摘要
目的探究N,N-二乙基-2-(2-(4-(2-^(18)F-氟乙氧基)苯基)-5,7-二甲基吡唑并[1,5-a]嘧啶-3-基)乙酰胺(^(18)F-DPA-714)和(R)-N-仲丁基-N-甲基-4-(3-(^(18)F-三氟甲基)苯基)喹唑啉-2-甲酰胺(^(18)F-TFQC)针对相对分子质量18×103转位蛋白(TSPO)单核苷酸多态性的结合特性,同时评估这2种分子探针在大鼠神经炎性反应模型中的PET显像效能及可行性。方法构建表达TSPO野生型[高亲和力结合(HAB)型]和突变型[低亲和力结合(LAB)型]的293T细胞模型。通过N-甲基-N-(1-甲基丙基)-1-(2-氯苯基)异喹啉-3-甲酰胺(PK11195)为抑制剂开展竞争抑制试验,测定2种探针的抑制常数K i。建立脂多糖诱导的大鼠神经炎性反应模型(n=6),用^(18)F-DPA-714和^(18)F-TFQC进行小动物PET/CT显像,对比模型显像剂摄取情况并计算右侧纹状体的SUV_(mean)/左侧纹状体SUV_(mean)比值(SUVR)。显像结束后,通过组织免疫荧光检测验证小胶质细胞和TSPO的表达分布。用重复测量方差分析比较组间SUVR差异。结果^(18)F-TFQC在293T-LAB型和293T-HAB型细胞上的K i分别为23.51和14.60nmol/L,其比值为1.61;^(18)F-DPA-714在上述2种细胞上的K i分别为45.23和6.47nmol/L,其比值为6.99。小动物PET显像表明,2种探针均可在神经炎性反应病灶处有特异性摄取,^(18)F-DPA-714在病灶处的SUVR整体数值略高于^(18)F-TFQC,但差异无统计学意义(F值:组间0.40,时间效应0.30,交叉效应0.03;均P>0.05)。结论与^(18)F-DPA-714相比,^(18)F-TFQC对TSPO基因多态性不敏感,更契合临床应用与推广需求,有望用于神经炎性反应早期鉴别以及抗炎药物治疗的疗效监测。
ObjectiveTo explore the binding characteristics of N,N-diethyl-2-(2-(4-(2-^(18)F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide(^(18)F-DPA-714)and(R)-N-sec-butyl-N-methyl-4-(3-(^(18)F-trifluoromethyl)phenyl)quinazoline-2-carboxamide(^(18)F-TFQC)to the single nucleotide polymorphisms of the 18×103 translocator protein(TSPO),and to evaluate the imaging efficacy and feasibility of those 2 molecular probes in neuroinflammation rat models.MethodsTo test the selectivity of^(18)F-DPA-714 and^(18)F-TFQC for TSPO polymorphisms,the wild-type(high-affinity binding,HAB)and mutant(low-affinity binding,LAB)sequences of the human TSPO gene were transfected into 293T cells respectively.A competitive inhibition assay was carried out with N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-3-isoquinoline carboxamide(PK11195)as an inhibitor to determine the binding affinities of 2 probes to TSPO polymorphisms.Rat neuroinflammation models(n=6)were established using lipopolysaccharide.Three days after modeling,small animal PET/CT imaging was performed using^(18)F-DPA-714 and^(18)F-TFQC,respectively,to observe and compare the uptake of the tracers,and the ratio of SUV_(mean)of the right striatum to SUV_(mean)of the left striatum(SUVR)was calculated.After the imaging,the expression and distribution of microglia and TSPO were detected by tissue immunofluorescence.Repeated-measures analysis of variance was used to analyze the SUVR data of different groups.ResultsThe inhibition constants(K i)of^(18)F-TFQC on 293T-LAB and 293T-HAB cells were 23.51 and 14.60 nmol/L,respectively,with a K i LAB/K i HAB ratio of 1.61,indicating low sensitivity to TSPO single nucleotide polymorphisms.The K i of^(18)F-DPA-714 for binding to 293T-LAB and 293T-HAB cells were 45.23 and 6.47 nmol/L,respectively,with a K i LAB/K i HAB ratio of 6.99.Small animal PET/CT imaging demonstrated that specifically uptake of both probes could be found in neuroinflammatory lesions.The overall SUVR of^(18)F-DPA-714 in the lesions within 60minutes was slightly higher than that of^(18)F-TFQC,but no significant difference was observed(F values:inter-group 0.40,time effect 0.30,cross-effect 0.03;all P>0.05).ConclusionsCompared with^(18)F-DPA-714,^(18)F-TFQC is less sensitive to TSPO gene polymorphisms,thus being more suitable for clinical application and promotion.It holds promise for the early identification of neuroinflammation and the efficacy monitoring of anti-inflammatory drug treatments.
作者
苏洪星
马玉飞
林卿玉
付哲荃
高新岩
马鹏程
石岱
罗宗化
程登峰
Su Hongxing;Ma Yufei;Lin Qingyu;Fu Zhequan;Gao Xinyan;Ma Pengcheng;Shi Dai;Luo Zonghua;Cheng Dengfeng(Department of Nuclear Medicine,Zhongshan Hospital,Fudan University,Shanghai 200032,China)
出处
《中华核医学与分子影像杂志》
北大核心
2025年第8期458-463,共6页
Chinese Journal of Nuclear Medicine and Molecular Imaging
基金
国家自然科学基金(82172002,82472037)。
