<br>专为 PET 研究设计的基于氟化喹喔啉的 κ-阿片受体 (KOR) 激动剂的合成和药理学评价,ChemMedChem

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专为 PET 研究设计的基于氟化喹喔啉的 κ-阿片受体 (KOR) 激动剂的合成和药理学评价
ChemMedChem ( IF 3.6 ) Pub Date : 2020-07-28 , DOI: 10.1002/cmdc.202000502
Giovanni Tangherlini _{1,

2} , Frederik Börgel ₁ , Dirk Schepmann ₁ , Samuel Slocum ₃ , Tao Che ₄ , Stefan Wagner ₅ , Katrin Schwegmann ₆ , Sven Hermann ₆ , Nadine Mykicki ₇ , Karin Loser _{2,

7,

8} , Bernhard Wünsch _{1,

2}

Affiliation

κ-阿片受体（KOR）在缓解疼痛、瘙痒性皮肤病、抑郁症和多发性硬化症等神经退行性疾病中发挥着重要作用。因此，设想使用氟化 PET 示踪剂对 KOR 进行成像。采用两种策略将 F 原子引入非常有效的顺式、反式构型全氢喹喔啉类中。尽管氟乙基三唑2的合成已有报道，氟吡咯烷14 (1-[2-(3,4-二氯苯基)乙酰基]-8-[(R)-3-氟吡咯烷-1-基]-全氢喹喔啉) 的制备方法为用羟基吡咯烷对环状硫酸衍生物进行S _N 2 取代，随后将OH部分转化为F取代基。氟吡咯烷14对相应的吡咯烷表现出类似的低纳摩尔 KOR 亲和力和选择性，但相应的醇的活性稍低。在 cAMP 和 β-arrestin 测定中， 14b （4 位质子）表现出与 U-50,488 相似的 KOR 激动活性。氟代衍生物14b和14c （CO ₂ CH ₃在 4 位）显示出 KOR 介导的 CD11c 抗炎活性，并且小鼠和人树突状细胞中 IFN-γ 的产生显着减少。化合物14b和14-c在小鼠和人类 T 细胞中也表现出抗炎和免疫调节活性。 PET示踪剂[ ¹⁸ F] -2是通过1,3-偶极环加成制备的。在体内，由于非常快的消除动力学，[ ¹⁸ F] -2没有标记 KOR。甲磺酸酯前体的亲核取代提供了[ ¹⁸ F]- 14c 。不幸的是，[ ¹⁸ F]- 14c的脱氟发生在体内，这通过体外研究进行了详细分析。

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Synthesis and Pharmacological Evaluation of Fluorinated Quinoxaline‐Based κ‐Opioid Receptor (KOR) Agonists Designed for PET Studies

κ‐Opioid receptors (KORs) play a predominant role in pain alleviation, itching skin diseases, depression and neurodegenerative disorders such as multiple sclerosis. Therefore, imaging of KOR by a fluorinated PET tracer was envisaged. Two strategies were followed to introduce a F atom into the very potent class of cis,trans‐configured perhydroquinoxalines. Whereas the synthesis of fluoroethyltriazole 2 has already been reported, fluoropyrrolidines 14 (1‐[2‐(3,4‐dichlorophenyl)acetyl]‐8‐[(R)‐3‐fluoropyrrolidin‐1‐yl]‐perhydroquinoxalines) were prepared by S_N2 substitution of a cyclic sulfuric acid derivative with hydroxypyrrolidine and subsequent transformation of the OH moiety into a F substituent. Fluoropyrrolidines 14 showed similar low‐nanomolar KOR affinity and selectivity to the corresponding pyrrolidines, but the corresponding alcohols were slightly less active. In the cAMP and β‐arrestin assay, 14b (proton at the 4‐position) exhibited similar KOR agonistic activity as U‐50,488. The fluoro derivatives 14b and 14c (CO₂CH₃ at the 4‐position) revealed KOR‐mediated anti‐inflammatory activity as CD11c and the IFN‐γ production were reduced significantly in mouse and human dendritic cells. Compounds 14b and 14‐c also displayed anti‐inflammatory and immunomodulatory activity in mouse and human T cells. The PET tracer [¹⁸F]‐2 was prepared by 1,3‐dipolar cycloaddition. In vivo, [¹⁸F]‐2 did not label KOR due to very fast elimination kinetics. Nucleophilic substitution of a mesylate precursor provided [¹⁸F]‐14c. Unfortunately, defluorination of [¹⁸F]‐14c occurred in vivo, which was analyzed in detail by in vitro studies.

更新日期：2020-10-05

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