Naphtho[1,2-][1,4]diazepinedione-Based P2X4 Receptor Antagonists from Structure-Activity Relationship Studies toward PET Tracer Development.

The P2X4 receptor is implicated in various pathological conditions, including neuropathic pain and cancer. This study reports the development of 1,4-naphthodiazepinedione-based P2X4 receptor antagonists aimed at both therapeutic applications and potential use as PET tracers for imaging P2X4 receptor expression in cancer. Structure-activity relationship studies aided by docking studies and molecular dynamics simulations led to a series of compounds with potent P2X4 receptor antagonism, promising inhibition of interleukin-1β release in THP-1 cells and suitability for radiolabeling with fluorine-18.

Joint estimation of activity, attenuation and motion in respiratory-self-gated time-of-flight PET.

Motivation: Whole-body Positron Emission Tomography (PET) imaging is often hindered by respiratory motion during acquisition, causing significant degradation in the quality of reconstructed activity images. An additional challenge in PET/CT imaging arises from the respiratory phase mismatch between CT-based attenuation correction and PET acquisition, leading to attenuation artifacts. To address these issues, we propose two new, purely data-driven methods for the joint estimation of activity, attenuation, and motion in respiratory self-gated time-of-flight (TOF) PET.

Piperazine-based P2X4 receptor antagonists.

The P2X4 receptor (P2X4R), a ligand-gated ion channel activated by ATP, plays a critical role in neuroinflammation, chronic pain, and cancer progression, making it a promising therapeutic target. In this study, we explored the design and synthesis of piperazine-based P2X4R antagonists, building on the structural framework of paroxetine. A series of over 35 compounds were synthesized to investigate structure-activity relationships (SARs) in a Ca²⁺-flux assay for P2X4R antagonistic activity.

Phenol (bio)isosteres in drug design and development.

Due to their versatile properties, phenolic compounds are integral to various biologically active molecules, including many pharmaceuticals. However, their application in drug design is often hindered by issues such as poor oral bioavailability, rapid metabolism, and potential toxicity. This review explores the use of phenol bioisosteres-structurally similar compounds that can mimic the biological activity of phenols while potentially offering improved drug-like properties.

Exploring P2X receptor activity: A journey from cellular impact to electrophysiological profiling.

The development of in vitro pharmacological assays relies on creating genetically modified cell lines that overexpress the target protein of interest. However, the choice of the host cell line can significantly impact the experimental outcomes. This study explores the functional characterization of P2X7 and P2X4 receptor modulators through cellular assays and advanced electrophysiological techniques.

Combining poly-epitope MoonTags and labeled nanobodies for signal amplification in cell-specific PET imaging in vivo.

Immunorecognition provides an excellent basis for targeted imaging techniques covering a wide range from basic research to diagnostics and from single cells to whole organisms. Fluorescence- or radioisotope-labeled antibodies, antibody fragments or nanobodies enable a direct signal readout upon binding and allow for versatile imaging from microscopy to whole-body imaging. However, as the signal intensity directly correlates with the number of labeled antibodies bound to their epitopes (1:1 binding), sensitivity for low-expressing epitopes can be limiting for visualization.

Which Comprehensive Geriatric Assessment (CGA) instruments are currently used in Germany: a survey.

Background: The Comprehensive Geriatric Assessment (CGA) records geriatric syndromes in a standardized manner, allowing individualized treatment tailored to the patient's needs and resources. Its use has shown a beneficial effect on the functional outcome and survival of geriatric patients. A recently published German S1 guideline for level 2 CGA provides recommendations for the use of a broad variety of different assessment instruments for each geriatric syndrome.

Synthesis, radiosynthesis and biochemical evaluation of fluorinated analogues of sphingosine-1-phosphate receptor 3 specific antagonists using PET.

Sphingosine-1-phosphate and its receptors (S1PRs) are involved in several diseases such as auto immunity, inflammation and cardiovascular disorders. The S1P analogue fingolimod (Gilenya®) is currently in use for the treatment of relapsing multiple sclerosis. S1PRs are also promising targets for clinical molecular imaging in vivo.

Therapy-induced modulation of tumor vasculature and oxygenation in a murine glioblastoma model quantified by deep learning-based feature extraction.

Glioblastoma presents characteristically with an exuberant, poorly functional vasculature that causes malperfusion, hypoxia and necrosis. Despite limited clinical efficacy, anti-angiogenesis resulting in vascular normalization remains a promising therapeutic approach. Yet, fundamental questions concerning anti-angiogenic therapy remain unanswered, partly due to the scale and resolution gap between microscopy and clinical imaging and a lack of quantitative data readouts.

Dispersion-corrected extracorporeal arterial input functions in PET studies of mice: a comparison to intracorporeal microprobe measurements.

Background: Kinetic modelling of dynamic PET typically requires knowledge of the arterial radiotracer concentration (arterial input function, AIF). Its accurate determination is very difficult in mice. AIF measurements in an extracorporeal shunt can be performed; however, this introduces catheter dispersion.

S100A8/A9-alarmin promotes local myeloid-derived suppressor cell activation restricting severe autoimmune arthritis.

Immune-suppressive effects of myeloid-derived suppressor cells (MDSCs) are well characterized during anti-tumor immunity. The complex mechanisms promoting MDSC development and their regulatory effects during autoimmune diseases are less understood. We demonstrate that the endogenous alarmin S100A8/A9 reprograms myeloid cells to a T cell suppressing phenotype during autoimmune arthritis.

Microwave-Assisted Synthesis, Structure, and Preliminary Biological Evaluation of Novel 6-Methoxy-5,6-dihydro-5-azapurines.

We herein disclose the microwave-assisted synthesis of previously unreported 6-methoxy-5,6-dihydro-5-azapurines, whose purine-like scaffold is promising for drug discovery. The method is simple, fast, and relies on easily accessible reagents such as trimethyl orthoformate, acetic acid, and aminotriazole-derived ,'-disubstituted formamidines. The preliminary biological evaluation revealed that selected representatives of synthesized 6-methoxy-5,6-dihydro-5-azapurines dose-dependently reduce the viability of HepG2 and A549 cancer cells having little to no influence on five tested purinergic receptors.

Optimized synthesis and pharmacological evaluation of HCN channel inhibitor EC18.

HCN4 channels are considered to be a promising target for cardiac pathologies, epilepsy, and multiple sclerosis. However, there are no subtype-selective HCN channel blockers available, and only a few compounds are reported to display subtype preferences, one of which is EC18 (cis-1). Herein, we report the optimized synthetic route for the preparation of EC18 and its evaluation in three different pharmacological models, allowing us to assess its activity on cardiac function, thalamocortical neurons, and immune cells.

The blood vasculature instructs lymphatic patterning in a SOX7-dependent manner.

Despite a growing catalog of secreted factors critical for lymphatic network assembly, little is known about the mechanisms that modulate the expression level of these molecular cues in blood vascular endothelial cells (BECs). Here, we show that a BEC-specific transcription factor, SOX7, plays a crucial role in a non-cell-autonomous manner by modulating the transcription of angiocrine signals to pattern lymphatic vessels. While SOX7 is not expressed in lymphatic endothelial cells (LECs), the conditional loss of SOX7 function in mouse embryos causes a dysmorphic dermal lymphatic phenotype.

Deciphering the heterogeneity of the Lyve1 perivascular macrophages in the mouse brain.

Perivascular macrophages (pvMs) are associated with cerebral vasculature and mediate brain drainage and immune regulation. Here, using reporter mouse models, whole brain and section immunofluorescence, flow cytometry, and single cell RNA sequencing, besides the Lyve1F4/80CD206CX3CR1 pvMs, we identify a CX3CR1 pvM population that shares phagocytic functions and location. Furthermore, the brain parenchyma vasculature mostly hosts Lyve1MHCII pvMs with low to intermediate CD45 expression.

Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on Monocytes.

Mechanisms keeping leukocytes distant of local inflammatory processes in a resting state despite systemic release of inflammatory triggers are a pivotal requirement for avoidance of overwhelming inflammation but are ill defined. Dimers of the alarmin S100A8/S100A9 activate Toll-like receptor-4 (TLR4) but extracellular calcium concentrations induce S100A8/S100A9-tetramers preventing TLR4-binding and limiting their inflammatory activity. So far, only antimicrobial functions of released S100A8/S100A9-tetramers (calprotectin) are described.

Imaging of the calcium activated potassium channel 3.1 (K 3.1) in vivo using a senicapoc-derived positron emission tomography tracer.

The calcium-activated potassium channel 3.1 (K 3.1) is overexpressed in many tumor entities and has predictive power concerning disease progression and outcome.

Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer's Disease.

Drug development efforts that focused on single targets failed to provide effective treatment for Alzheimer's disease (AD). Therefore, we designed cholinesterase inhibition (ChEI)-based multi-target-directed ligands (MTDLs) to simultaneously target AD-related receptors. We built a library of 70 compounds, sequentially screened for ChEI, and determined σR, σR, NMDAR-GluN2B binding affinities, and P2X7R antagonistic activities.