Several orexin receptor
antagonists have been reported in recent years, but currently there are no imaging tools to probe the density and function of orexin receptors in vivo. To date there are no published data on the pharmacokinetics (PK) and accumulation of some lead orexin receptor antagonists. Evaluation of CNS pharmacokinetics in the pursuit of positron emission tomography (PET) radiotracer development could be used to elucidate the association of orexin receptors with diseases and to facilitate the drug discovery and development. To this end, we designed and evaluated carbon-11 labeled compounds based on diazepane orexin receptor antagonists previously described. One of the synthesized compounds, [C-11]CW4, showed high brain uptake in rats and further evaluated in non-human primate (NHP) using PET-MR check details imaging. PET Apoptosis inhibitor scans performed in a baboon showed appropriate early brain uptake for consideration as a radiotracer. However, [C-11]CW4 exhibited
fast kinetics and high nonspecific binding, as determined after co-administration of [C-11]CW4 and unlabeled CW4. These properties indicate that [C-11]CW4 has excellent brain penetrance and could be used as a lead compound for developing new CNS-penetrant PET imaging probes of orexin receptors.(C) 2013 Elsevier Inc. All rights reserved.”
“Purpose: Senescence related regulatory pathways serve as barriers to cancer immortalization and progression but they are currently not well defined. FILIP1L is a growth inhibitory gene with multiple isoforms whose expression is increased in senescent prostate and prostate cancer cells, and decreased in many cancers. We investigated whether DNA methylation Flavopiridol (Alvocidib) regulates FILIP1L in senescence and in prostate cancer development.
Materials and Methods: FILIP1L mRNA expression
was assessed in prostate cancer and associated normal prostate tissues using quantitative polymerase chain reaction. A tissue microarray was constructed using 95 prostate cancer specimens and 45 benign prostate specimens. Vectra (TM) imaging was used to quantitate nuclear and cytoplasmic FILIP1L protein expression. Bisulfite sequencing and Pyrosequencing (R) were used to assess methylation. Prostate cancer cell lines were treated with 2′-deoxy-5-azacytidine and mRNA expression was assessed.
Results: FILIP1L isoform 2 mRNA was increased in replicatively senescent human prostate epithelial cells and decreased in prostate cancer specimens. We verified a reduction in nuclear FILIP1L protein in prostate cancer using tissue microarrays (p = 0.006). A CpG island 5′ of the isoform 2 translational start site was identified that showed hypermethylation in prostate cancer cell lines and tumors compared to normal prostate cells and tissues. Pyrosequencing confirmed FILIP1L hypermethylation in all 14 tumors compared to paired normal tissues (p < 0.0001).