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000277979 1001_ $$aErlitz, Katharina Sophie$$b0
000277979 245__ $$aNaphtho[1,2-b][1,4]diazepinedione-Based P2X4 Receptor Antagonists from Structure-Activity Relationship Studies toward PET Tracer Development.
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000277979 520__ $$aThe P2X4 receptor is implicated in various pathological conditions, including neuropathic pain and cancer. This study reports the development of 1,4-naphthodiazepinedione-based P2X4 receptor antagonists aimed at both therapeutic applications and potential use as PET tracers for imaging P2X4 receptor expression in cancer. Structure-activity relationship studies aided by docking studies and molecular dynamics simulations led to a series of compounds with potent P2X4 receptor antagonism, promising in vitro inhibition of interleukin-1β release in THP-1 cells and suitability for radiolabeling with fluorine-18. The most potent compounds were further evaluated for their physicochemical properties, metabolic stability, and in vivo biodistribution using PET imaging in mice. While these antagonists exhibited strong receptor binding and serum stability, rapid in vivo metabolism limited their potential as PET tracers, highlighting the need for further structural optimization. This study advances the understanding of P2X4 receptor antagonism and underscores the challenges in developing effective PET tracers for this target.
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000277979 650_7 $$2NLM Chemicals$$aPurinergic P2X Receptor Antagonists
000277979 650_7 $$2NLM Chemicals$$aReceptors, Purinergic P2X4
000277979 650_7 $$2NLM Chemicals$$aFluorine Radioisotopes
000277979 650_2 $$2MeSH$$aStructure-Activity Relationship
000277979 650_2 $$2MeSH$$aPositron-Emission Tomography: methods
000277979 650_2 $$2MeSH$$aHumans
000277979 650_2 $$2MeSH$$aAnimals
000277979 650_2 $$2MeSH$$aPurinergic P2X Receptor Antagonists: chemistry
000277979 650_2 $$2MeSH$$aPurinergic P2X Receptor Antagonists: pharmacology
000277979 650_2 $$2MeSH$$aPurinergic P2X Receptor Antagonists: metabolism
000277979 650_2 $$2MeSH$$aPurinergic P2X Receptor Antagonists: pharmacokinetics
000277979 650_2 $$2MeSH$$aPurinergic P2X Receptor Antagonists: chemical synthesis
000277979 650_2 $$2MeSH$$aMice
000277979 650_2 $$2MeSH$$aReceptors, Purinergic P2X4: metabolism
000277979 650_2 $$2MeSH$$aTissue Distribution
000277979 650_2 $$2MeSH$$aFluorine Radioisotopes
000277979 650_2 $$2MeSH$$aMolecular Docking Simulation
000277979 650_2 $$2MeSH$$aMale
000277979 7001_ $$aPrinz, Ann-Kathrin$$b1
000277979 7001_ $$aWagner, Stefan$$b2
000277979 7001_ $$00000-0001-5613-5308$$aMassa, Joana$$b3
000277979 7001_ $$00000-0002-2109-5817$$aDunker, Calvin$$b4
000277979 7001_ $$aHöhl, Meike$$b5
000277979 7001_ $$0P:(DE-2719)2811029$$aGriep, Angelika$$b6$$udzne
000277979 7001_ $$0P:(DE-2719)2811671$$aMcManus, Róisín M$$b7
000277979 7001_ $$00000-0001-6928-4847$$aSchelhaas, Sonja$$b8
000277979 7001_ $$aKoch, Oliver$$b9
000277979 7001_ $$00000-0001-5151-0930$$aJunker, Anna$$b10
000277979 773__ $$0PERI:(DE-600)1491411-6$$a10.1021/acs.jmedchem.4c02171$$gVol. 68, no. 7, p. 6965 - 7002$$n7$$p6965 - 7002$$tJournal of medicinal chemistry$$v68$$x0095-9065$$y2025
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