[18F]NP3-627, a candidate PET imaging agent targeting the NLRP3 inflammasome in the central nervous system.

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL ChemMedChem Pub Date : 2024-11-14 DOI:10.1002/cmdc.202400816

David Michael Whitehead, Christian Fischer, Emmanuelle Briard, Christopher Farady, Nadège Graveleau, Joel Karrer, Klemens Kaupmann, Guillaume Lapointe, Angela Mackay, Lisa Reichert, Michael Wright, Linjing Mu, Yves P Auberson

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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 (17b), 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.

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[18F]NP3-627，一种靶向中枢神经系统 NLRP3 炎症小体的 PET 成像候选药物。

我们描述了对 NLRP3 蛋白的一种候选正电子发射断层扫描 (PET) 成像剂的鉴定。NLRP3 在免疫系统中发挥着关键作用，由于其表达量低且具有细胞特异性，已被证明是一种难以开发的成像剂靶点。最近描述的一系列基于哒嗪的抑制剂具有更好的渗透性和脑穿透特性，被用作开发合适的 PET 成像剂的起点。对亲和力、非特异性结合和药代动力学特性进行优化后，确定了氨基哒嗪 (R)-2-(6-((1- 环丙基哌啶-3-基)氨基)哒嗪-3-基)-5-氟-3-甲基苯酚 (17b)，它符合成功成像剂的临床前特征，其三价版本在放射性配体饱和结合试验中表现出极好的特异性，证实了其成像潜力。通过 F 标记，产生了[18F]NP3-627，这是一种拟议的 PET 成像剂。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.