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Abstract: The radiosynthesis and the radiopharmacological characterization of [ 11 C]AL-438 as a nonsteroidal ligand for the glucocorticoid receptor (GR) is described. Radiolabeling of the corresponding desmethyl precursor 10 with [11C]MeI gave [ 11 C]AL-438 in decay-corrected radiochemical yields of 30±4% (based upon [11C]CO2) within 35min at a specific radioactivity of 10–15GBq/μmol at the end-of-synthesis. The radiopharmacological evaluation of [ 11 C]AL-438 involved biodistribution and small animal PET imaging in rats, and autoradiography studies using rat brain sections. Biodistribution studies were performed in male Wistar rats and demonstrated high radioactivity uptake in pituitary and brain. However, the inability of high dose corticosterone to block binding would suggest that the radioactivity accumulation in the brain was not receptor-mediated. [Copyright &y& Elsevier]

Abstract: The study describes the use of [18F]FDG as 18F building block for the direct labelling of various aminooxy-functionalised peptides via chemoselective oxime formation. [Copyright &y& Elsevier]

Radioligand [18F]ONO-8430506 ([18F]8) was prepared and tested as a novel autotaxin (ATX) PET imaging agent derived from highly potent ATX inhibitor ONO-8430506. [Display omitted] We have prepared and tested radioligand [18F]ONO-8430506 ([18F]8) as a novel ATX PET imaging agent derived from highly potent ATX inhibitor ONO-8430506. Radioligand [18F]8 could be prepared in good and reproducible radiochemical yields of 35 ± 5% (n = 6) using late-stage radiofluorination chemistry. ATX binding analysis showed that 9-benzyl tetrahydro- b -carboline 8 has about five times better inhibitory potency than clinical candidate GLPG1690 and somewhat less inhibitory potency than ATX inhibitor PRIMATX. The binding mode for compound 8 inside the catalytic pocket of ATX using computational modelling and docking protocols revealed that compound 8 resembled a comparable binding mode to that of ATX inhibitor GLPG1690. However, PET imaging studies with radioligand [18F]8 showed only relatively low tumour uptake and retention (SUV 60min 0.21 ± 0.03) in the tested 8305C human thyroid tumour model reaching a tumour-to-muscle ratio of ∼ 2.2 after 60 min. [ABSTRACT FROM AUTHOR]

A novel class of modified 1,5-disubstituted tetrazoles was designed and synthesized, their biological activity as cyclooxygenases inhibitors was screened, and their molecular docking studies were performed. The structural modifications of the first category included the 4-methylsulfonyl phenyl at C-1 of the central moiety and the linkers (–OH, –CH 2 OH, –CH 2 CH 2 OH) with different lengths at the para position of the N-1 phenyl group. For the second category, the 4-methylsulfonyl phenyl group at C-1 was replaced with 4-aminosulfonyl phenyl. While for the third category, a methylene unit was inserted between the C-1 of the tetrazole central ring and the 4-(methylsulfonyl)phenyl group, keeping the same linkers of various extensions at the para position of the N-1 phenyl group. Among the screened compounds, tetrazole 4i showed the best inhibition potency and selectivity values for both COX-2 enzyme (IC 50 = 3 μM, SI > 67) and COX-1 isoenzyme (IC 50 > 200 μM). Compounds 4e , 4h , and 4i , which have the highest inhibition potency toward COX-2 were selected for the molecular docking studies to verify their inhibition and selectivity for COX-2 over COX-1 with their modified structure. The obtained theoretical studies are in agreement with the in vitro bioassay screening results, which supports the importance of the structural modifications for our studied compounds. [ABSTRACT FROM AUTHOR]

Cyclooxygenase-2 (COX-2) is the key enzyme in the prostaglandin synthesis pathway which is involved in various pathophysiological conditions. The enzyme is membrane bound and located inside of the endoplasmic reticulum and nuclear membrane. Effective perfusion of inhibitors to the active site requires lipophilic drugs, which consequently display high unspecific background accumulation, for example, in fatty tissues. The objective of this work was the development of a small molecule radiolabeled with a long-lived iodine radioisotope to enable longer imaging times and better target-to-background ratios. A group of iodinated compounds ( 8 – 10 ) was synthesized and identified as selective COX-2 inhibitors (COX-2 IC 50 = 0.85–13 μM). Molecular docking results provided the theoretical support for the experimental COX-2 inhibition data. Furthermore, a novel 125 I-containing trifluoro-pyrimidine compound ([ 125 I]Pyricoxib) was prepared via radioiododestannylation reaction as potent and selective COX-2 inhibitor. Radiosynthesis of [ 125 I]Pyricoxib was accomplished with innovative fluorous chemistry using fluorous chloroamine-T (F-CAT) as novel oxidizing agent in high radiochemical yields of 91 ± 4%. [ABSTRACT FROM AUTHOR]

Abstract: The observation that the cyclooxygenase-2 (COX-2) isozyme is over-expressed in multiple types of cancer, relative to that in adjacent non-cancerous tissue, prompted this investigation to prepare a group of hybrid fluorescent conjugates wherein the COX inhibitors ibuprofen, (S)-naproxen, acetyl salicylic acid, a chlororofecoxib analog and celecoxib were coupled via a linker group to an acridone, dansyl or rhodamine B fluorophore. Within this group of compounds, the ibuprofen-acridone conjugate (10) showed potent and selective COX-2 inhibition (COX-2 IC50 =0.67μM; SI=110.6), but its fluorescence emission (λ em =417, 440nm) was not suitable for fluorescent imaging of cancer cells that over-express the COX-2 isozyme. In comparison, the celecoxib-dansyl conjugate (25) showed a slightly lower COX-2 potency and selectivity (COX-2 IC50 =1.1μM; SI>90) than the conjugate 10, and it possesses a better fluorescence emission (λ em =500nm). Ultimately, a celecoxib-rhodamine B conjugate (28) that exhibited moderate COX-2 potency and selectivity (COX-2 IC50 =3.9μM; SI>25) having the best fluorescence emission (λ em =580nm) emerged as the most promising biomarker for fluorescence imaging using a colon cancer cell line that over-expresses the COX-2 isozyme. [Copyright &y& Elsevier]

Abstract: A new synthesis of O-(2-[18F]fluoroethyl)-l-tyrosine [18F]FET was developed using a NanoTek® microfluidic synthesis system (Advion BioSciences, Inc.). Optimal reaction conditions were studied through screening different reaction parameters like temperature, flow rate, reaction time, concentration of the labeling precursor, and the applied volume ratio between the labeling precursor and [18F]fluoride. [18F]FET was obtained after HPLC purification with 50% decay-corrected radiochemical yield starting from as little as 40μg of labeling precursor. Small animal PET studies in EMT-6 tumor bearing mice showed radioactivity accumulation in the tumor (SUV60min 1.21±0.2) resulting in an slightly increasing tumor-to-muscle ratio over time. [Copyright &y& Elsevier]

Abstract: A series of novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors was prepared via treatment of various diaryl amides with tetrachlorosilane/sodium azide. All compounds were tested in cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles contained a methylsulfonyl or sulfonamide group as COX-2 pharmacophore displayed only low inhibitory potency towards COX-2. Most potent compounds showed IC50 values of 6 and 7μM for COX-2. All compounds showed IC50 values greater 100μM for COX-1 inhibition. [Copyright &y& Elsevier]

Abstract: Human polo-like kinase 1 (Plk1) is involved in cell proliferation and overexpressed in a broad variety of different cancer types. Due to its crucial role in cancerogenesis Plk1 is a potential target for diagnostic and therapeutic applications. Peptidic ligands can specifically interact with the polo-box domain (PBD) of Plk1, a C-terminal located phosphoepitope binding motif. Recently, phosphopeptide MQSpTPL has been identified as ligand with high binding affinity. However, a radiolabeled version of this peptide showed only insufficient cellular uptake. The present study investigated peptide dimers consisting of PBD-targeting phosphopeptide MQSpTPL and a cell-penetrating peptide (CPP) moiety. The new constructs demonstrate superior uptake in different cancer cell-lines compared to the phosphopeptide alone. Furthermore, we could demonstrate binding of phosphopeptide-CPP dimers to PBD of Plk1 making the compounds interesting leads for the development of molecular probes for imaging Plk1 in cancer. [Copyright &y& Elsevier]

Abstract: A series of 1,5-diaryl-substituted tetrazole derivatives was synthesized via conversion of readily available diaryl amides into corresponding imidoylchlorides followed by reaction with sodium azide. All compounds were evaluated by cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles 3a–e showed IC50 values ranging from 0.42 to 8.1mM for COX-1 and 2.0 to 200μM for COX-2. Most potent compound 3c (IC50 (COX-2)=2.0μM) was further used in molecular modeling docking studies. [Copyright &y& Elsevier]

Abstract: Two neurotensin(8–13)-containing peptide heterodimers were prepared via copper(I)-mediated click chemistry. The resulting peptide dimers could be obtained in 28–31% yield after HPLC purification. Neurotensin(8–13)-containing peptide dimers were used in an in vitro binding assay to determine binding affinity towards the neurotensin receptor-1 (NTR1). The determined IC50 values of 8.3μM and 0.7μM indicate only very low binding affinity of the neurotensin(8–13)-containing peptide heterodimers towards the NTR1. [Copyright &y& Elsevier]