多巴胺D4受体显像剂18F-FDTP的研制和受体结合分析

    Radiochemical Synthesis and Receptor Binding Assay of 18F-FDTP as a Putative Dopamine D4 Receptor Imaging Agent

    • 摘要: 研发多巴胺D4受体显像剂,采用“一锅两步法”制备了一种潜在的多巴胺D4受体PET显像剂3-(4-18F氟苄基)-8, 9-二甲氧基-1, 2, 3, 4-四氢苯并吡喃3, 4-c吡啶-5-酮(18F-FDTP),并用高效液相色谱法进行了分离纯化。其合成时间为105 min,放射化学产率为19.8%(衰变校正),纯化后放射化学纯度大于97%,比活度大于6.3×104 PBq/mol。通过体外受体竞争结合分析,测定FDTP对多巴胺D4受体的亲和常数为8.1 nmol/L,对D2, D3受体的亲和常数分别大于5 800, 3 000 nmol/L;通过分配实验,测得其脂水分配系数为0.85。初步的体外研究显示,18F-FDTP 有希望用于D4受体显像,但还需经进一步试验证实。

       

      Abstract: Imaging of dopamine D4 receptor with specific radioligand has been of increasing interest in recent years. Herein, a putative dopamine D4 receptor tracer, 3-(4-18Ffluorobenzyl)-8, 9-dimethoxy-1, 2, 3, 4-tetrahydrochromeno3, 4-c pyridin-5-one (18F-FDTP) was reportedly prepared from 18F- through a two-step one-pot method. Fluorine-18 was introduced to trimethylammoniumbenzaldehyde triflate by a nucleophilic halogen displacement on it. The fluorine-18 labeled intermediate was then reductively aminated with 8, 9-dimethoxy-1, 2, 3, 4-tetrahydrochromeno3, 4-c pyridine-5-one to form the target molecule. The radiochemical synthesis of 18F-FDTP take about 105 min with a total radiochemical yield of 19.8% (decaycorrected). Its radiochemical purity is greater than 97% after purification via HPLC and its specific activity is greater than 6.3×104 PBq/mol. Through in vitroreceptor binding assay, the Ki of FDTP for D4.2 receptor is determined to be 8.1 nmol/L, and for D3, D2 to be greater than 3 000, 5 800 nmol/L, respectively. The receptor binding experimental results exposed that FDTP demonstrated nanomolar Ki value for binding to the D4 receptor with several hundredfold selectivities towards dopamine D2 and D3 receptors. The lipophilicity of it is determined to be 0.85. In conclusion, 18F-FDTP is radiochemically synthesized and its preliminary in vitrostudies indicate that 18F-FDTP shows promise as a potential imaging agent for dopamine D4 receptor and further studies, such as in vivodistribution and PET imaging studies, are needed to evaluate the new tracer. 

       

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