A Fast-Binding, Functionally Reversible, COX-2 Radiotracer for CNS PET Imaging.

Cyclooxygenase-2 (COX-2) is an enzyme that plays a pivotal role in peripheral inflammation and pain via the prostaglandin pathway. In the central nervous system (CNS), COX-2 is implicated in neurodegenerative and psychiatric disorders as a potential therapeutic target and biomarker. However, clinical studies with COX-2 have yielded inconsistent results, partly due to limited mechanistic understanding of how COX-2 activity relates to CNS pathology. Therefore, developing COX-2 positron emission tomography (PET) radiotracers for human neuroimaging is of interest. This study introduces [11C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [11C]BRD1158 was developed by prioritizing potency at COX-2, isoform selectivity over COX-1, fast binding kinetics, and free fraction in the brain. Evaluated through in vivo PET neuroimaging in rodent models with human COX-2 overexpression, [11C]BRD1158 demonstrated high brain uptake, fast target-engagement, functional reversibility, and excellent specific binding, which is advantageous for human imaging applications. Lastly, post-mortem samples from Huntington's disease (HD) patients and preclinical HD mouse models showed that COX-2 levels were elevated specifically in disease-affected brain regions, primarily from increased expression in microglia. These findings indicate that COX-2 holds promise as a novel clinical marker of HD onset and progression, one of many potential applications of [11C]BRD1158 human PET.

The Role of DJ-1 in Cellular Metabolism and Pathophysiological Implications for Parkinson's Disease.

DJ-1 is a multifunctional protein associated with pathomechanisms implicated in different chronic diseases including neurodegeneration, cancer and diabetes. Several of the physiological functions of DJ-1 are not yet fully understood; however, in the last years, there has been increasing evidence for a potential role of DJ-1 in the regulation of cellular metabolism. Here, we summarize the current knowledge on specific functions of DJ-1 relevant to cellular metabolism and their role in modulating metabolic pathways. Further, we illustrate pathophysiological implications of the metabolic effects of DJ-1 in the context of neurodegeneration in Parkinson´s disease.

Assembly of a Tripeptide and Anti-Inflammatory Drugs into Supramolecular Hydrogels for Sustained Release.

Supramolecular hydrogels offer interesting opportunities for co-assembly with drugs towards sustained release over time, which could be achieved given that the drug participates in the hydrogel nanostructure, and it is not simply physically entrapped within the gel matrix. dLeu-Phe-Phe is an attractive building block of biomaterials in light of the peptide's inherent biocompatibility and biodegradability. This study evaluates the assembly of the tripeptide in the presence of either of the anti-inflammatory drugs ketoprofen or naproxen at levels analogous to commercial gel formulations. Fourier-transformed infrared (FT-IR), circular dichroism, Thioflavin T fluorescence, transmission electron microscopy (TEM), and oscillatory rheometry are used. Drug release over time is monitored by means of reverse-phase high performance liquid chromatography, and shows different kinetics for the two drugs.