Kuge Yuji, Katada Yumiko, Shimonaka Sayaka, Temma Takashi, Kimura Hiroyuki, Kiyono Yasushi, Yokota Chiaki, Minematsu Kazuo, Seki Koh-ichi, Tamaki Nagara, Ohkura Kazue, Saji Hideo
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Nucl Med Biol. 2006 Jan;33(1):21-7. doi: 10.1016/j.nucmedbio.2005.10.004.
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 (125)I-labeled celecoxib analogue with a sulfonamide moiety ((125)I-IATP).
The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation by hydrogen peroxide. The biodistribution of (125)I-IMTP and (125)I-IATP was determined by the ex vivo tissue counting method in rats. Distribution of the labeled compounds to rat blood cells was measured.
The COX-2 inhibitory potency of IMTP (IC(50) = 5.16 microM) and IATP (IC(50) = 8.20 microM) was higher than that of meloxicam (IC(50) = 29.0 microM) and comparable to that of SC-58125 (IC(50) = 1.36 microM). The IC(50) ratios (COX-1/COX-2) indicated the high isoform selectivity of IMTP and IATP for COX-2. Significant levels of (125)I-IMTP and (125)I-IATP were observed in the kidneys and the brain (organs known to express COX-2). The blood clearance of (125)I-IMTP was much faster than that of (125)I-IATP. Distribution of (125)I-IATP to blood cells (88.0%) was markedly higher than that of (125)I-IMTP (18.1%), which was decreased by CA inhibitors.
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 (125)I-IMTP. (123)I-IMTP may be a potential SPECT radiopharmaceutical for COX-2 expression.
尽管最近有几种环氧化酶-2（COX-2）抑制剂已被放射性标记，但其用于成像COX-2表达的潜力仍不明确。特别是，COX-2抑制剂的磺酰胺部分可能会导致放射性示踪剂在血液中的清除缓慢，这是由于其对红细胞中碳酸酐酶（CA）的亲和力所致。因此，我们设计了一种甲砜型类似物，5-（4-碘苯基）-1-[4-（甲基磺酰基）苯基]-3-三氟甲基-1H-吡唑（IMTP）。在本研究中，将放射性碘化的IMTP与具有磺酰胺部分的（125）I标记的塞来昔布类似物（（125）I-IATP）进行比较，评估其潜力。
通过测量COX催化的过氧化氢氧化来评估COX抑制效力。采用离体组织计数法测定大鼠体内（125）I-IMTP和（125）I-IATP的生物分布。测量标记化合物在大鼠血细胞中的分布。
IMTP（IC50 = 5.16 microM）和IATP（IC50 = 8.20 microM）的COX-2抑制效力高于美洛昔康（IC50 = 29.0 microM），与SC-58125（IC50 = 1.36 microM）相当。IC50比值（COX-1/COX-2）表明IMTP和IATP对COX-2具有高同工型选择性。在肾脏和大脑（已知表达COX-2 的器官）中观察到显著水平的（125）I-IMTP和（125）I-IATP。（125）I-IMTP的血液清除速度比（125）I-IATP快得多。（125）I-IATP在血细胞中的分布（88.0%）明显高于（125）I-IMTP（18.1%），CA抑制剂可降低其分布。
我们的结果表明IMTP对COX-2具有高抑制效力和选择性。将磺酰胺部分替换为甲砜部分可有效改善化合物的血液清除，表明（125）I-IMTP与CA的交叉反应性丧失。（123）I-IMTP可能是一种用于COX-2表达的潜在单光子发射计算机断层显像（SPECT）放射性药物。
