[18F]FP2OP 的制备及其作为正电子发射断层扫描心肌灌注显像剂的生物分布。
Preparation and biodistribution of [18F]FP2OP as myocardial perfusion imaging agent for positron emission tomography.
机构信息
Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, 19 Xinjiekou Outer St, Beijing 100875, China.
出版信息
Bioorg Med Chem. 2010 Feb;18(3):1312-20. doi: 10.1016/j.bmc.2009.12.022. Epub 2009 Dec 26.
UNLABELLED
Myocardial extractions of pyridaben, a mitochondrial complex I (MC-I) inhibitor, is well correlated with blood flow. Based on the synthesis and characterization of pyridaben analogue 2-tert-butyl-5-[2-(2-[(18)F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([(18)F]FP2OP), this study assessed its potential to be developed as myocardial perfusion imaging (MPI) agent.
METHODS
The tosylate labeling precursor 2-(2-(4-(tert-butyl-5-chloro-6-oxo-1,6-dihydro-pyridazin-4-yloxymethyl)benzyloxy)ethoxy)ethyl ester (OTs-P2OP) and the nonradioactive 2-tert-butyl-5-[2-(2-[(19)F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([(19)F]FP2OP) were synthesized and characterized by IR, (1)H NMR, (13)C NMR and MS analysis. By substituting tosyl of precursor OTs-P2OP with (18)F, the radiolabeled complex [(18)F]FP2OP was prepared and further evaluated for its in vitro physicochemical properties, in vivo biodistribution, the metabolic stability in mice, ex vivo autoradiography and cardiac PET/CT imaging.
RESULTS
Starting with [(18)F]F(-) Kryptofix 2.2.2./K(2)CO(3) solution, the total reaction time for [(18)F]FP2OP was about 100 min, with final high-performance liquid chromatography purification included. Typical decay-corrected radiochemical yield stayed at 41+/-5.3%, the radiochemical purity, 98% or more. Biodistribution in mice showed that the heart uptake of [(18)F]FP2OP was 41.90+/-4.52%ID/g at 2 min post-injection time, when the ratio of heart/liver, heart/lung and heart/blood reached 6.83, 9.49 and 35.74, respectively. Lipophilic molecule was further produced by metabolized [(18)F]FP2OP in blood and urine at 30 min. Ex vivo autoradiography demonstrates that [(18)F]FP2OP may have high affinity with MC-I and that can be blocked by [(19)F]FP2OP or rotenone (a known MC-I inhibitor). Cardiac PET images were obtained in a Chinese mini-swine at 5, 15, 30 and 60 min post-injection time with high quality.
CONCLUSION
[(18)F]FP2OP was synthesized with high radiochemical yield. The promising biological properties of [(18)F]FP2OP suggest high potential as MPI agent for positron emission tomography in the future.
目的
以线粒体复合物 I（MC-I）抑制剂哒螨灵的心肌提取率与血流密切相关为基础，根据哒螨灵类似物 2-叔丁基-5-[2-（2-（（18）F]氟乙氧基）乙氧基]苄氧基]-4-氯-2H-哒嗪-3-酮（[（18）F]FP2OP）的合成和表征，本研究评估了其作为心肌灌注成像（MPI）剂的潜力。
方法
对 tosylate 标记前体 2-（2-（4-（叔丁基-5-氯-6-氧代-1,6-二氢-哒嗪-4-基氧基甲基）苄氧基）乙氧基）乙基酯（OTs-P2OP）和非放射性 2-叔丁基-5-[2-（2-（（19）F]氟乙氧基）乙氧基]苄氧基]-4-氯-2H-哒嗪-3-酮（[（19）F]FP2OP）进行了合成和表征，采用 IR、（1）H NMR、（13）C NMR 和 MS 分析。通过用（18）F 取代前体 OTs-P2OP 的 tosyl，制备了放射性标记的复合物[（18）F]FP2OP，并进一步评估了其体外理化性质、体内分布、在小鼠中的代谢稳定性、离体放射性自显影和心脏 PET/CT 成像。
结果
从[（18）F]F（-）Kryptofix 2.2.2./K2CO3溶液开始，[（18）F]FP2OP 的总反应时间约为 100min，最后包括高效液相色谱纯化。典型的衰变校正放射性化学产率保持在 41+/-5.3%，放射化学纯度在 98%以上。在小鼠中的生物分布显示，[（18）F]FP2OP 在注射后 2 分钟时的心脏摄取率为 41.90+/-4.52%ID/g，此时心脏/肝脏、心脏/肺和心脏/血液的比值分别达到 6.83、9.49 和 35.74。在 30 分钟时，血液和尿液中代谢生成的亲脂性分子[（18）F]FP2OP。离体放射性自显影表明[（18）F]FP2OP 可能与 MC-I 具有高亲和力，并且可以被[（19）F]FP2OP 或鱼藤酮（一种已知的 MC-I 抑制剂）阻断。在注射后 5、15、30 和 60 分钟时，在中国小型猪中获得了高质量的心脏 PET 图像。
结论
[（18）F]FP2OP 的放射性化学产率很高。[（18）F]FP2OP 的有前途的生物学特性表明，它具有作为正电子发射断层扫描未来 MPI 剂的高潜力。
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