[18F]NP3‐627, a Candidate PET Imaging Agent Targeting the NLRP3 Inflammasome in the Central Nervous System

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. 18 F labeling led to [ 18 F]NP3‐627 , the proposed PET imaging agent.