Despite the broad implications of the cannabinoid type 2 receptor (CB2) in neuroinflammatory processes, a suitable CB2-targeted probe is currently lacking in clinical routine. In this work, we synthesized 15 fluorinated pyridine derivatives and tested their binding affinities toward CB2 and CB1. With a sub-nanomolar affinity (K i for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18-d 6 exhibited outstanding in vitro performance characteristics and was radiofluorinated with an average radiochemical yield of 10.6 ± 3.8% (n = 16) and molar activities ranging from 52 to 65 GBq/μmol (radiochemical purity > 99%). [18F]RoSMA-18-d 6 showed exceptional CB2 attributes as demonstrated by in vitro autoradiography, ex vivo biodistribution, and positron emission tomography (PET). Further, [18F]RoSMA-18-d 6 was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [18F]RoSMA-18-d 6 is a promising CB2 PET radioligand for clinical translation.
The molecular vibrations of ethene adsorbed on roughened Cu(111) surfaces have been investigated with high resolution electron energy loss spectroscopy and density-functional-theory calculations. The roughness was introduced by sputtering or evaporation of copper, respectively, on the cooled surface. We found stabilization of the ethene layer compared to ethene adsorbed on pristine Cu(111). Furthermore, two new vibrational features observed on the rough surface can be assigned to frustrated translations and rotations of the ethene molecule on surface defects and are indicative of a different binding on the rough surface.
Detailed information on the metabolic fate of lead compounds can be a powerful tool for an informed approach to the stabilization of metabolically labile compounds in the lead optimization phase. The combination of high performance liquid chromatography (HPLC) with nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) has been used to give comprehensive structural data on metabolites of novel drugs in development. Recently, increased automation and the embedding of on-line solid-phase extraction (SPE) into a integrated LC-SPE-NMR-MS system have improved enormously the detection limits of this approach. The new technology platform allows the analysis of complex mixtures from microsome incubations, combining low material requirements with relatively high throughput. Such characteristics make it possible to thoroughly characterize metabolites of selected compounds at earlier phases along the path to lead identification and clinical candidate selection, thus providing outstanding guidance in the process of eliminating undesired metabolism and detecting active or potentially toxic metabolites. Such an approach was applied at the lead identification stage of a backup program on metabotropic glutamate receptor 5 (mGlu5) allosteric inhibition. The major metabolites of a lead 5-aminothiazole-4-carboxylic acid amide 1 were synthesized and screened, revealing significant in vitro activity and possible involvement in the overall pharmacodynamic behavior of 1. The information collected on the metabolism of the highly active compound 1 was pivotal to the synthesis of related compounds with improved microsomal stability.
enamel is secreted by ameloblasts derived from tooth epithelial stem cells (Scs). Humans cannot repair or regenerate enamel, due to early loss of tooth epithelial Scs. contrarily in the mouse incisors, epithelial Scs are maintained throughout life and endlessly generate ameloblasts, and thus enamel. Here we isolated Sox2-GFP+ tooth epithelial Scs which generated highly cellular spheres following a novel in vitro strategy. this system enabled analysis of Sc regulation by various signaling molecules, and supported the stimulatory and inhibitory roles of Shh and Bmp, respectively; providing better insight into the heterogeneity of the Scs. further, we generated a novel mouse reporter, Enamelin-tdTomato for identification of ameloblasts in live tissues and cells, and used it to demonstrate presence of ameloblasts in the new 3D co-culture system of dental SCs. Collectively, our results provide means of generating 3D tooth epithelium from adult SCs which can be utilized toward future generation of enamel. Postnatally, stem cells (SC) remain within organ-specific SC niches and provide the source of reparative and regenerative potential. Continuously-growing rodent incisors contain epithelial and mesenchymal SC niches, which unceasingly produce the mineralized constituents of the adult tooth: enamel and dentin, respectively (reviewed in 1). The epithelial SCs reside in the labial cervical loops (LaCL) situated at the proximal end of the tooth, and are surrounded by their progeny, as well as the mesenchymal cells of dental pulp and follicle. Within the LaCL, these SCs are located in the loosely-arranged stellate reticulum and can be identified as slowly dividing, label-retaining cells, which express Sox2, Lgr5, Ptch1, Gli1, ABCG2, Bmi-1, and Oct3/4, among other genes 2-7. In vivo studies and in vitro explant cultures have demonstrated that the survival, proliferation, and differentiation of tooth epithelial SCs are regulated through complex, but not fully elucidated, interactions with the surrounding cells. An intricate signaling network involving several signaling pathways, including FGF, BMP, Activin, and Follistatin, regulates maintenance of SCs, transit-amplifying cell (TAC) proliferation, and ameloblast differentiation (reviewed in 8). In addition, we recently showed that functionally distinct Patched receptors establish multimodal Hedgehog signaling in the cervical loop 9 , which enables simultaneous regulation of maintenance of SCs and ameloblast differentiation, as previously reported 7,10. Published data have demonstrated that Fgf10 and Fgf3 positively regulate SCs, similar to Shh signaling, while BMP4 and mesenchyme-derived Wnt signaling have a negative effect on this population 10-12. Intriguingly, the incisor SC niche is characterized by exclusive lack of Wnt signaling, attributed to the enrichment of Wnt inhibitors 13. Epithelial SCs in mouse incisors continuously generate ameloblasts in a stepwise process during which the cells transit through increasing degrees of differentiation marked by the expression of...
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