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@ARTICLE{Erlitz:277979,
author = {Erlitz, Katharina Sophie and Prinz, Ann-Kathrin and Wagner,
Stefan and Massa, Joana and Dunker, Calvin and Höhl, Meike
and Griep, Angelika and McManus, Róisín M and Schelhaas,
Sonja and Koch, Oliver and Junker, Anna},
title = {{N}aphtho[1,2-b][1,4]diazepinedione-{B}ased {P}2{X}4
{R}eceptor {A}ntagonists from {S}tructure-{A}ctivity
{R}elationship {S}tudies toward {PET} {T}racer
{D}evelopment.},
journal = {Journal of medicinal chemistry},
volume = {68},
number = {7},
issn = {0095-9065},
address = {Washington, DC},
publisher = {ACS},
reportid = {DZNE-2025-00511},
pages = {6965 - 7002},
year = {2025},
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.},
keywords = {Structure-Activity Relationship / Positron-Emission
Tomography: methods / Humans / Animals / Purinergic P2X
Receptor Antagonists: chemistry / Purinergic P2X Receptor
Antagonists: pharmacology / Purinergic P2X Receptor
Antagonists: metabolism / Purinergic P2X Receptor
Antagonists: pharmacokinetics / Purinergic P2X Receptor
Antagonists: chemical synthesis / Mice / Receptors,
Purinergic P2X4: metabolism / Tissue Distribution / Fluorine
Radioisotopes / Molecular Docking Simulation / Male /
Purinergic P2X Receptor Antagonists (NLM Chemicals) /
Receptors, Purinergic P2X4 (NLM Chemicals) / Fluorine
Radioisotopes (NLM Chemicals)},
cin = {AG Latz / AG McManus},
ddc = {610},
cid = {I:(DE-2719)1013024 / I:(DE-2719)1013042},
pnm = {351 - Brain Function (POF4-351) / 352 - Disease Mechanisms
(POF4-352)},
pid = {G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39805099},
doi = {10.1021/acs.jmedchem.4c02171},
url = {https://pub.dzne.de/record/277979},
}