Journal Article

DZNE-2025-00511

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Naphtho[1,2-b][1,4]diazepinedione-Based P2X4 Receptor Antagonists from Structure-Activity Relationship Studies toward PET Tracer Development.

Erlitz, K. S. ; Prinz, A.-K. ; Wagner, S. ; Massa, J. ; Dunker, C. ; Höhl, M. ; Griep, A.DZNE* ; McManus, R. M.DZNE* ; Schelhaas, S. ; Koch, O. ; Junker, A.

2025
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.4c02171

Abstract: The 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.

Keyword(s): Structure-Activity Relationship (MeSH) ; Positron-Emission Tomography: methods (MeSH) ; Humans (MeSH) ; Animals (MeSH) ; Purinergic P2X Receptor Antagonists: chemistry (MeSH) ; Purinergic P2X Receptor Antagonists: pharmacology (MeSH) ; Purinergic P2X Receptor Antagonists: metabolism (MeSH) ; Purinergic P2X Receptor Antagonists: pharmacokinetics (MeSH) ; Purinergic P2X Receptor Antagonists: chemical synthesis (MeSH) ; Mice (MeSH) ; Receptors, Purinergic P2X4: metabolism (MeSH) ; Tissue Distribution (MeSH) ; Fluorine Radioisotopes (MeSH) ; Molecular Docking Simulation (MeSH) ; Male (MeSH) ; Purinergic P2X Receptor Antagonists ; Receptors, Purinergic P2X4 ; Fluorine Radioisotopes

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Contributing Institute(s):

1. Innate Immunity in Neurodegeneration (AG Latz)
2. Translational Neuroimmunology (AG McManus)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; Index Chemicus ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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