Development and Evaluation of Endothelin-A Receptor (Radio)Ligands for Positron Emission Tomography

Michel, Kristin; Büther, Katrin; Law, Marilyn P.; Wagner, Stefan; Schober, Otmar; Hermann, Sven; Schäfers, Michael; Riemann, Burkhard; Höltke, Carsten; Kopka, Klaus

doi:10.1021/jm101110w

Cited by 16 publications

(9 citation statements)

References 48 publications

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“…over two steps . More significantly, a formal synthesis of the ET A receptor radioligand 8 was achieved using the developed visible-light-promoted polysubstituted olefins synthesis as a key step (Scheme b) . Under optimal reaction conditions, the coupling of diazo compound 1q with sulfur ylide 2i afforded olefin 3qi in 56% yield.…”

Section: Resultsmentioning

confidence: 99%

Visible-Light-Promoted Polysubstituted Olefins Synthesis Involving Sulfur Ylides as Carbene Trapping Reagents

Cai

Lü

et al. 2020

J. Org. Chem.

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A blue-light-emitting diode (LED) promoted coupling of aryl diazoacetates with sulfur ylides is described. This protocol features mild conditions, good functional group tolerance, and broad substrate scope for both aryl diazoacetates with sulfur ylides. Under optimal reaction conditions, a wide range of trisubstituted olefins is obtained in moderate to good yield, which can be further transferred to other biologically important heterocycles after a two-step simple operation.

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Section: Resultsmentioning

confidence: 99%

Visible-Light-Promoted Polysubstituted Olefins Synthesis Involving Sulfur Ylides as Carbene Trapping Reagents

Cai

Lü

et al. 2020

J. Org. Chem.

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“…The propargyl derivative 13h was obtained by alkylation of secondary amine 12 with propargyl bromide. Cu + -catalyzed 1,3-dipolar cycloaddition , of alkyne 13h with 2-fluoroethyl azide provided the triazole derivative 14 . The triazole moiety led to increased size and polarity of the side chain.…”

Section: Resultsmentioning

confidence: 99%

“…Reaction of the chloroacetamide 15 with 2-fluoroethanol and NaH afforded the fluoroethyl ether 16 in 80% yield. Nucleophilic substitution of 15 with NaN 3 led to the azide 17 , which underwent a 1,3-dipolar cycloaddition (click reaction) , with 5-fluoropent-1-yne to produce fluoropropyltriazole 18 .…”

Section: Resultsmentioning

confidence: 99%

Development of Novel Quinoxaline-Based κ-Opioid Receptor Agonists for the Treatment of Neuroinflammation

et al. 2018

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Neuroinflammatory disorders, such as multiple sclerosis or experimental autoimmune encephalomyelitis (EAE), an established mouse model mimicking part of the human pathology, are characterized by inflammatory infiltrates containing T helper 1 (TH1) and TH17 cells, which cause demyelination and neurodegeneration. Disease onset and perpetuation are mediated by peripherally generated autoreactive T cells infiltrating into the central nervous system, where they are restimulated by antigen-presenting cells. Here, we show that newly designed peripherally active, potent, and selective κ-opioid receptor (KOR) agonists comprising the ethylenediamine KOR pharmacophore in a perhydroquinoxaline scaffold exhibit potent anti-inflammatory capacities in primary antigen presenting cells as well as T cells. In the EAE model, the secondary amine 12 and the triazole 14 were able to ameliorate disease severity and to delay disease onset by blocking effector T cell activation. Importantly, the beneficial effects were mediated via signaling through KOR because off-target effects were excluded by using KOR-deficient mouse mutants.

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“…Besides its key physiological functions in particularly in the cardiovascular system, the ET axis also plays a major role in growth and progression of various tumors. To date, most of the efforts have been directed towards the development of radioactive receptor ligands for the visualization of endothelin receptor expression in vivo in cancer or in the heart [86,87,88,89,90,91,92].…”

Section: Introductionmentioning

confidence: 99%

Less Exploited GPCRs in Precision Medicine: Targets for Molecular Imaging and Theranostics

et al. 2018

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Precision medicine relies on individually tailored therapeutic intervention taking into account individual variability. It is strongly dependent on the availability of target-specific drugs and/or imaging agents that recognize molecular targets and patient-specific disease mechanisms. The most sensitive molecular imaging modalities, Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET), rely on the interaction between an imaging radioprobe and a target. Moreover, the use of target-specific molecular tools for both diagnostics and therapy, theranostic agents, represent an established methodology in nuclear medicine that is assuming an increasingly important role in precision medicine. The design of innovative imaging and/or theranostic agents is key for further accomplishments in the field. G-protein-coupled receptors (GPCRs), apart from being highly relevant drug targets, have also been largely exploited as molecular targets for non-invasive imaging and/or systemic radiotherapy of various diseases. Herein, we will discuss recent efforts towards the development of innovative imaging and/or theranostic agents targeting selected emergent GPCRs, namely the Frizzled receptor (FZD), Ghrelin receptor (GHSR-1a), G protein-coupled estrogen receptor (GPER), and Sphingosine-1-phosphate receptor (S1PR). The pharmacological and clinical relevance will be highlighted, giving particular attention to the studies on the synthesis and characterization of targeted molecular imaging agents, biological evaluation, and potential clinical applications in oncology and non-oncology diseases. Whenever relevant, supporting computational studies will be also discussed.

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Development and Evaluation of Endothelin-A Receptor (Radio)Ligands for Positron Emission Tomography

Cited by 16 publications

References 48 publications

Visible-Light-Promoted Polysubstituted Olefins Synthesis Involving Sulfur Ylides as Carbene Trapping Reagents

Visible-Light-Promoted Polysubstituted Olefins Synthesis Involving Sulfur Ylides as Carbene Trapping Reagents

Development of Novel Quinoxaline-Based κ-Opioid Receptor Agonists for the Treatment of Neuroinflammation

Less Exploited GPCRs in Precision Medicine: Targets for Molecular Imaging and Theranostics

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