TY  - JOUR
AU  - Erlitz, Katharina Sophie
AU  - Prinz, Ann-Kathrin
AU  - Wagner, Stefan
AU  - Massa, Joana
AU  - Dunker, Calvin
AU  - Höhl, Meike
AU  - Griep, Angelika
AU  - McManus, Róisín M
AU  - Schelhaas, Sonja
AU  - Koch, Oliver
AU  - Junker, Anna
TI  - Naphtho[1,2-b][1,4]diazepinedione-Based P2X4 Receptor Antagonists from Structure-Activity Relationship Studies toward PET Tracer Development.
JO  - Journal of medicinal chemistry
VL  - 68
IS  - 7
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - DZNE-2025-00511
SP  - 6965 - 7002
PY  - 2025
AB  - 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.
KW  - Structure-Activity Relationship
KW  - Positron-Emission Tomography: methods
KW  - Humans
KW  - Animals
KW  - Purinergic P2X Receptor Antagonists: chemistry
KW  - Purinergic P2X Receptor Antagonists: pharmacology
KW  - Purinergic P2X Receptor Antagonists: metabolism
KW  - Purinergic P2X Receptor Antagonists: pharmacokinetics
KW  - Purinergic P2X Receptor Antagonists: chemical synthesis
KW  - Mice
KW  - Receptors, Purinergic P2X4: metabolism
KW  - Tissue Distribution
KW  - Fluorine Radioisotopes
KW  - Molecular Docking Simulation
KW  - Male
KW  - Purinergic P2X Receptor Antagonists (NLM Chemicals)
KW  - Receptors, Purinergic P2X4 (NLM Chemicals)
KW  - Fluorine Radioisotopes (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39805099
DO  - DOI:10.1021/acs.jmedchem.4c02171
UR  - https://pub.dzne.de/record/277979
ER  -