Exploration of (R)-[C]YH168 as a PET tracer for imaging monoacylglycerol lipase in the brain: from mice to non-human primates.

Purpose: The monoacylglycerol lipase (MAGL) plays a pivotal role in modulating the endocannabinoid system and is considered an attractive therapeutic target for diseases in both the central nervous system and periphery. The current study aimed to develop and evaluate a suitable carbon-11 labeled tracer for imaging MAGL in preclinical studies.

Methods: (R)-YH168 was synthesized via a multi-step pathway and its half-maximal inhibitory concentration (IC) values were measured using an enzymatic assay.

Antiviral drug discovery with an optimized biochemical dengue protease assay: Improved predictive power for antiviral efficacy.

The viral NS2B-NS3 protease is a promising drug target to combat dengue virus (DENV) and other emerging flaviviruses. The discovery of novel DENV protease inhibitors with antiviral efficacy is hampered by the low predictive power of biochemical assays. We herein present a comparative evaluation of biochemical DENV protease assay conditions and their benchmarking against antiviral efficacy and a protease-specific reporter gene assay.

[F]NP3-627, a Candidate PET Imaging Agent Targeting the NLRP3 Inflammasome in the Central Nervous System.

We describe the identification of a candidate positron emission tomography (PET) imaging agent for the NLRP3 protein. NLRP3 plays a critical role in the immune system and has proven a difficult target for the development of imaging agents due to its low and cell-specific expression profile. A recently described series of pyridazine-based inhibitors, with improved permeability and brain-penetration properties, was used as a starting point for the development of a suitable PET imaging agent.

Flipping the GPCR Switch: Structure-Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists.

We report a blueprint for the rational design of G protein coupled receptor (GPCR) ligands with a tailored functional response. The present study discloses the structure-based design of cannabinoid receptor type 2 (CBR) selective inverse agonists ()- and ()-, which were derived from privileged agonist HU-308 by introduction of a phenyl group at the -dimethylheptyl side chain. Epimer ()- exhibits high affinity for CBR with = 39.

Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel Au cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated Au fragment.

Highly cytotoxic gold(i)-phosphane dithiocarbamate complexes trigger an ER stress-dependent immune response in ovarian cancer cells.

Ovarian cancer is a highly aggressive disease which is treated by surgery and platinum chemotherapy. However, a significant proportion of treated patients develop resistance to platinum treatment resulting in tumor relapse. Acquired platinum resistance has been recently correlated with activation of pro-survival endoplasmic reticulum (ER) stress responses.

Review of the Nearctic genus Wilcoxia James (Diptera: Asilidae: Stenopogoninae), with descriptions of three new species.

The robber fly genus Wilcoxia is revised based on external morphological features of adults. For each species the following is provided: type specimen information, diagnostic features, description, natural history including associated prey data, and geographical distribution (derived from georeferenced localities for both examined specimens and literature records). A key to adults of Wilcoxia, supplemented with photographs of habitus and selected morphological features, is included.

Gold-Catalyzed Regiospecific Annulation of Unsymmetrically Substituted 1,5-Diynes for the Precise Synthesis of Bispentalenes.

Precise control of the selectivity in organic synthesis is important to access the desired molecules. We demonstrate a regiospecific annulation of unsymmetrically substituted 1,2-di(arylethynyl)benzene derivatives for a geometry-controlled synthesis of linear bispentalenes, which is one of the promising structures for material science. A gold-catalyzed annulation of unsymmetrically substituted 1,2-di(arylethynyl)benzene could produce two isomeric pentalenes, but both electronic and steric effects on the aromatics at the terminal position of the alkyne prove to be crucial for the selectivity; especially a regiospecific annulation was achieved with sterically blocked substituents; namely, 2,4,6-trimetyl benzene or 2,4-dimethyl benzene.

Feasibility of liver stiffness measurement in morbidly obese patients undergoing bariatric surgery using XL probe.

Objective: Prevalence of non-alcoholic fatty liver disease is rising in the Western world and reaches up to 90% in patients undergoing bariatric surgery. Fibroscan(®) as a non-invasive tool for liver stiffness measurement (LSM) has several limitations in morbidly obese patients. Only few data exist about the technical feasibility and accuracy of LSM in these patients.