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The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) is an important molecule in neurotransmission. We have recently developed the first positron emission tomography (PET) tracer [11C]K-2 to visualize and quantify AMPARs in the living human brain. After injection, [11C]K-2 is hydrolyzed at the terminal amide (and is thus metabolized to a major metabolite, [11C]K-2OH) within 10 min, representing the PET image in rodents and humans. Here, we found that K-2OH did not penetrate the cell membrane but slowly passed through the blood brain barrier (BBB) with paracellular transport. Furthermore, major efflux transporters in the BBB did not carry K-2OH. Logan graphical analysis exhibited reversible binding kinetics of this radiotracer in healthy individuals; these results demonstrated that the PET image of this tracer represents cell surface AMPARs with passive penetration of [11C]K-2OH through the BBB, resulting in reversible binding kinetics. Thus, PET images with this tracer depict the physiologically crucial fraction of AMPARs.

[11C]K-2, a radiotracer exhibiting high affinity and selectivity for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), is suitable for the quantification of AMPARs in living human brains and potentially useful in the identification of epileptogenic foci in patients. This study aimed to estimate the radiation doses of [11C]K-2 in various organs and calculate the effective dose after injection of [11C]K-2 in healthy human subjects. Twelve healthy male subjects were registered and divided into two groups (370 or 555 MBq of [11C]K-2), followed by 2 h whole-body scans. We estimated the radiation dose of each organ and then calculated the effective dose for each subject. The highest uptake of [11C]K-2 was observed in the liver, while the brain also showed relatively high uptake. The urinary bladder exhibited the highest radiation dose. The kidneys and liver also showed high radiation doses after [11C]K-2 injections. The effective dose of [11C]K-2 ranged from 5.0 to 5.2 μSv/MBq. Our findings suggest that [11C]K-2 is safe in terms of the radiation dose and adverse effects. The injection of 370–555 MBq (10 to 15 mCi) for PET studies using this radiotracer is applicable in healthy human subjects and enables serial PET scans in a single subject.

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) receptors play a central role in neurotransmission and neuronal function. A positron emission tomography (PET) tracer for AMPA receptors, [Derivatives of K-2 labeled withSome of the synthesized

[11C]K-2, a radiotracer exhibiting high affinity and selectivity for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), is suitable for the quantification of AMPARs in living human brains and potentially useful in the identification of epileptogenic foci in patients. This study aimed to estimate the radiation doses of [11C]K-2 in various organs and calculate the effective dose after injection of [11C]K-2 in healthy human subjects. Twelve healthy male subjects were registered and divided into two groups (370 or 555 MBq of [11C]K-2), followed by 2 h whole-body scans. We estimated the radiation dose of each organ and then calculated the effective dose for each subject. The highest uptake of [11C]K-2 was observed in the liver, while the brain also showed relatively high uptake. The urinary bladder exhibited the highest radiation dose. The kidneys and liver also showed high radiation doses after [11C]K-2 injections. The effective dose of [11C]K-2 ranged from 5.0 to 5.2 μSv/MBq. Our findings suggest that [11C]K-2 is safe in terms of the radiation dose and adverse effects. The injection of 370–555 MBq (10 to 15 mCi) for PET studies using this radiotracer is applicable in healthy human subjects and enables serial PET scans in a single subject.

Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4–10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders. A newly developed PET tracer allows visualization of AMPA receptors in the living human brain, providing a new tool to study their potential involvement in neurological or psychiatric disorders.

As the Required Data Rate for VLSI System Communication Increases, Channel Bandwidthlimitation Becomes a Crucial Problem as High-Frequency Channel Loss Degrades the Transmission Performance.In this Paper, we Compare Non-Return-to-Zero (NRZ) Binary and 4-PAM (pulse Amplitudemodulation) Coding Techniques for High-Speed Data Transmission by Fabricating a Test Board of a Microstripline. by Extracting the Micro-Strip Line Parameters, we Carry out Co-Simulations to Evaluate Spectrallyefficient Coding for High-Speed Data Transmission.We Consider the Conditions for which 4-Pamsignaling Provides an Advantage over NRZ Signaling from the Viewpoint of Channel Profiles.

Background/Aims: Somatostatin receptor (SSTR) scintigraphy (SRS) is the standard imaging modality for evaluation of gastroenteropancreatic neuroendocrine tumor (GEP-NET) in Western countries. However, this modality was not approved in Japan until recently. The purpose of this study was to evaluate the clinical efficacy of SRS for detecting GEP-NET in Japanese patients. Methods: Japanese patients with advanced GEP-NET were enrolled and evaluated by the SRS and CT. We also compared SRS and immunohistochemical expression of SSTR type 2a (SSTR2a). Results: We enrolled 16 patients and the primary sites were the pancreas in 9, the stomach in 1, the small intestine in 2, the colon in 3, and unknown in 1. SRS showed positive findings in 3 (100%) of grade 1 (G1) and in 12 (92.3%) of grade 2 (G2) lesions. In the liver, SRS and CT detected lesions in 13 and 14 cases, respectively. The concordance rate of SSTR2a expression with SRS findings was 93.8% in the whole body and 92.9% in the liver. Conclusions: SRS could detect almost all of G1 and G2. SRS could be useful to detect lesions, with a high concordance rate with CT and pathological findings. We confirmed that SRS is a useful and reliable modality for Japanese patients.

The performance of advanced VLSI systems is limited by the interconnection bandwidthinside/between chips rather than individual performance of transistors. The attenuation or deteriorationof signals, arises from physical phenomena in transmission lines, restricts the maximum frequencyat which the signal can transmit. This paper investigates coding techniques that can modifysignal spectrum suited to channel frequency response based on the concept of spectrum shaping ofsignals. We discuss three types of coding techniques for high-speed serial links to evaluate their performanceas well as the feasibility for realizing efficient data transmission.

A procedure for the synthesis of a11C-labeled oligopeptide containing [1-11C]1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid ([1-11C]Tpi) from the corresponding Trp•HCl-containing peptides has been developed involving a Pictet-Spengler reaction with [11C]formaldehyde. The synthesis of [1-11C]Tpi from Trp and [11C]formaldehyde was examined as a model reaction with the aim of developing a facile and effective method for the labeling of peptides with carbon-11. The Pictet-Spengler reaction of Trp and [11C]formaldehyde in acidic media (TsOH or HCl) afforded the desired [1-11C]Tpi in a moderate radiochemical yield. Herein, the application of a Pictet-Spengler reaction to an aqueous solution of Trp•HCl gave the desired product with a radiochemical yield of 45.2%. The RGD peptide cyclo[Arg-Gly-Asp-D-Tyr-Lys] was then selected as a substrate for the labeling reaction with [11C]formaldehyde. The radiolabeling of a Trp•HCl-containing RGD peptide using the Pictet-Spengler reaction was successful. Furthermore, the remote-controlled synthesis of a [1-11C]Tpi-containing RGD peptide was attempted by using an automatic production system to generate [11C]CH3I. The radiochemical yield of the [1-11C]Tpi-containing RGD at the end of synthesis (EOS) was 5.9 ± 1.9% (n = 4), for a total synthesis time of about 35 min. The specific activity was 85.7 ± 9.4 GBq/µmol at the EOS. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.

We successfully completed the total synthesis of kulokekahilide-2, a cytotoxic depsipeptide from the Cephalaspiedean mollusk Phillinopsis speciosa. We have revised the absolute stereochemistry of kulokekahilide-2 to 21-l-Ala, 24-d-MePhe, 37-l-Ile, 43-d-Ala, 15-d-Hica, and 5S,6S,7S-Dtda. We also investigated the cause of the mis-assignment of the configuration in the originally proposed kulokekahilide-2 and concluded that methanolysis using MeONa caused partial racemization, which led to the mis-assignment. The structure–activity relationships of kulokekahilide-2 and its analogs indicate the importance of an l-amino acid at position 21.

form, 100–200 mesh) wasobtained from Bio-Rad Laboratories, Inc (Tokyo, Japan). Reagentsused in standard productions were analytical grade from WakoPure Chemical Industries, Ltd (Osaka, Japan) and used withoutfurther purification. Water was purified using a Milli-Q purifica-tion system. To reduce the amount of metal impurity ultrapuregrade conc nitric acid, conc HCl and water, all for Ultra Trace

Automated radiosynthesis of [2- 11 C-carbonyl]dantrolene, the substrate of breast cancer resistance protein (BCRP/ABCG2), was performed for the first time through a multi-step/one-pot labeling sequence that started with ethyl 2-{2-[5-(4-nitrophenyl)furfurylidene]hydrazino}acetate and used [ 11 C]phosgene as a labeling agent. After optimization of the automated synthesis conditions and parameters, [2- 11 C-carbonyl]dantrolene was obtained at a radiochemical yield of 34.0±8.4% (decay-corrected). The radiochemical purity was greater than 98% and the specific activity was 46.8±15.2 GBq/μmol at the end of the synthesis.

Certain small-molecule inhibitors that target epidermal growth factor receptor (EGFR), such as Gefitinib, Erlotinib, and Lapatinib, provide a new approach for cancer treatment. In accordance with the pharmacophore model for inhibitor competition at EGFR-binding site, this study proposes a rationalized design for a novel 4-anilinoquinoline EGFR tyrosine kinase inhibitor, [6,7-dimethoxyethoxy]-quinolin-4-yl]-(3-ethynylphenyl)-amine (YCU07). This is the first study to apply ring-closing metathesis toward synthesis of the quinoline nucleus for this 4-anilinoquinoline EGFR inhibitor. YCU07 expressed significant inhibitory activity for EGFR tyrosine kinase in A431 cells, as confirmed by an ABTS microwell peroxidase substrate system read colorimetrically at 405 nm. Injection of (68)Ga-labeled glutamic acid polypeptide (GAP)-YCU07 conjugate in nude mice implanted with A431 was imaged by animal PET camera (LabPET8; Gamma Medica-Ideas) and computed tomography (eXplore Locus; GE Healthcare), to evaluate its biodistribution. (68)Ga-GAP-YCU accumulated in the receptor-positive tumors, with uptake values of 1.50% +/- 0.09% and 2.36% +/- 0.36% of injected activity per gram tissue at 30 and 90 minutes, respectively.

Introduction Carbon-11-labeled phosgene is an important labeling precursor for PET molecular probes. Despite the usefulness of [ 11 C]phosgene, some difficulties, especially in the formation of [ 11 C]phosgene process from [ 11 C]CCl 4 , hamper its use. The present article shows a simple preparation method for [ 11 C]phosgene. Method [ 11 C]CCl 4 was obtained using the conventional method by passing a mixture of [ 11 C]CH 4 and Cl 2 through a heated quartz tube. The [ 11 C]CCl 4 was transformed to [ 11 C]phosgene simply by passing through a pretreatment tube of a Kitagawa gas detection system for the working-environmental CCl 4 concentration measurement at room temperature with a flow rate of 50 ml/min. Result This tube successfully transformed [ 11 C]CCl 4 to [ 11 C]phosgene at room temperature. [ 11 C]Phosgene was obtained at nearly 80% radiochemical yield (EOB) in a short synthesis time with high reproducibility. Conclusion A high yield and reliable [ 11 C]phosgene production method using a gas detector tube system for working-environmental CCl 4 concentration measurement was developed.

Kulokekahilide-2 is a 26-membered cyclic depsipeptide that exhibits potent cytotoxicity against HeLa and P388 cells with IC50 values of 3.2 and 16 ng/mL, respectively. We have achieved a total synthesis of natural kulokekahilide-2, the NMR spectra of which showed complex signals because of trans and cis conformers at the amide bond. Besides, the spectra revealed that a mixture of 26- and 24-membered cyclic depsipeptides had been produced due to intramolecular ester exchange. The isolated 24-membered compound was transformed into the 26-membered compound over a period of several days. The two isomers have been shown to be in equilibrium and to display almost the same cytotoxicity.

Antibacterial sargaquinoic acid derivatives were isolated from the brown alga Sargassum sagamianum. The structures of these quinone metabolites were confirmed by NMR and mass spectroscopy, and by c...

An attempt to carry out a total synthesis of kulokekahilide-2 ( 1 ) by macrolactonization of a seco acid prepared from a suitably protected hexapeptide and a dioxy acid moiety unexpectedly resulted in the formation of the 43-epimer ( 1a ) of the cytotoxic depsipeptide, for which structure 1b has previously been proposed. A second attempt involving macrolactamization of the corresponding amino acid gave the target product, 1b , but the spectral data of the product did not match those of natural 1 . Furthermore, neither 1a nor 1b showed any cytotoxicity, from which it is concluded that the structure of natural 1 is incorrect and should be re-examined.

From the two species of bivalves, Calyptogena soyoae around a cold seep and Bathymodiolus septemdierum near hydrothermal vents in the sea, sterols were isolated using high- pressure liquid chromatography analysis of the lipid fraction guided by characteristic 1 H NMR signals of the sterol skeleton. The minor sterol composition of C. soyoae included 24-methylenecycloartanal, cycloeucalenol, and obtusifoliol, which are known phytosterols. From B. septemdierum, lathosterol and cholesterol as main sterols together with more diverse sterols were obtained. The difference between these species and their sterol contents is most likely because of feeding modes and metabolism of nutrients from their habitat.

The cytotoxic depsipeptide kulokekahilide-1, which contains two unusual amino acids, 4-phenylvaline and 3-amino-2-methylhexanoic acid, was isolated from the cephalaspidean mollusk Philinopsis speciosa. Structure elucidation of kulokekahilide-1 was carried out by spectroscopic analysis and chemical degradation. The absolute stereochemistry was determined by Marfey analysis for amino acids and chiral HPLC analysis for hydroxy acids. All four stereoisomers of 4-phenylvaline and 3-amino-2-methylhexanoic acid, which were necessary for Marfey analysis, were synthesized by use of the Heck reaction and Evans's method, respectively. Kulokekahilide-1 showed cytotoxicity against P388 murine leukemia cells with an IC(50) value of 2.1 microg/mL.

Kulokekahilide-2 is a potent cytotoxic depsipeptide isolated from the Hawaiian marine mollusk Philinopsis speciosa . The structure of kulokekahilide-2 was reported to be composed of five amino acids ( l -Ala, l -Ile, MeGly, l -MePhe, d -Ala) and two hydroxy acids ( d -Hica, 5 S ,6 S ,7 S -Dtda); however, following its total synthesis, the 1 H NMR spectrum of the synthetic compound was found to be different from that of the natural one, suggesting that the stereochemistry of the reported structure was incorrect. To determine the stereochemistry of the natural compound, arrays of analogues have been prepared using different sets of chiral amino acids, and the absolute stereochemistry of kulokekahilide-2 has been unambiguously confirmed to involve the combination 21- l -Ala, 24- d -MePhe, and 43- d -Ala.

A procedure for the synthesis of a(11)C-labeled oligopeptide containing [1-(11)C]1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid ([1-(11)C]Tpi) from the corresponding Trp•HCl-containing peptides has been developed involving a Pictet-Spengler reaction with [(11) C]formaldehyde. The synthesis of [1-(11)C]Tpi from Trp and [(11)C]formaldehyde was examined as a model reaction with the aim of developing a facile and effective method for the labeling of peptides with carbon-11. The Pictet-Spengler reaction of Trp and [(11)C]formaldehyde in acidic media (TsOH or HCl) afforded the desired [1-(11)C]Tpi in a moderate radiochemical yield. Herein, the application of a Pictet-Spengler reaction to an aqueous solution of Trp•HCl gave the desired product with a radiochemical yield of 45.2%. The RGD peptide cyclo[Arg-Gly-Asp-D-Tyr-Lys] was then selected as a substrate for the labeling reaction with [(11)C]formaldehyde. The radiolabeling of a Trp•HCl-containing RGD peptide using the Pictet-Spengler reaction was successful. Furthermore, the remote-controlled synthesis of a [1-(11)C]Tpi-containing RGD peptide was attempted by using an automatic production system to generate [(11)C]CH3 I. The radiochemical yield of the [1-(11) C]Tpi-containing RGD at the end of synthesis (EOS) was 5.9 ± 1.9% (n = 4), for a total synthesis time of about 35 min. The specific activity was 85.7 ± 9.4 GBq/µmol at the EOS.

The cytotoxic depsipeptide kulokekahilide-1, which contains two unusual amino acids, 4-phenylvaline and 3-amino-2-methylhexanoic acid, was isolated from the cephalaspidean mollusk Philinopsis speciosa. Structure elucidation of kulokekahilide-1 was carried out by spectroscopic analysis and chemical degradation. The absolute stereochemistry was determined by Marfey analysis for amino acids and chiral HPLC analysis for hydroxy acids. All four stereoisomers of 4-phenylvaline and 3-amino-2-methylhexanoic acid, which were necessary for Marfey analysis, were synthesized by use of the Heck reaction and Evans's method, respectively. Kulokekahilide-1 showed cytotoxicity against P388 murine leukemia cells with an IC50 value of 2.1 μg/mL.

Antibacterial sargaquinoic acid derivatives were isolated from the brown alga Sargassum sagamianum. The structures of these quinone metabolites were confirmed by NMR and mass spectroscopy, and by c...

Red algae are well known as a source of halogenated monoterpenes such as derivatives of ochtodene. From Carpopeltis crispata, we have isolated four new ochtodene derivatives: dibromodichloro-, dibromochloro-, and bromodichlorocyclomonoterpenes. The structures of these monoterpenes were confirmed by NMR and mass spectroscopy and compared with spectral data in the literature.

A cytotoxic depsipeptide, kulokekahilide-2 (1), was isolated from a cephalaspidean mollusk, Philinopsis speciosa. The structure elucidation of kulokekahilide-2 was carried out by spectroscopic analysis and chemical degradation. Kulokekahilide-2 showed potent cytotoxicity against several cell lines (P388, SK-OV-3, MDA-MB-435, and A-10 with IC50 values ranging from 4.2 to 59.1 nM) indicating cancer cell selectivity.

Nine novel oxylipin metabolites together with several known ones were isolated from the brown alga Eisenia bicyclis. Five (1−5) of them are ecklonialactone derivatives containing a chlorine or an iodine atom, and two (6 and 7) are cymathere type oxylipins with a lactone ring or a chlorine atom. The structures of these oxylipin metabolites were confirmed by NMR and mass spectroscopy and compared with spectral data in the literature. The postulated biosynthetic pathway of these metabolites is discussed.