目的通过18氟-氟脱氧葡萄糖(18F-FDG)小动物正电子发射计算机体层摄影术(micro PET)成像技术来研究激活小鼠棕色脂肪(BAT)细胞的不同方法,并研究这些激活方法在肥胖及糖尿病模型小鼠减体质量及降糖作用的潜在价值。方法对正常小鼠(23只...目的通过18氟-氟脱氧葡萄糖(18F-FDG)小动物正电子发射计算机体层摄影术(micro PET)成像技术来研究激活小鼠棕色脂肪(BAT)细胞的不同方法,并研究这些激活方法在肥胖及糖尿病模型小鼠减体质量及降糖作用的潜在价值。方法对正常小鼠(23只)给予温度刺激(冷刺激6只,冷刺激后热刺激6只)及交感神经系统相关药物(去甲肾上腺素3只,冷刺激后普萘洛尔3只)干预,对照组5只不行任何干预,行18F-FDG micro PET成像,计算BAT与肝脏18F-FDG的摄取比值(BAT/L)。在肥胖模型小鼠(14只)研究中,通过高脂饮食8周建立肥胖模型小鼠后,随机分成BRL37344干预组(6只)及肥胖对照组(8只)。肥胖BRL37344干预组通过腹腔给药每只2.5 mg/kg,每周3次共2周,肥胖对照组给以相同频率的0.9%氯化钠溶液。糖尿病模型小鼠(12只)研究中,高脂饮食8周后给予连续3 d腹腔注射链脲佐菌素160 mg/kg建立糖尿病模型小鼠(血糖大于11.1 mmol/L者),随机分成BRL37344干预组(6只)及糖尿病对照组(6只),各组给药方法同肥胖模型小鼠。模型小鼠在建模前后、完成干预后行18F-FDG micro PET成像,计算BAT/L,并测定肥胖模型小鼠的体质量变化、肥胖模型及糖尿病模型小鼠尾静脉血糖、总胆固醇、低密度脂蛋白水平,分析这些指标与BAT/L的相关性。结果正常小鼠mirco PET显像分析中,冷刺激和去甲肾上腺素刺激下BAT/L(5.70±0.75及5.77±0.50)显著高于正常对照小鼠BAT/L(3.63±0.79;P<0.05及P<0.01)。冷刺激后行热刺激、普萘洛尔小鼠的BAT/L(3.04±1.10及0.73±0.16)显著低于仅行冷刺激干预小鼠的BAT/L(5.70±0.75;P<0.01)。肥胖模型小鼠micro PET显像分析中,肥胖小鼠BAT/L较正常对照组显著降低(3.15±1.67 vs 5.33±1.48;P<0.05),肥胖模型BRL37344干预组BAT/L明显高于肥胖对照组(6.64±1.97 vs 4.20±1.13;P<0.05)。糖尿病模型小鼠BAT/L显著低于正常对照组(1.97±0.68 vs 5.33±1.48;P<0.05),糖尿病模型BRL37344干预组BAT/L显著高于糖尿病模型对照组(5.25±1.51 vs 2.32±1.01;P<0.01)。血生物化学分析中,肥胖模型小鼠及糖尿病模型小鼠BRL37344干预组血糖分别显著低于肥胖对照组(6.88±0.57 vs 8.47±1.54;P<0.05)及糖尿病模型对照组(8.84±2.86 vs 19.99±9.44;P<0.05)。肥胖及糖尿病模型小鼠BRL37344干预组血糖水平与其micro PET显像BAT/L均存在显著负相关性(r=-0.71,P=0.003及r=-0.74,P=0.010)。肥胖模型小鼠体质量分析中,肥胖模型小鼠BRL37344干预组体质量显著低于肥胖对照组[(52.52±4.22)g vs(59.09±6.89)g;P=0.001]。结论小鼠BAT细胞受温度刺激及交感神经系统相关药物调控,并可通过18F-FDG micro PET成像方法动态监测。肥胖模型与糖尿病模型小鼠BAT细胞活性降低,但仍具有被β3肾上腺素受体激动剂激活的潜能,且激活BAT细胞可产生降糖及减质量作用。激活BAT细胞可能是一种潜在的治疗肥胖及糖尿病的手段。展开更多
This work was to develop a semi-automated synthesis of 18F-9-fluoropropyl-9-desmethyl-DTBZ (18F-FP-DTBZ) and validate its potential as a vesicular monoamine transporter 2 (VMAT2) ligand.18F-FP-DTBZ was synthesized by ...This work was to develop a semi-automated synthesis of 18F-9-fluoropropyl-9-desmethyl-DTBZ (18F-FP-DTBZ) and validate its potential as a vesicular monoamine transporter 2 (VMAT2) ligand.18F-FP-DTBZ was synthesized by a semi-automated procedure in a 21-35% yield without decay correction and with a radiochemical purity of >98%.Bioistribution in rats exhibited a favorable brain uptakes of the ligand (0.31±0.04 ID% at 60min post injection,n=8).The highest radioactivity located in VMAT2 enriched striatal tissue.The target-to-nontarget ratio (striatum/cerebellum,ST/CB) was 4.81±0.84.Blocking studies implied that striatum uptake could be blocked by DTBZ (a VMAT2 inhibitor) but could not by CFT (a dopamine transporter inhibitor).MicroPET imaging with 18F-FP-DTBZ in normal rats gave high quality images in which high radioactivity were observed in the striatal tissue.Time-and-activity curves revealed good retention in the target (striatum) and rapid clearance in the background (cerebellum),which resulted in a maximum ST/CB ratio of 5.08±0.81 (n=3) in 80-120min.By contrast,the 6-hydroxydopamine unilateral lesioned rats gave asymmetrical striata images with higher 18F-FP-DTBZ concentration on the unlesioned side (unlesioned-ST/CB=5.21±0.38,n=3) than the lesioned (lesioned-ST/CB=2.34±0.51).The results validated that 18F-FP-DTBZ is a favorable PET ligand binding to VMAT2.展开更多
文摘目的通过18氟-氟脱氧葡萄糖(18F-FDG)小动物正电子发射计算机体层摄影术(micro PET)成像技术来研究激活小鼠棕色脂肪(BAT)细胞的不同方法,并研究这些激活方法在肥胖及糖尿病模型小鼠减体质量及降糖作用的潜在价值。方法对正常小鼠(23只)给予温度刺激(冷刺激6只,冷刺激后热刺激6只)及交感神经系统相关药物(去甲肾上腺素3只,冷刺激后普萘洛尔3只)干预,对照组5只不行任何干预,行18F-FDG micro PET成像,计算BAT与肝脏18F-FDG的摄取比值(BAT/L)。在肥胖模型小鼠(14只)研究中,通过高脂饮食8周建立肥胖模型小鼠后,随机分成BRL37344干预组(6只)及肥胖对照组(8只)。肥胖BRL37344干预组通过腹腔给药每只2.5 mg/kg,每周3次共2周,肥胖对照组给以相同频率的0.9%氯化钠溶液。糖尿病模型小鼠(12只)研究中,高脂饮食8周后给予连续3 d腹腔注射链脲佐菌素160 mg/kg建立糖尿病模型小鼠(血糖大于11.1 mmol/L者),随机分成BRL37344干预组(6只)及糖尿病对照组(6只),各组给药方法同肥胖模型小鼠。模型小鼠在建模前后、完成干预后行18F-FDG micro PET成像,计算BAT/L,并测定肥胖模型小鼠的体质量变化、肥胖模型及糖尿病模型小鼠尾静脉血糖、总胆固醇、低密度脂蛋白水平,分析这些指标与BAT/L的相关性。结果正常小鼠mirco PET显像分析中,冷刺激和去甲肾上腺素刺激下BAT/L(5.70±0.75及5.77±0.50)显著高于正常对照小鼠BAT/L(3.63±0.79;P<0.05及P<0.01)。冷刺激后行热刺激、普萘洛尔小鼠的BAT/L(3.04±1.10及0.73±0.16)显著低于仅行冷刺激干预小鼠的BAT/L(5.70±0.75;P<0.01)。肥胖模型小鼠micro PET显像分析中,肥胖小鼠BAT/L较正常对照组显著降低(3.15±1.67 vs 5.33±1.48;P<0.05),肥胖模型BRL37344干预组BAT/L明显高于肥胖对照组(6.64±1.97 vs 4.20±1.13;P<0.05)。糖尿病模型小鼠BAT/L显著低于正常对照组(1.97±0.68 vs 5.33±1.48;P<0.05),糖尿病模型BRL37344干预组BAT/L显著高于糖尿病模型对照组(5.25±1.51 vs 2.32±1.01;P<0.01)。血生物化学分析中,肥胖模型小鼠及糖尿病模型小鼠BRL37344干预组血糖分别显著低于肥胖对照组(6.88±0.57 vs 8.47±1.54;P<0.05)及糖尿病模型对照组(8.84±2.86 vs 19.99±9.44;P<0.05)。肥胖及糖尿病模型小鼠BRL37344干预组血糖水平与其micro PET显像BAT/L均存在显著负相关性(r=-0.71,P=0.003及r=-0.74,P=0.010)。肥胖模型小鼠体质量分析中,肥胖模型小鼠BRL37344干预组体质量显著低于肥胖对照组[(52.52±4.22)g vs(59.09±6.89)g;P=0.001]。结论小鼠BAT细胞受温度刺激及交感神经系统相关药物调控,并可通过18F-FDG micro PET成像方法动态监测。肥胖模型与糖尿病模型小鼠BAT细胞活性降低,但仍具有被β3肾上腺素受体激动剂激活的潜能,且激活BAT细胞可产生降糖及减质量作用。激活BAT细胞可能是一种潜在的治疗肥胖及糖尿病的手段。
基金Supported by the National Natural Science Foundation of China (30970844)the Outstanding Medical Professionals Foundation of Jiangsu Province (RC2011096)Natural Science Foundation of Jiangsu Province of China (BK2010155)
文摘This work was to develop a semi-automated synthesis of 18F-9-fluoropropyl-9-desmethyl-DTBZ (18F-FP-DTBZ) and validate its potential as a vesicular monoamine transporter 2 (VMAT2) ligand.18F-FP-DTBZ was synthesized by a semi-automated procedure in a 21-35% yield without decay correction and with a radiochemical purity of >98%.Bioistribution in rats exhibited a favorable brain uptakes of the ligand (0.31±0.04 ID% at 60min post injection,n=8).The highest radioactivity located in VMAT2 enriched striatal tissue.The target-to-nontarget ratio (striatum/cerebellum,ST/CB) was 4.81±0.84.Blocking studies implied that striatum uptake could be blocked by DTBZ (a VMAT2 inhibitor) but could not by CFT (a dopamine transporter inhibitor).MicroPET imaging with 18F-FP-DTBZ in normal rats gave high quality images in which high radioactivity were observed in the striatal tissue.Time-and-activity curves revealed good retention in the target (striatum) and rapid clearance in the background (cerebellum),which resulted in a maximum ST/CB ratio of 5.08±0.81 (n=3) in 80-120min.By contrast,the 6-hydroxydopamine unilateral lesioned rats gave asymmetrical striata images with higher 18F-FP-DTBZ concentration on the unlesioned side (unlesioned-ST/CB=5.21±0.38,n=3) than the lesioned (lesioned-ST/CB=2.34±0.51).The results validated that 18F-FP-DTBZ is a favorable PET ligand binding to VMAT2.
