Upregulation of the cannabinoid type 2 receptors (CB₂R) unveils inflammation processes of pathological disorders, such as cancer, pain, or neurodegenerative diseases. Among others, CB₂R agonist A-836339 has been labeled with carbon-11 for PET imaging of the CB₂R and displayed promising results in a mouse model of Alzheimer’s disease. The aim of the present work was to develop fluorinated analogs of A-836339 for labeling with fluorine-18 to design a new PET tracer for CB₂R imaging. Seven fluorinated analogs of A-836339 were synthesized in two to three steps and their binding affinities and selectivities for both the human and the mouse CB₂R were measured as well as their early ADME profiles. Among them, compound 2f (K_ihCB2R = 0.1 nM, K_ihCB1R/K_ihCB2R = 300) displayed high affinity and selectivity for CB₂R but also promising lipophilicity, kinetic solubility, and membrane permeation properties and was further selected for in vitro metabolism studies. Incubation of 2f with human or rat liver microsomes followed by LC/MS analysis revealed the presence of six different metabolites mainly resulting from oxidation reactions. A tosylated precursor of 2f was synthesized in two steps and radiolabeled with fluorine-18 to afford [¹⁸F]2f in 15 ± 5% radiochemical yield and a molar activity of 110 ± 30 GBq/μmol. Autoradiographies of rat spleen and biodistribution studies in healthy rats including pretreatments with either CB₂R or CB₁R-specific compounds suggested that [¹⁸F]2f is a specific tracer for the CB₂R in vivo. We have therefore demonstrated here that [¹⁸F]2f is a promising novel tracer for imaging CB₂R in vivo using PET. Further investigation in animal models of inflammation will follow.

中文翻译：

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从噻唑衍生物的构效关系到对大麻素亚型2 PET成像的新型放射性示踪剂的体内评价

大麻素2型受体（CB ₂ R）的上调揭示了病理性疾病（例如癌症，疼痛或神经退行性疾病）的炎症过程。其中，CB ₂ R激动剂A-836339已被碳11标记，用于CB ₂ R的PET成像，并在阿尔茨海默氏病小鼠模型中显示出令人鼓舞的结果。本工作的目的是开发用于氟18标记的A-836339氟化类似物，以设计用于CB ₂ R成像的新型PET示踪剂。通过两到三个步骤合成了七个A-836339氟化类似物，它们对人和小鼠CB ₂的结合亲和力和选择性R及其早期ADME配置文件进行了测量。其中，化合物2f（K _ihCB2R = 0.1 nM，K _ihCB1R / K _ihCB2R = 300）对CB ₂ R表现出高亲和力和选择性，但还具有亲脂性，动力学溶解性和膜渗透性，因此被进一步选择用于体外代谢研究。用人或大鼠肝微粒体温育2f，然后进行LC / MS分析，发现存在六种不同的代谢产物，这些代谢产物主要是由氧化反应引起的。分两步合成了2f的甲苯磺酸化前体，并用氟18进行了放射性标记，得到[¹⁸ F] 2f的放射化学产率为15±5％，摩尔活性为110±30 GBq /μmol。对大鼠脾脏的放射自显影和健康大鼠的生物分布研究（包括用CB ₂ R或CB ₁ R特异性化合物进行的预处理）表明[ ¹⁸ F] 2f是体内CB ₂ R的特异性示踪剂。因此，我们在这里证明了[ ¹⁸ F] 2f是一种有前途的新型示踪剂，可用于使用PET在体内对CB ₂ R成像。随后将对炎症动物模型进行进一步研究。