摘要目的:开发并验证一种靶向大麻素1型(CB1)受体的新型PET示踪剂 N-环己基-4-((2，4-二氯苯基)(4-(氟- 18F)苯基)甲基)哌嗪-1-甲酰胺( 18F-SQKJ-2)，用于诊断与恐惧记忆相关的精神疾病。 方法:采用亲核取代的放射性化学合成方法制备 18F-SQKJ-2。行CB1受体阻断实验：取7只ICR小鼠，分为阻断组(4只)与对照1组(3只)，阻断组予利莫那班阻断CB1受体，对照1组不行阻断，对比2组动物不同器官对 18F-SQKJ-2的摄取[每克组织百分注射剂量率(%ID/g)]差异，分析 18F-SQKJ-2对CB1受体的亲和力和特异性。通过动物组织匀浆研究 18F-SQKJ-2体外代谢稳定性，取10只C57小鼠建立恐惧记忆小鼠模型(恐惧组6只，对照2组4只)，分析2组的僵立时间百分比；通过microPET显像检测 18F-SQKJ-2脑内分布，计算各脑区相对总脑摄取，分析2组恐惧记忆相关脑区CB1受体相对总脑摄取的差异。采用两独立样本 t检验和Mann-Whitney U检验分析数据。 结果:成功合成 18F-SQKJ-2，放化纯≥98.0%，校正放射化学产率(12.3±6.0)%( n＝4)。体外代谢稳定性实验显示， 18F-SQKJ-2在肝脏、血液和脑中60min内基本稳定。CB1受体阻断实验示，阻断组小鼠脑部 18F-SQKJ-2摄取较对照1组明显降低[(0.95±0.28)与(3.44±1.16)%ID/g； t＝－3.57， P＝0.023]。恐惧组小鼠的僵立时间百分比明显高于对照2组[43.28%(39.46%，52.93%)与2.74%(1.52%，4.85%)； Z＝－2.45， P＝0.010]。 18F-SQKJ-2 microPET显像示恐惧组小鼠大脑皮质 18F-SQKJ-2的相对总脑摄取较对照2组明显增加[(5.83±0.47)%与(5.00±0.52)%； t＝2.42， P＝0.046]。 结论:成功制备 18F-SQKJ-2，其放化纯和代谢稳定性符合要求，具有可视化、定量化研究恐惧记忆的潜力。

abstractsObjective:To develop and validate a novel PET tracer, N-cyclohexyl-4-((2, 4-dichlorophenyl)(4-(fluoro- 18F)phenyl)methyl)piperazine-1-carboxamide ( 18F-SQKJ-2), targeting cannabinoid type 1 (CB1) receptors for diagnosing psychiatric disorders associated with fear memory. Methods:18F-SQKJ-2 was prepared using a nucleophilic substitution radiochemical synthesis method. For the CB1 receptor blocking experiment, 7 ICR mice were divided into blocking group ( n=4; rimonabant for blocking treatment) and control group 1 ( n=3; no rimonabant blocking treatment). The affinity and specificity of 18F-SQKJ-2 for CB1 receptors were analyzed based on the differences in 18F-SQKJ-2 uptake (percentage injected dose per gram of tissue, %ID/g) by various organs between two groups. The metabolic stability of 18F-SQKJ-2 in vitro was studied using animal tissue homogenates. Ten C57 mice were used to establish fear memory mouse models (fear group, n=6; control group 2, n=4), and the percentage of freezing time was compared between 2 groups. MicroPET scans were used to detect the intracranial distribution of 18F-SQKJ-2, and the relative uptake in each brain region compared to total brain uptake was calculated. Statistical analysis was conducted to compare the differences in CB1 receptor relative total brain uptake in fear-related brain regions between 2 groups. Independent-sample t test and Mann-Whitney U test were used to analyze the data. Results:18F-SQKJ-2 was successfully synthesized with a radiochemical purity ≥98.0% and a corrected radioactive yield of (12.3±6.0)%( n=4). In vitro metabolic stability experiments showed that 18F-SQKJ-2 was basically stable in the liver, blood, and brain within 60min. The CB1 receptor blocking experiment demonstrated that the uptake of 18F-SQKJ-2 in the brains of mice in blocking group was significantly lower than that in control group 1 ((0.95±0.28) vs (3.44±1.16) %ID/g; t=-3.57, P=0.023). The percentage of freezing time in fear group was significantly higher than that in control group 2 (43.28%(39.46%, 52.93%) vs 2.74%(1.52%, 4.85%); Z=-2.45, P=0.010). 18F-SQKJ-2 microPET imaging showed that the uptake of 18F-SQKJ-2 in the cerebral cortex of mice in fear group was significantly increased compared with that in control group 2 ((5.83±0.47)% vs (5.00±0.52)%; t=2.42, P=0.046). Conclusion:18F-SQKJ-2 is successfully prepared with acceptable radiochemical purity and metabolic stability, demonstrating potential for visualizing and quantifying fear memory.