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Molecular Imaging of Inflammation in Osteoarthritis Using a Water-Soluble Fluorocoxib
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2020-02-24 , DOI: 10.1021/acsmedchemlett.9b00512
Md Jashim Uddin 1 , Anoop Vemulapalli 1 , Hiroaki Niitsu 2 , Brenda C Crews 1 , Connor G Oltman 1 , Philip J Kingsley 1 , Taylor E Kavanaugh 3 , Sean K Bedingfield 3 , J Oliver Mcintyre 4 , Matthew Milad 1 , Ansari M Aleem 1 , Robert J Coffey 2 , Craig L Duvall 3 , Lawrence J Marnett 1
Affiliation  

Clinical imaging approaches to detect inflammatory biomarkers, such as cyclooxygenase-2 (COX-2), may facilitate the diagnosis and therapy of inflammatory diseases. To this end, we report the discovery of N-[(rhodamin-X-yl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide chloride salt (fluorocoxib D), a hydrophilic analog of fluorocoxib A. Fluorocoxib D inhibits COX-2 selectively in purified enzyme preparations and cells. It exhibits adequate photophysical properties to enable detection of COX-2 in intact cells, in a mouse model of carrageenan-induced acute footpad inflammation and inflammation in a mouse model of osteoarthritis. COX-2-selectivity was verified either by blocking the enzyme’s active site with celecoxib or by molecular imaging with nontargeted 5-carboxy-X-rhodamine dye. These data indicate that fluorocoxib D is an ideal candidate for early detection of inflammatory or neoplastic lesions expressing elevated levels of COX-2.

中文翻译:

使用水溶性氟考昔对骨关节炎炎症的分子成像

检测炎症生物标志物(如环氧合酶 2 (COX-2))的临床成像方法可能有助于炎症疾病的诊断和治疗。为此,我们报告了N -[(rhodamin-X-yl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1 H-indol-3-yl]acetamide chloride salt (fluorocoxib D),一种 fluorocoxib A 的亲水类似物。Fluorocoxib D 在纯化的酶制剂和细胞中选择性地抑制 COX-2。它表现出足够的光物理特性,可以在角叉菜胶诱导的急性足垫炎症小鼠模型和骨关节炎小鼠模型中检测完整细胞中的 COX-2。通过用塞来昔布阻断酶的活性位点或用非靶向 5-羧基-X-罗丹明染料进行分子成像来验证 COX-2 的选择性。这些数据表明,氟考昔 D 是早期检测表达升高水平 COX-2 的炎症或肿瘤病变的理想候选者。
更新日期:2020-02-24
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