Synthesis and Preliminary Evaluation of 11C-Labeled VU0467485/AZ13713945 and Its Analogues for Imaging Muscarinic Acetylcholine Receptor Subtype 4

Muscarinic acetylcholine receptors (mAChRs) have five distinct subunits (M₁–M₅) and are involved in the action of the neurotransmitter acetylcholine in the central and peripheral nervous system. Attributed to the promising clinical efficacy of xanomeline, an M₁/M₄-preferring agonist, in patients of schizophrenia and Alzheimer's disease, M₁- or M₄-selective mAChR modulators have been developed that target the topographically distinct allosteric sites. Herein we report the synthesis and preliminary evaluation of ¹¹C-labeled positron emission tomography (PET) ligands based on a validated M₄R positive allosteric modulator VU0467485 (AZ13713945) to facilitate drug discovery. [¹¹C]VU0467485 and two other ligands were prepared in high radiochemical yields (>30 %, decay-corrected) with high radiochemical purity (>99 %) and high molar activity (>74 GBq μmol⁻¹). In vitro autoradiography studies indicated that these three ligands possess moderate-to-high in vitro specific binding to M₄R. Nevertheless, further physiochemical property optimization is necessary to overcome the challenges associated with limited brain permeability.     

Synthesis and radical polymerization of methacrylate endowed with bicyclobis(γ‐butyrolactone) moiety through methylene linker

A series of methacrylates bearing bicyclobis(γ‐butyrolactone) (BBL) moiety were synthesized and radically polymerized to afford the corresponding poly(methacrylate)s bearing BBL moiety in the side chain, with expecting that the high polarity and rigidity of BBL would be inherited by the polymers. The resulting polymers were soluble in polar aprotic solvents such as dimethyl sulfoxide and N,N‐dimethylformamide because of the high polarity of the BBL moiety. The glass transition temperatures (T_g) of the polymers depended on the length of methylene linker that tethered the methacrylate and BBL moieties, making the use of shorter linkers lead to higher T_gs. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2462–2468     

Synthesis of oligo(spiroketal)s by polycondensation of silyl ethers derived from naturally occurring myo‐inositol with 1,4‐cyclohexanedione

Oligo(spiroketal)s (OSKs) were synthesized from myo‐inositol, a naturally occurring cyclic compound bearing six hydroxyl groups. The successful synthesis of OSKs was achieved using silyl ethers 2 derived from 1,4‐di‐O‐alkylated myo‐inositol 1 as monomers, which underwent polycondensation with 1,4‐cyclohexanedione (CHD) at 0 °C in the presence of trimethylsilyl triflate as a catalyst. Because of the irreversible nature of the condensation reaction of silyl ethers with ketones, the resulting OSKs 7 had higher molecular weights than previously reported OSKs that were obtained by polycondensation of tetraols 1 with CHD, where backward hydrolysis of the ketal functions occurred. In addition, another series of OSKs, 8, were synthesized using silyl ethers 3 derived from 2,5‐di‐O‐alkylated myo‐inositol 6 , which are more symmetric monomers than silyl ethers 2 . Silyl ethers 3 underwent efficient polycondensation with CHD, whereas tetraol 6 did not, demonstrating that the derivation of such tetraols into the corresponding silyl ethers is a powerful strategy to access OSKs. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 2407–2414     

A consistent grayscale‐free topology optimization method using the level‐set method and zero‐level boundary tracking mesh

This paper proposes a level‐set based topology optimization method incorporating a boundary tracking mesh generating method and nonlinear programming. Because the boundary tracking mesh is always conformed to the structural boundary, good approximation to the boundary is maintained during optimization; therefore, structural design problems are solved completely without grayscale material. Previously, we introduced the boundary tracking mesh generating method into level‐set based topology optimization and updated the design variables by solving the level‐set equation. In order to adapt our previous method to general structural optimization frameworks, the incorporation of the method with nonlinear programming is investigated in this paper. To successfully incorporate nonlinear programming, the optimization problem is regularized using a double‐well potential. Furthermore, the sensitivities with respect to the design variables are strictly derived to maintain consistency in mathematical programming. We expect the investigation to open up a new class of grayscale‐free topology optimization. The usefulness of the proposed method is demonstrated using several numerical examples targeting two‐dimensional compliant mechanism and metallic waveguide design problems. Copyright © 2014 John Wiley & Sons, Ltd.     

General topology optimization method with continuous and discrete orientation design using isoparametric projection

A general topology optimization method, which is capable of simultaneous design of density and orientation of anisotropic material, is proposed by introducing orientation design variables in addition to the density design variable. In this work, the Cartesian components of the orientation vector are utilized as the orientation design variables. The proposed method supports continuous orientation design, which is out of the scope of discrete material optimization approaches, as well as design using discrete angle sets. The advantage of this approach is that vector element representation is less likely to fail into local optima because it depends less on designs of former steps, especially compared with using the angle as a design variable (Continuous Fiber Angle Optimization) by providing a flexible path from one angle to another with relaxation of orientation design space. An additional advantage is that it is compatible with various projection or filtering methods such as sensitivity filters and density filters because it is free from unphysical bound or discontinuity such as the one at θ = 2π and θ = 0 seen with direct angle representation. One complication of Cartesian component representation is the point‐wise quadratic bound of the design variables; that is, each pair of element values has to reside in a given circular bound. To overcome this issue, we propose an isoparametric projection method, which transforms box bounds into circular bounds by a coordinate transformation with isoparametric shape functions without having the singular point that is seen at the origin with polar coordinate representation. A new topology optimization method is built by taking advantage of the aforementioned features and modern topology optimization techniques. Several numerical examples are provided to demonstrate its capability. Copyright © 2014 John Wiley & Sons, Ltd.     

Determination of emotional content of video clips by low-level audiovisual features

Affective analysis of video content has greatly increased the possibilities of the way we perceive and deal with media. Different kinds of strategies have been tried, but results are still opened to improvements. Most of the problems come from the lack of standardized test set and real affective models. In order to cope with these issues, in this paper we describe the results of our work on the determination of affective models for evaluation of video clips using audiovisual low-level features. The affective models were developed following two classes of psychological theories of affect: categorial and dimensional. The affective models were created from real data, acquired through a series of user experiments. They reflect the affective state of a viewer after watching a certain scene from a movie. We evaluate the detection of Pleasure, Arousal and Dominance coefficients as well as the detection rate of six affective categories. For this end, two Bayesian network topologies are used, a Hidden Markov Model and an Autoregressive Hidden Markov Model. The measurements were done using audio-only models, video-only models and fused models. Fusion is done using two different methods, a Decision Level Fusion and Feature Level Fusion. All tests were conducted using localized affective models, both categorial and dimensional. Results are presented in terms of detection rate and accuracy for affective families, affective dimensions and probabilistic networks. Arousal was the best detected dimension, followed by dominance and pleasure.     

Thermodynamic Properties of Ionic Semiclathrate Hydrate Formed with Tetrabutylammonium Propionate

The phase equilibrium temperature and dissociation heat of tetrabutylammonium propionate (TBAPr) hydrate are reported. TBAPr hydrate is a type of ionic semiclathrate hydrates and also could potentially be used as thermal energy storage material. The temperature‐composition phase diagram of the TBAPr hydrate was determined in a defined range of mass fractions. Considering the dissociation heat of differential scanning calorimetry (DSC) measurements, multiple peaks of heat flow were observed in the TBAPr‐water system at the TBAPr mass fraction lower than 0.35, and there was a single peak at the mass fraction higher than 0.37.