Background Reactive oxygen species (ROS)-induced oxidative stress damages many cellular components such as fatty acids, DNA, and proteins. This damage is implicated in many disease pathologies including cancer and neurodegenerative and cardiovascular diseases. Antioxidants like ascorbate (vitamin C, ascorbic acid) have been shown to protect against the deleterious effects of oxidative stress in patients with cancer. In contrast, other data indicate potential tumor-promoting activity of antioxidants, demonstrating a potential temporal benefit of ROS. However, quantifying real-time tumor ROS is currently not feasible, since there is no way to directly probe global tumor ROS. In order to study this ROS-induced damage and design novel therapeutics to prevent its sequelae, the quantitative nature of positron emission tomography (PET) can be harnessed to measure in vivo concentrations of ROS. Therefore, our goal is to develop a novel translational ascorbate-based probe to image ROS in cancer in vivo using noninvasive PET imaging of tumor tissue. The real-time evaluations of ROS state can prove critical in developing new therapies and stratifying patients to therapies that are affected by tumor ROS. Methods We designed, synthesized, and characterized a novel ascorbate derivative ( E )-5-(2-chloroethylidene)-3-((4-(2-fluoroethoxy)benzyl)oxy)-4-hydroxyfuran-2(5H)-one (KS1). We used KS1 in an in vitro ROS MitoSOX-based assay in two different head and neck squamous cancer cells (HNSCC) that express different ROS levels, with ascorbate as reference standard. We radiolabeled 18 F-KS1 following 18 F-based nucleophilic substitution reactions and determined in vitro reactivity and specificity of 18 F-KS1 in HNSCC and prostate cancer (PCa) cells. MicroPET imaging and standard biodistribution studies of 18 F-KS1 were performed in mice bearing PCa cells. To further demonstrate specificity, we performed microPET blocking experiments using nonradioactive KS1 as a blocker. Results KS1 was synthesized and characterized using 1 H NMR spectra. MitoSOX assay demonstrated good correlations between increasing concentrations of KS1 and ascorbate and increased reactivity in SCC-61 cells (with high ROS levels) versus rSCC-61cells (with low ROS levels). 18 F-KS1 was radiolabeled with high radiochemical purity (> 94%) and specific activity (~ 100 GBq/μmol) at end of synthesis (EOS). Cell uptake of 18 F-KS1 was high in both types of cancer cells, and the uptake was significantly blocked by nonradioactive KS1, and the ROS blocker, superoxide dismutase (SOD) demonstrating specificity. Furthermore, 18 F-KS1 uptake was increased in PCa cells under hypoxic conditions, which have been shown to generate high ROS. Initial in vivo tumor upta...
Background: Recently, there has been a lot of scientific interest in exploring the syntheses of oxygen and nitrogen-containing heterocyclic compounds due to their pharmacological activities. In addition, benzisoxazoles play a very important role in organic synthesis as key intermediates. Objective: In this paper, we focused on developing a novel synthetic route for biologically active arylisoxazoles under normal conditions, and simplified it to get high purities and yields, and also reported their anti-inflammatory activities. Method: An efficient and simple method has been explored for the synthesis of novel 3-methyl arylisoxazoles from o-nitroaryl halides via o-ethoxyvinylnitroaryls, using dihydrated stannous chloride (SnCl2.2H2O) in MeOH / EtOAc (1:1) via Domino rearrangement in one pot synthesis. Result: We synthesized novel 3-methylarylisoxazoles from o-nitroarylhalides via o-ethoxyvinylnitroaryls, using dihydrated stannous chloride (SnCl2.2H2O) in MeOH / EtOAc (1:1) via domino rearrangement. In this reduction, nitro group and ethoxy vinyl group change to the functional acyl ketones, followed by hetero cyclization. Here, the reaction proceeds without the isolation of intermediates like 2-acylnitroarenes and 2- acylanilines. All the synthesized compounds were completely characterized by the NMR and mass spectra. The compounds were also explored for their anti-inflammatory activity by carrageenan-induced inflammation in the albino rats (150-200 g) of either sex used in this entire study with the use of Diclofenac sodium as the standard drug. The initial evaluations identified leading targets with good to moderate anti-inflammatory activity. Conclusion: A simple, one-pot and convenient method has been explored for the synthesis of novel 3- methylarylisoxazoles with high purity and reaction yields. All the compounds 3a, 3c, 3d, 3f, 3g and 3h exhibited 51-64% anti-inflammatory activities.
BackgroundG‐protein‐coupled receptors (GPCRs) plays a key role in regulating glucose metabolism. While GPR119 (an important GPCR) agonists have shown potential for improving neurologic and cognitive function in patients with AD and type2 diabetes mellitus (T2DM), clinical interventions targeting GPR119 will require accurate in vivo measures such as PET imaging. We recently synthesized a series of novel piperdine analogs, identifying two analogs (T1 and T2) with high GPR119 binding potency (2‐5 nM) for PET radiochemistry. Here we report their radiochemistry and initial biological evaluations in neuronal cells, normal rodents, and monkeys (vervets).Method[18F]T1/T2 radiochemistry was performed in TRASIS‐AIO automated module following [18F]¯‐based nucleophilic substitution of corresponding precursors. [18F]T1 and T2 in vitro assays were performed in three patient‐derived cell lines with different GPR119 expression (MDM‐MD‐231<NCI‐H1716<HepG2), with and without GPR119 agonists and non‐radioactive T1/T2. Dynamic 0‐60 min brain microPET/CT imaging and biodistribution were performed in normal balb/c mice (n=4). Healthy adult female vervets (n=6, 4.5‐6.7 kg) underwent 0‐90 min brain PET imaging. Standard uptake value (SUVmax) and time‐activity curves (TACs) were calculated for whole brain PET/MR images.ResultBoth [18F]T1 and T2 were produced in high radiochemical purities (>98%) and specific activities (∼3800‐4500 mCi/µmol), decay corrected to end of synthesis. Radioactive cell uptake was lower in MDM‐MD‐231 cells (lowest GPR119 expression) and higher in HepG2 cells (higher GPR119 expression); uptake also significantly increased with GPR119 agonists and T1/T2 treatments compared to baseline. [18F]T2 showed slightly better brain uptake in mice compared to [18F]T1 (SUVmax= 0.35±0.07 Vs. 0.55±0.09 g/mL). Biodistribution of [18F]T2 (%ID/mg = 1.01±0.09) also showed high brain uptake. SUVmax (avg=2.6±0.1 g/mL) and TACs of both [18F]T1 and [18F]T2 in monkey brains demonstrated rapid distribution across BBB within 10 min and favorable clearance within 90 min of tracer injection (Fig 1).ConclusionRadiochemistry was successfully automated and optimized. Cell uptake showed direct relationships between radiotracer uptake and GPR119 expression. MicroPET imaging, biodistribution in rodents and monkey PET imaging demonstrated excellent brain uptake and favorable pharmacokinetics, indicating BBB penetration. These data suggest for the first time that [18F]T1 and T2 have potential for imaging GPR119 in brains of humans with AD or T2DM.
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