Whitehead, David, Fischer, Christian-4, Briard, Emmanuelle, Farady, Christopher, Graveleau, Nadege, Karrer, Joel, Kaupmann, Klemens, Lapointe, Guillaume, Mackay, Angela, Reichert, Lisa, Wright, Michael, Mu, Linjing and Auberson, Yves (2024) [18F]NP3-627, a Candidate PET Imaging Agent Targeting the NLRP3 Inflammasome in the Central Nervous System. ChemMedChem. e202400816. ISSN 1860-7187

Abstract

We describe the identification of a candidate positron emission tomography (PET) imaging agent for the NLRP3 protein. NLRP3 plays a critical role in the immune system and has proven a difficult target for the development of imaging agents due to its low and cell-specific expression profile. A recently described series of pyridazine-based inhibitors, with improved permeability and brain-penetration properties, was used as a starting point for the development of a suitable PET imaging agent. Optimization of affinity, non-specific binding and pharmacokinetic properties led to the identification of aminopyridazine (R)-2-(6-((1-cyclopropylpiperidin-3-yl)amino)pyridazin-3-yl)-5-fluoro-3-methylphenol (17 b), which meets the preclinical profile of a successful imaging agent, and whose tritiated version demonstrated excellent specificity in a radioligand saturation binding assay, confirming its imaging potential.18F labeling led to [18F]NP3-627, the proposed PET imaging agent.

Item Type:	Article
Date Deposited:	17 Dec 2024 00:45
Last Modified:	17 Dec 2024 00:45
URI:	https://oak.novartis.com/id/eprint/55628