Zgodba o Apoloniju, tirskem kralju, se prvič omenja konec 6. stol. po Kr. pri krščanskem pesniku Venanciju Fortunatu (Carmina 6.8.5). Njen avtor je neznan, najverjetneje pa temelji na grškem ...originalu iz 3. stol. po Kr., ki je izgubljen. V pozni antiki je bil žanr ljubezenskih zgodb zelo priljubljen. Ne glede na to se je do danes v celoviti obliki ohranilo zgolj pet romanov z ljubezensko vsebino. Žanr ljubezenskih romanov se je najverjetneje razvil proti koncu helenistične dobe (1. stol. pr. Kr.). Grški roman z ljubezensko vsebino je vplival tudi na latinsko literaturo in posledično tudi na razvoj romana v današnji obliki.
Maro Duka (Μάρω Δούκα) se je rodila leta 1947 v mestu Hania na Kreti. Leta 1966 se je preselila v Atene, kjer je začela s študijem na Oddelku za zgodovino in arheologijo na Filozofski fakulteti. ...Kmalu zatem, ko se je vpisala na univerzo, natančneje 21. aprila 1967, je v Grčiji prišlo do državnega udara. To je vzpodbudilo takrat dvajsetletno Maro, da se je pridružila študentskim gibanjem, ki so se borila proti represivni hunti. V tistem času jo je vojaška oblast zaprla, ker je skrivala člana odporniškega gibanja, a je k sreči prejela le pogojno kazen. Roman z naslovom Αρχαία σκουριά (Mačje zlato) je nastal leta 1979, kmalu po koncu diktature (padla je leta 1974) in v času, ko se je v Grčiji ponovno začela vzpostavljati demokracija.
Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of antibacterial agents that target bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Our recently disclosed crystal ...structure of an NBTI ligand in complex with DNA gyrase and DNA revealed that the halogen atom in the para position of the phenyl right hand side (RHS) moiety is able to establish strong symmetrical bifurcated halogen bonds with the enzyme; these are responsible for the excellent enzyme inhibitory potency and antibacterial activity of these NBTIs. To further assess the possibility of any alternative interactions (e.g., hydrogen-bonding and/or hydrophobic interactions), we introduced various non-halogen groups at the
-position of the phenyl RHS moiety. Considering the hydrophobic nature of amino acid residues delineating the NBTI's binding pocket in bacterial topoisomerases, we demonstrated that designed NBTIs cannot establish any hydrogen-bonding interactions with the enzyme; hydrophobic interactions are feasible in all respects, while halogen-bonding interactions are apparently the most preferred.
V zgodovini srečamo zgolj peščico žensk, ki bi tako močno zaznamovale svoj čas in okolje, v katerem so delovale, kot ju je sv. Hildegarda iz Bingna. Renska sibila, kot so jo poimenovali njeni ...kasnejši občudovalci, je s svojo bogato literarno zapuščino pomembno vplivala na razvoj teologije in mistike 12. stoletja. Tega so se zavedali že njeni sodobniki, ki so ji priznavali avtoriteto tako v cerkveni kot posvetni sferi. Vseeno pa se je kot ženska, ki je posegala na področja, tradicionalno rezervirana za moške, morala soočiti s številnimi preprekami in ovirami. Njeni vsestranski dosežki se lahko po obsegu in kvaliteti primerjajo z dosežki bolj znanih filozofov in učenjakov, ki so jim bile zgodovinske okoliščine morda bolj naklonjene. Njen holistični pristop, ki je viden v vseh njenih delih, z obilico inovativnosti povezuje teologijo, glasbo, medicino, naravoslovje in celo jezikoslovje, v katerih lahko zaznamo vplive antičnih in sodobnih virov, velikokrat pa so njena opažanja plod skrbnega opazovanja okolice, ki je med drugim močno vplivala na razvoj njene misli. Videnja, ki naj bi jih že od zgodnjega otroštva prejemala od Boga, so tako dobila končno podobo v pisni obliki prav v samostanskem okolju, najprej v Disibodenbergu in nato v Rupertsbergu, kjer so najprej nastala njena teološka dela, nato pa so jim sledila še ostala.
Broad availability and cost-effectiveness of 99Mo/99mTc generators worldwide support the use, and thus the development, of novel 99mTc-labelled radiopharmaceuticals. In recent years, preclinical and ...clinical developments for neuroendocrine neoplasms patient management focused on somatostatin receptor subtype 2 (SST2) antagonists, mainly due to their superiority in SST2-tumour targeting and improved diagnostic sensitivity over agonists. The goal of this work was to provide a reliable method for facile preparation of a 99mTc-labelled SST2 antagonist, 99mTcTc-TECANT-1, in a hospital radiopharmacy setting, suitable for a multi-centre clinical trial. To ensure successful and reproducible on-site preparation of the radiopharmaceutical for human use shortly before administration, a freeze-dried three-vial kit was developed. The final composition of the kit was established based on the radiolabelling results obtained during the optimisation process, in which variables such as precursor content, pH and buffer, as well as kit formulations, were tested. Finally, the prepared GMP-grade batches met all predefined specification parameters together with long-term kit stability and stability of the product 99mTcTc-TECANT-1. Furthermore, the selected precursor content complies with micro-dosing, based on an extended single-dose toxicity study, where histopathology NOEL was established at 0.5 mg/kg BW, being more than 1000 times higher than the planned human dose of 20 µg. In conclusion, 99mTcTc-TECANT-1 is suitable to be advanced into a first-in-human clinical trial.
Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project ...“TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. 99mTcTc-TECANT-1 showed higher hydrophilicity and lower protein binding than 99mTc-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while 99mTcTc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, 99mTcTc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to 99mTcTc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for 99mTcTc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of 99mTcTc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist.
CCK2R antagonists: from SAR to clinical trials Novak, Doroteja; Anderluh, Marko; Kolenc Peitl, Petra
Drug discovery today,
August 2020, 2020-08-00, 20200801, Volume:
25, Issue:
8
Journal Article
Peer reviewed
•The CCK2 receptor is involved in numerous (patho)physiological processes.•Many CCK2 receptor antagonists have shown promising results in in-vivo animal models.•High attrition rates are seen in ...clinical settings due to off-target effects.•Netazepide (YF476) and nastorazepide (Z-360) are in Phase II clinical trials.•Nastorazepide (Z-360) serves as a lead compound for development of imaging agents.
The widespread involvement of the cholecystokinin-2/gastrin receptor (CCK2R) in multiple (patho)physiological processes has propelled extensive searches for nonpeptide small-molecule CCK2R antagonists. For the past three decades, considerable research has yielded numerous chemically heterogeneous compounds. None of these entered into the clinic, mainly because of inadequate biological effects. However, it appears that the ultimate goal of a clinically useful CCK2R antagonist is now just around the corner, with the most promising compounds, netazepide and nastorazepide, now in Phase II clinical trials. Here, we illustrate the structure–activity relationships (SARs) of stablished CCK2R antagonists of various structural classes, and the most recent proof-of-concept studies where new applicabilities of CCK2R antagonists as visualizing agents are presented.
The quest for the first clinically useful CCK2R antagonist: is it a never-ending story, or are we on the verge of a breakthrough?
The widespread involvement of the cholecystokinin-2/gastrin receptor (CCK
R) in multiple (patho)physiological processes has propelled extensive searches for nonpeptide small-molecule CCK
R ...antagonists. For the past three decades, considerable research has yielded numerous chemically heterogeneous compounds. None of these entered into the clinic, mainly because of inadequate biological effects. However, it appears that the ultimate goal of a clinically useful CCK
R antagonist is now just around the corner, with the most promising compounds, netazepide and nastorazepide, now in Phase II clinical trials. Here, we illustrate the structure-activity relationships (SARs) of stablished CCK
R antagonists of various structural classes, and the most recent proof-of-concept studies where new applicabilities of CCK
R antagonists as visualizing agents are presented.
The cholecystokinin-2/gastrin receptor (CCK
R) is considered a suitable target for the development of radiolabelled antagonists, due to its overexpression in various tumours, but no such compounds ...are available in clinical use. Therefore, we designed novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated ligands based on CCK
R antagonist Z360/nastorazepide. As a proof of concept that CCK
R antagonistic activity can be retained by extending the Z360/nastorazepide structure using suitable linker, we present herein three compounds containing various PEG linkers synthesised on solid phase and in solution. The antagonistic properties were measured in a functional assay in the A431-CCK
R cell line (in the presence of agonist G17), with IC
values of 3.31, 4.11 and 10.4 nM for compounds containing PEG
, PEG
and PEG
, respectively. All compounds were successfully radiolabelled with indium-111, lutetium-177 and gallium-68 (incorporation of radiometal >95 %). The gallium-68-labelled compounds were stable for up to 2 h (PBS, 37 °C). log D
values were determined for indium-111- and gallium-68-labelled compounds, showing improved hydrophilicity compared to the reference compound.
The cholecystokinin‐2/gastrin receptor (CCK2R) is considered a suitable target for the development of radiolabelled antagonists, due to its overexpression in various tumours, but no such compounds ...are available in clinical use. Therefore, we designed novel 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid‐conjugated ligands based on CCK2R antagonist Z360/nastorazepide. As a proof of concept that CCK2R antagonistic activity can be retained by extending the Z360/nastorazepide structure using suitable linker, we present herein three compounds containing various PEG linkers synthesised on solid phase and in solution. The antagonistic properties were measured in a functional assay in the A431‐CCK2R cell line (in the presence of agonist G17), with IC50 values of 3.31, 4.11 and 10.4 nM for compounds containing PEG4, PEG6 and PEG12, respectively. All compounds were successfully radiolabelled with indium‐111, lutetium‐177 and gallium‐68 (incorporation of radiometal >95 %). The gallium‐68‐labelled compounds were stable for up to 2 h (PBS, 37 °C). log D7.4 values were determined for indium‐111‐ and gallium‐68‐labelled compounds, showing improved hydrophilicity compared to the reference compound.
The overexpression of CCK2R in several tumours makes it a target of interest for the development of radiolabelled ligands. We have successfully radiolabelled a series of PEG‐containing CCK2R antagonists with either radiodiagnostic or therapeutic radionuclides. The favourable hydrophilicity, stability and retained antagonistic properties hold promise for potential progress into in vivo studies for this type of compound.
PDF
