Ohba Hiroyuki, Kanazawa Masakatsu, Kakiuchi Takeharu, Tsukada Hideo
Central Research Laboratory, Hamamatsu Photonics K.K., 5000 Hirakuchi, Hamamatsu, Shizuoka, 434-8601, Japan.
EJNMMI Res. 2016 Dec;6(1):82. doi: 10.1186/s13550-016-0241-4. Epub 2016 Nov 21.
In the present study, 2-tert-butyl-4-chloro-5-[6-(4-F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one (F-BCPP-BF), a PET probe for mitochondrial complex I (MC-I), was used to validate whether MC-I is a useful biomarker for detecting acetaminophen-induced dysfunctions in the liver and kidney. The kinetic and distribution of F-BCPP-BF were assessed in rats using high-resolution animal PET in vivo. The binding specificity of F-BCPP-BF to MC-I in the liver and kidney was confirmed by the pre-administration of rotenone, a specific MC-I inhibitor. The effects of acetaminophen on MC-I activity were assessed 2 and 24 h after the administration of vehicle or acetaminophen at a dose of 100 or 300 mg/kg. Biochemical parameters in plasma and urine were assessed 2, 6, and 24 h after the administration of vehicle or acetaminophen.
The uptake of F-BCPP-BF by the liver and kidney was significantly inhibited by the pre-administration of rotenone. Two and more hours after the administration of acetaminophen, the uptake of F-BCPP-BF was dose-dependently reduced in the liver, even at 100 mg/kg, and in the kidney at 300 mg/kg, whereas biological parameters started to be affected 6 h or later at doses of 300 mg/kg.
The present study demonstrated that F-BCPP-BF has potential as a PET probe for the quantitative imaging of hepatic and renal dysfunction as impaired MC-I activity in the early phase of the treatment for an overdose of acetaminophen in the living body with PET.
在本研究中，使用线粒体复合物I（MC-I）的正电子发射断层扫描（PET）探针2-叔丁基-4-氯-5-[6-(4-氟丁氧基)-吡啶-3-基甲氧基]-2H-哒嗪-3-酮（F-BCPP-BF）来验证MC-I是否为检测对乙酰氨基酚诱导的肝肾损伤的有用生物标志物。使用高分辨率动物PET在体内评估F-BCPP-BF在大鼠体内的动力学和分布。通过预先给予特异性MC-I抑制剂鱼藤酮，证实了F-BCPP-BF在肝肾中与MC-I的结合特异性。在给予溶媒或剂量为100或300 mg/kg的对乙酰氨基酚后2小时和24小时，评估对乙酰氨基酚对MC-I活性的影响。在给予溶媒或对乙酰氨基酚后2、6和24小时，评估血浆和尿液中的生化参数。
预先给予鱼藤酮可显著抑制肝脏和肾脏对F-BCPP-BF的摄取。给予对乙酰氨基酚两小时及更长时间后，肝脏中F-BCPP-BF的摄取呈剂量依赖性降低，即使在100 mg/kg时也是如此，而在肾脏中，300 mg/kg时F-BCPP-BF的摄取降低；而生物参数在300 mg/kg剂量下6小时或更晚开始受到影响。
本研究表明，F-BCPP-BF有潜力作为PET探针，用于在PET活体成像中对乙酰氨基酚过量治疗早期阶段因MC-I活性受损导致的肝肾损伤进行定量成像。
