Synthesis and evaluation of radioiodinated cyclooxygenase-2 inhibitors as potential SPECT tracers for cyclooxygenase-2 expression
Synthesis and evaluation of radioiodinated cyclooxygenase-2 inhibitors as potential SPECT tracers for cyclooxygenase-2 expression
复制标题
DOI：
10.1016/j.nucmedbio.2005.10.004
复制
发表时间：
2006-01-01
影响因子：
3.1
通讯作者：
Saji, H
中科院分区：
文献类型：
--
作者：
Kuge, Y;Katada, Y;Saji, H
尽管几种COX-2抑制剂最近已经被放射性标记，但它们成像COX-2表达的潜力仍然不清楚。特别是，环氧合酶-2抑制剂的磺胺部分可能会导致放射性示踪剂的缓慢血液清除，因为它与红细胞中的碳酸酐酶(CA)有亲和力。因此，我们设计了一个甲基砜类类似物，5-(4-iodophenyl)-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole(IMTP)。在这项研究中，与I-125标记的含磺酰胺部分的塞来昔布类似物(I-125-IATP)相比，放射性碘标记的IMTP的潜力被评估。方法：通过测量COX催化的过氧化氢氧化来评估COX抑制活性。用体外组织计数法测定I-125-IMTP和I-125-IATP在大鼠体内的生物分布。结果：IMTP(IC50=5.16mU M)和IATP(IC50=8.20mU)对COX-2的抑制作用高于美洛昔康(IC50~29.0mU)，与SC-58125(IC50=1.36mU M)相当。IC50比值(COX-1/COX-2)表明IMTP和IATP对COX-2具有较高的异构体选择性。在肾脏和脑(已知表达COX-2的器官)中观察到I-125-IMTP和125MATP的显著水平。I-125-IMTP的血液清除速度明显快于I-125-IATP。~(125)I-IATP在血细胞中的分布(88.0%)明显高于I-125-IMTP(18.1%)，后者被CA抑制剂抑制。结论：IMTP对COX-2具有较高的抑制活性和选择性。在I-125-IMTP中，磺胺部分取代甲基砜部分有效地改善了化合物的血液清除性，表明失去了与CA的交叉反应。I-123-IMTP可能成为抑制COX-2表达的SPECT放射性药物。(C)2006 Elsevier Inc.保留所有权利。
Although several COX-2 inhibitors have recently been radiolabeled, their potential for imaging COX-2 expression remains unclear. In particular, the sulfonamide moiety of COX-2 inhibitors may cause slow blood clearance of the radiotracer, due to its affinity for carbonic anhydrase (CA) in erythrocytes. Thus, we designed a methyl sulfone-type analogue, 5-(4-iodophenyl)-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole (IMTP). In this study, the potential of radioiodinated IMTP was assessed in comparison with a I-125-labeled celecoxib analogue with a sulfonamide moiety (I-125-IATP).Methods: The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation by hydrogen peroxide. The biodistribution of I-125-IMTP and I-125-IATP was determined by the ex vivo tissue counting method in rats. Distribution of the labeled compounds to rat blood cells was measured.Results: The COX-2 inhibitory potency of IMTP (IC50=5.16 mu M) and IATP (IC50=8.20 mu M) was higher than that of meloxicam (IC50-29.0 mu M) and comparable to that of SC-58125 (IC50=1.36 mu M). The IC50 ratios (COX-1/COX-2) indicated the high isoform selectivity of IMTP and IATP for COX-2. Significant levels of I-125-IMTP and 125 MATP were observed in the kidneys and the brain (organs known to express COX-2). The blood clearance of I-125-IMTP was much faster than that of I-125-IATP. Distribution of (125) I-IATP to blood cells (88.0%) was markedly higher than that of I-125-IMTP (18.1%), which was decreased by CA inhibitors.Conclusions: Our results showed a high inhibitory potency and selectivity of IMTP for COX-2. The substitution of a sulfonamide moiety to a methyl sulfone moiety effectively improved the blood clearance of the compound, indicating the loss of the cross reactivity with CA in I-125-IMTP. I-123-IMTP may be a potential SPECT radiopharmaceutical for COX-2 expression. (c) 2006 Elsevier Inc. All rights reserved.