In recent years, a number of drugs targeting the prostate-specific membrane antigen (PSMA) have become important tools in the diagnosis and treatment of prostate cancer. In the present work, we report on the synthesis and preclinical evaluation of a series of 18F-labeled PSMA ligands for diagnostic application based on the theragnostic ligand PSMA-617. By applying modifications to the linker structure, insight into the structure-activity relationship could be gained, highlighting the importance of hydrophilicity and stereoselectivity on interaction with PSMA and hence the biodistribution. Selected compounds were co-crystallized with the PSMA protein and analyzed by X-rays with mixed results. Among these, PSMA-1007 (compound 5) showed the best interaction with the PSMA protein. The respective radiotracer [18F]PSMA-1007 was translated into the clinic and is, in the meantime, subject of advanced clinical trials.
- MeSH
- antigeny povrchové MeSH
- glutamátkarboxypeptidasa II antagonisté a inhibitory MeSH
- lidé MeSH
- ligandy MeSH
- nádory prostaty diagnostické zobrazování MeSH
- niacinamid analogy a deriváty chemie farmakologie MeSH
- oligopeptidy chemie farmakologie MeSH
- pozitronová emisní tomografie MeSH
- radiofarmaka farmakologie MeSH
- radioizotopy fluoru chemie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Plant defense metabolites are well known to be regulated developmentally. The optimal defense (OD) theory posits that a tssue's fitness values and probability of attack should determine defense metabolite allocations. Young leaves are expected to provide a larger fitness value to the plant, and therefore their defense allocations should be higher when compared with older leaves. The mechanisms that coordinate development with defense remain unknown and frequently confound tests of the OD theory predictions. Here we demonstrate that cytokinins (CKs) modulate ontogeny-dependent defenses in Nicotiana attenuata. We found that leaf CK levels highly correlate with inducible defense expressions with high levels in young and low levels in older leaves. We genetically manipulated the developmental patterns of two different CK classes by using senescence- and chemically inducible expression of CK biosynthesis genes. Genetically modifying the levels of different CKs in leaves was sufficient to alter ontogenic patterns of defense metabolites. We conclude that the developmental regulation of growth hormones that include CKs plays central roles in connecting development with defense and therefore in establishing optimal patterns of defense allocation in plants.
- MeSH
- acetáty metabolismus farmakologie MeSH
- býložravci fyziologie MeSH
- časové faktory MeSH
- cyklopentany metabolismus farmakologie MeSH
- cytokininy metabolismus MeSH
- geneticky modifikované rostliny MeSH
- interakce hostitele a parazita účinky léků MeSH
- listy rostlin genetika metabolismus parazitologie MeSH
- Manduca fyziologie MeSH
- nemoci rostlin genetika parazitologie MeSH
- oxylipiny metabolismus farmakologie MeSH
- regulace genové exprese u rostlin účinky léků MeSH
- regulátory růstu rostlin metabolismus farmakologie MeSH
- rostlinné proteiny genetika metabolismus MeSH
- tabák genetika metabolismus parazitologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Cytokinins (CKs) are well-established as important phytohormonal regulators of plant growth and development. An increasing number of studies have also revealed the function of these hormones in plant responses to biotic and abiotic stresses. While the function of certain CK classes, including trans-zeatin and isopentenyladenine-type CKs, have been studied in detail, the role of cis-zeatin-type CKs (cZs) in plant development and in mediating environmental interactions is less well defined. Here we provide a comprehensive summary of the current knowledge about abundance, metabolism and activities of cZs in plants. We outline the history of their analysis and the metabolic routes comprising cZ biosynthesis and degradation. Further we provide an overview of changes in the pools of cZs during plant development and environmental interactions. We summarize studies that investigate the role of cZs in regulating plant development and defence responses to pathogen and herbivore attack and highlight their potential role as 'novel' stress-response markers. Since the functional roles of cZs remain largely based on correlative data and genetic manipulations of their biosynthesis, inactivation and degradation are few, we suggest experimental approaches using transgenic plants altered in cZ levels to further uncover their roles in plant growth and environmental interactions and their potential for crop improvement.
