethane-1,2-diamine-κ2 N,N′}bis(pyridine-κN)platinum(II) dinitrate), [Pt(C5H5N)2(C17H18N2)](NO3)2, is asymmetric. Of the two pyridine ligands, only one is π-stacked with anthracene, resulting in an asymmetric structure. Moreover, the angle of orientation of each pyridine ligand is variable. Further examination of the packing motif confirms an intermolecular edge-to-face interaction.

The anorexigenic neuropeptide NEFA/nucleobindin 2 (NUCB2)/nesfatin-1-containing neurons are distributed in the brain regions involved in feeding regulation. In spite of the growing knowledge of its physiological functions through extensive studies, its molecular mechanism of reaction, including its receptor, remains unknown. NUCB2/nesfatin-1 is also involved in various peripheral regulations, including glucose homeostasis. In pancreatic beta-cells, NUCB2/nesfatin-1 is reported to enhance glucose-stimulated insulin secretion (GSIS) but its exact mechanism remains unknown. To clarify this mechanism, we measured the effect of nesfatin-1 on the electrical activity of pancreatic beta-cells. Using mouse primary beta cells, we measured changes in the ATP-sensitive K+ (KATP) channel current, the voltage-gated K+ (Kv) channel current, and insulin secretion upon application of nesfatin-1. Nesfatin-1 inhibited the Kv channel, but KATP channel activity was unaffected. Nesfatin-1 enhanced insulin secretion to a same level as Kv channel blocker tetraethylammonium (TEA). The effect was not further enhanced when nesfatin-1 and TEA were applied simultaneously. The inhibition binding assay with [125I]nesfatin-1 in Kv2.1 channels, major contributor of Kv current in beta cell, expressing HEK239 cells indicated the binding of nesfatin-1 on Kv2.1 channel. Because Kv channel inhibition enhances insulin secretion under high glucose conditions, our present data suggest a possible mechanism of nesfatin-1 on enhancing GSIS through regulation of ion channels rather than its unidentified receptor.

Methionine uptake after myocardial infarction has been proven to reflect myocardial inflammation. The effect of postconditioning on the post-infarction inflammatory process, however, remains to be elucidated.Methods and Results:In control (n=22) and postconditioning rats (n=23), the left coronary artery was occluded for 30 min, followed by reperfusion for 1, 3, 7, and 14 days. Postconditioning was performed immediately following the reperfusion.

The word "theranostics," a portmanteau word made by combining "therapeutics" and "diagnostics," refers to a personalized medicine concept. Recently, the word, "radiotheranostics," has also been used in nuclear medicine as a term that refer to the use of radioisotopes for combined imaging and therapy. For radiotheranostics, a diagnostic probe and a corresponding therapeutic probe can be prepared by introducing diagnostic and therapeutic radioisotopes into the same precursor. These diagnostic and therapeutic probes can be designed to show equivalent pharmacokinetics, which is important for radiotheranostics. As imaging can predict the absorbed radiation dose and thus the therapeutic and side effects, radiotheranostics can help achieve the goal of personalized medicine. In this review, I discuss the use of radiolabeled probes targeting bone metastases, sigma-1 receptor, and αVβ3 integrin for radiotheranostics.

Radioactive nuclides leak into the surrounding environment after nuclear power plant disasters, such as the Chernobyl accident and the Fukushima Daiichi Nuclear Power Plant disaster. Cesium-137 (137Cs) (t1/2=30.1 year), a water-soluble radionuclide with a long physical half-life, contaminates aquatic ecosystems and food products. In humans, 137Cs concentrates in muscle tissue and has a long biological half-life, indicating it may be harmful. myo-Inositol-hexakisphosphate (IP6) is a compound found in grain, beans, and oil seeds. IP6 has the ability to form insoluble complexes with metals, including lanthanum (La) and zinc (Zn). We hypothesized that La-IP6 and Zn-IP6 may promote the elimination of 137Cs from the body through the adsorption of La-IP6 and Zn-IP6 to 137Cs in the gastrointestinal tract. Therefore, in this study, we evaluated the adsorptive capacity of La-IP6 and Zn-IP6 complexes with 137Cs in vitro and in vivo. La-IP6 and Zn-IP6 complexes were stable in acidic solution (pH 1.2) at 37°C. In vitro binding assays indicated that La-IP6 and Zn-IP6 complexes adsorbed 137Cs, with the adsorption capacity of Zn-IP6 to 137Cs greater than that of La-IP6. To evaluate the usefulness of La-IP6 and Zn-IP6 in vivo, La-IP6 or Zn-IP6 was administrated to mice after intravenous injection of 137Cs. However, the biodistribution of 137Cs in the La-IP6 treated group and the Zn-IP6 treated group was nearly identical to the non-treated control group, indicating that La-IP6 and Zn-IP6 were not effective at promoting the elimination of 137Cs in vivo.

Introduction: In cholinergic neurons, high affinity choline uptake (HACU) by the high affinity choline transporter (HAChT) is a rate-limiting and regulatory step for the synthesis of Acetylcholine (Ach).Thus, HAChT appear to be a relatively specific presynaptic marker for cholinergic neurons in Alzheimer’s disease. Objectives: The principle objective of the study is to check the affinity of tetrahydroaminoacridine (THA) derivatives for HAChT. Another objective of the research work is to clarify whether the hemicholinium-3 (ChT inhibitor) and HACU enhancer molecules share the same binding sites or not. Materials and Methods: The inhibition activities of tacrine, the 2,3-dimethylfuran derivative of tacrine (DMTA) and their corresponding 2-oxo-1-pyrrolidineacetyl derivatives, namely PTAA and MKC-231 were measured by displacement of a typical HAChT antagonist [ 3 H]HC-3 in rat cerebral membrane. The percentage of inhibition against the binding of [ 3 H]HC-3 to HAChT were calculated using GraphPad Prism v4 software. Results: Hemicholinium-3 showed affinity for HAChT (IC 50 = 20 nM) in the in vitro binding assay. A very insignificant inhibition activity (IC 50 = 1000 nM) of Tacrine was revealed. The newly synthesized tacrine derivatives, DMTA and PTAA did not show any affinity for HAChT. Although MKC-231 was reported to enhance cholinergic activity at synaptic terminals, it did not show any affinity for the HAChT in [ 3 H]HC-3 binding assay. Conclusion: In vitro [ 3 H]HC-3 binding assay revealed no affinity of MKC-231, tacrine and its corresponding2-oxo-1-pyrrolidineacetate derivative towards HAChT. So, it is worthy to develop radiolabeled HC-3 derivatives with high affinity for HAChT, which can diffuse the BBB, to enable the in vivo investigation of HACU system. Bangladesh J. Nuclear Med. 17(2): 97-102, July 2014

Herein we report the syntheses, characterization, photophysical and photochemical properties, and in vitro biological efficacy of Zn(II) and In(III) porphyrins coordinated with Pt(II) groups. In-Pt porphyrin showed excellent therapeutic potential in BALB/c mice having Colon26 tumors. These results imply that the mixed-metal complex In-4cisPtTPyP could be a promising anticancer agent for photodynamic therapy.

The purpose of this study is to develop peptide-based platelet-derived growth factor receptor &beta, (PDGFR&beta, ) imaging probes and examine the effects of several linkers, namely un-natural amino acids (D-alanine and &beta, alanine) and ethylene-glycol (EG), on the properties of Ga-DOTA-(linker)-IPLPPPRRPFFK peptides. Seven radiotracers, 67Ga-DOTA-(linker)-IPLPPPRRPFFK peptides, were designed, synthesized, and evaluated. The stability and cell uptake in PDGFR&beta, positive peptide cells were evaluated in vitro. The biodistribution of [67Ga]Ga-DOTA-EG2-IPLPPPRRPFFK ([67Ga]27) and [67Ga]Ga-DOTA-EG4-IPLPPPRRPFFK ([67Ga]28), which were selected based on in vitro stability in murine plasma and cell uptake rates, were determined in BxPC3-luc-bearing nu/nu mice. Seven 67Ga-labeled peptides were successfully synthesized with high radiochemical yields (&gt, 85%) and purities (&gt, 99%). All evaluated radiotracers were stable in PBS (pH 7.4) at 37 &deg, C. However, only [67Ga]27 and [67Ga]28 remained more than 75% after incubation in murine plasma at 37 &deg, C for 1 h. [67Ga]27 exhibited the highest BxPC3-luc cell uptake among the prepared radiolabeled peptides. As regards the results of the biodistribution experiments, the tumor-to-blood ratios of [67Ga]27 and [67Ga]28 at 1 h post-injection were 2.61 &plusmn, 0.75 and 2.05 &plusmn, 0.77, respectively. Co-injection of [67Ga]27 and an excess amount of IPLPPPRRPFFK peptide as a blocking agent can significantly decrease this ratio. However, tumor accumulation was not considered sufficient. Therefore, further probe modification is required to assess tumor accumulation for in vivo imaging.

Binary complexes of tartaric acid with lanthanide(III) ions were investigated. The studies have been performed in aqueous solution using the potentiometric method with computer analysis of the data for detection of the complexes set, determination of the stability constants of these compounds. The mode of the coordination of complexes found was determined using spectroscopy, which shows: Infrared, circular dichroism, ultraviolet, visible as well as luminescence spectroscopy. The overall stability constants of the complexes as well as the equilibrium constants of the reaction were determined. Analysis of the equilibrium constants of the reactions and spectroscopic data allowed the effectiveness of the carboxyl groups in the process of complex formation.

Sigma-1 receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the sigma-1 receptor. In this study, we aimed to develop probes with higher affinity for the sigma-1 receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the sigma-1 receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The sigma-1 receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol ( 5 ) (K i = 5.8 nM) exhibited the highest binding affinity; therefore, we introduced radioiodine into the benzene ring in 5 . The radioiodine labeled probe [ 125 I]2-(4-(3-(4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([ 125 I] 10 ) showed high accumulation in the sigma-1 receptor expressing DU-145 cells both in vitro and in vivo . Co-injection of [ 125 I] 10 with an excess level of a sigma receptor ligand, haloperidol, resulted in a significant decrease in the tumor accumulation in vitro and in vivo , indicating sigma receptor-mediated tumor uptake. These results provide useful information for developing sigma-1 receptor imaging probes.