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 ^(18)F-FDTP as a Putative Dopamine D_4 Receptor Imaging Agent

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6.3×104PBq/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5800,3000 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。

Imaging of dopamine I34 receptor with specific radioligand has been of increasing interest in recent years. Herein, a putative dopamine I34 receptor tracer, 3-（4-[^18F] fluorobenzyl）-8, 9-dimethoxy-1, 2, 3, 4-tetrahydrochromeno[3, 4-c] pyridin-5-one （lS F-FDTP） was reportedly prepared from ^18F- through a two-step one-pot method. Fluorine-18 was introduced to trimethylammoniumbenzaldehyde 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-tetrahydrochromeno[3, 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% （decaycorrected）, Its radiochemical purity is greater than 97% after purification via HPLC and its specific activity is greater than 6.3 × 10^4 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 hun- dred-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.