Evaluation of a Positron Emission Tomography Tracer Targeting Colony-Stimulating Factor 1 Receptor for Detecting Pulmonary Inflammation.

Colony-stimulating factor 1 receptor (CSF1R) is a type III receptor tyrosine kinase that is crucial for immune cell activation, survival, proliferation, and differentiation. Its expression significantly increases in macrophages during inflammation, playing a crucial role in regulating inflammation resolution and termination. Consequently, CSF1R has emerged as a critical target for both therapeutic intervention and imaging of inflammatory diseases. Herein, we have developed a radiotracer, 1-[4-((7-(dimethylamino)quinazolin-4-yl)oxy)phenyl]-3-(4-[18F]fluorophenyl)urea ([18F]17), for in vivo positron emission tomography (PET) imaging of CSF1R. Compound 17 exhibits a comparable inhibitory potency against CSF1R as the well-known CSF1R inhibitor PLX647. The radiosynthesis of [18F]17 was successfully performed by radiofluorination of aryltrimethyltin precursor with a yield of approximately 12% at the end of synthesis, maintaining a purity exceeding 98%. In vivo stability and biodistribution studies demonstrate that [18F]17 remains >90% intact at 30 min postinjection, with no defluorination observed even at 60 min postinjection. The PET/CT imaging study in lipopolysaccharide-induced pulmonary inflammation mice indicates that [18F]17 offers a more sensitive characterization of pulmonary inflammation compared to traditional [18F]FDG. Notably, [18F]17 shows a higher discrepancy in uptake ratio between mice with pulmonary inflammation and the sham group. Furthermore, the variations in [18F]17 uptake ratio observed on day 7 and day 14 correspond to lung density changes observed in CT imaging. Moreover, the expression levels of CSF1R on day 7 and day 14 follow a trend similar to the uptake pattern of [18F]17, indicating its potential for accurately characterizing CSF1R expression levels and effectively monitoring the pulmonary inflammation progression. These results strongly suggest that [18F]17 has promising prospects as a CSF1R PET tracer, providing diagnostic opportunities for pulmonary inflammatory diseases.

Direct electrochemical reductive amination between aldehydes and amines with a H/D-donor solvent.

A novel electrochemical synthesis protocol has been achieved for reductive amination between aldehydes and amines in undivided cells at room temperature. Under metal-free and external-reductant-free electrolysis conditions, various important secondary amine products are obtained in moderate-to-high yields. Deuterium-labeling experiments have demonstrated that low-toxicity DMSO acts both as a solvent and a H-donor in the reaction. On this basis, various deuterium-labeled products with good-to-excellent D-incorporation have been synthesized by using DMSO-d6 as a solvent. Furthermore, a molecule with GR-antagonistic activity has been synthesized through further sulfonylation.

Electrochemical Desulfurative Cyclization Accessing Oxazol-2-amine Derivatives via Intermolecular C-N/C-O Bond Formation.

A practical protocol has been established to access diverse oxazol-2-amine derivatives in one step via the electrochemical desulfurative cyclization of isothiocyanates and α-amino ketones. On the basis of the cycle of in situ generation of iodine/desulfurative cyclization/iodide anion regeneration, the reaction is performed under metal-free and external-oxidant-free electrolytic conditions to achieve the formation of intermolecular C-O and C-N bonds, providing oxazol-2-amines in moderate to excellent yields.

Design, synthesis and biological evaluation of indole-based [1,2,4]triazolo[4,3-a] pyridine derivatives as novel microtubule polymerization inhibitors.

A series of indole-based [1,2,4]triazolo [4,3-a]pyridine derivatives was designed and synthesized as novel microtubulin polymerization inhibitors by using a conformational restriction strategy. These compounds exhibited moderate to potent anti-proliferative activities against a panel of cancer cell lines (HeLa, A549, MCF-7 and HCT116). Among them, compound 12d featuring a N-methyl-5-indolyl substituent at the C-6 position of the [1,2,4]triazolo [4,3-a]pyridine core exhibited the highest antiproliferative activity with the IC50 values ranging from 15 to 69 nM, and remarkable inhibitory effect on tubulin polymerization with an IC50 value of 1.64 µM. Mechanistic studies revealed that compound 12d induced cellular apoptosis and cell cycle arrest at the G2/M phase in a dose-dependent fashion. Moreover, compound 12d significantly suppressed wound closure and disturbed microtubule networks.