Novel PET Probes 18F-BCPP-EF and 18F-BCPP-BF for Mitochondrial Complex I: A PET Study in Comparison with 18F-BMS-747158-02 in Rat Brain
Novel PET Probes 18F-BCPP-EF and 18F-BCPP-BF for Mitochondrial Complex I: A PET Study in Comparison with 18F-BMS-747158-02 in Rat Brain
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DOI：
10.2967/jnumed.113.125328
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发表时间：
2014-03-01
影响因子：
9.3
通讯作者：
Harada, Norihiro
中科院分区：
文献类型：
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作者：
Tsukada, Hideo;Nishiyama, Shingo;Harada, Norihiro
我们开发了新的PET探针，2-叔丁基-4-氯-5-{6-[2-（三氟甲基）苯基]-1-甲基}-2-（三氟甲基）苯基}-2-（三氟甲基）苯基}-2-（三氟甲基）苯基。（2-F-18-氟乙氧基）-乙氧基]-吡啶-3-基甲氧基}-2H-哒嗪-3-酮（F-18-BCPP-EF）和2-叔丁基-4-氯-5-[6-（三氟甲基）苯基]-2-甲基-IH-吡唑-4-甲酰胺（4-F-18-氟丁氧基）-吡啶-3-基甲氧基]-2H-哒嗪-3-酮（F-18-BCPP-BF），用于脑中线粒体复合物I（MC-I）活性的定量成像，并与F-18-BMS-747158-02（F-18-BMS）进行比较，初步评价其特性。研究方法：F-18-BCPP-EF、F-18-BCPP-BF和F-18-BMS对MC-I的亲和力使用H-3-二氢鱼藤酮和牛心肌细胞亚线粒体颗粒的体外结合测定进行分析。将F-18-BCPP-EF、F-18-BCPP-BF或F-18-BMS静脉注射到大鼠中，并通过解剖方法测定每个器官中的摄取（标准化摄取值）。鱼藤酮，一种特异性的MC-I抑制剂，对每个探针的摄取的影响进行了评估全身PET成像大鼠。使用F-18-BCPP-EF对缺血脑模型大鼠进行成像。结果：F-18-BCPP-BF、F-18-BMS、F-18-BCPP-EF对MC-I的亲和力大小顺序为：F-18-BCPP-BF > F-18-BMS > F-18-BCPP-EF。注射后60 min，F-18-BCPP-EF和F-18-BMS的摄取在心脏中高，在脑中中等，在肌肉和骨骼中低。F-18-BCPP-BF在注射后提供随时间增加的骨摄取。预先给予鱼藤酮可显著降低F-18-BCPP-EF和F-18-BMS向脑和心脏的摄取，但F-18-BCPP-EF的降低程度比F-18-BMS更明显。鱼藤酮不影响F-18-BCPP-BF在大脑或心脏中的摄取。F-18-BCPP-EF对皮质缺血性神经元损伤进行成像，即使在第7天，当F-18-FDG在损伤区域显示高摄取时，也没有任何小胶质细胞活化的干扰。结论：本研究表明，F-18-BCPP-EF可能是一种潜在的PET探针，用于定量成像MC-I活性及其在活体脑中的缺血性损伤。
We developed novel PET probes, 2-tert-butyl-4-chloro-5-{6-[2-(2-F-18-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one (F-18-BCPP-EF) and 2-tert-butyl-4-chloro-5-[6-(4-F-18-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one (F-18-BCPP-BF), for quantitative imaging of mitochondrial complex I (MC-I) activity in the brain and preliminarily evaluated their properties in comparison with F-18-BMS-747158-02 (F-18-BMS). Methods: The affinity of F-18-BCPP-EF, F-18-BCPP-BF, and F-18-BMS to MC-I was analyzed using in vitro binding assays with H-3-dihydrorotenone and bovine cardiomyocyte submitochondrial particles. F-18-BCPP-EF, F-18-BCPP-BF, or F-18-BMS was intravenously injected into rats, and the uptake (standardized uptake value) in each organ was determined by dissection method. The effects of rotenone, a specific MC-I inhibitor, on the uptake of each probe were assessed by whole-body PET imaging in rats. Ischemic brain model rats were imaged using F-18-BCPP-EF. Results: The rank order of affinity to MC-I was F-18-BCPP-BF > F-18-BMS > F-18-BCPP-EF. The uptake of F-18-BCPP-EF and F-18-BMS was high in the heart, intermediate in brain, and low in muscle and bone 60 min after the injection. F-18-BCPP-BF provided increasing bone uptake with time after the injection. The uptake of F-18-BCPP-EF and F-18-BMS into the brain and heart was significantly decreased by preadministration of rotenone; however, the reduction degree of F-18-BCPP-EF was more pronounced than that of F-18-BMS. Rotenone did not affect F-18-BCPP-BF uptake in either the brain or the heart. F-18-BCPP-EF imaged the cortical ischemic neuronal damage without any disturbance by microglial activation even on day 7 when F-18-FDG showed high uptake in the damaged area. Conclusion: The present study demonstrated that F-18-BCPP-EF could be a potential PET probe for quantitative imaging of MC-I activity and its ischemic damage in the living brain with PET.