NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China.
Nucl Med Biol. 2021 May-Jun;96-97:9-18. doi: 10.1016/j.nucmedbio.2021.02.004. Epub 2021 Feb 20.
Vesicular monoamine transporter 2 (VMAT2) has been associated with the risk of PD. Genetic reduction of VMAT2 level is reported to increase the vulnerability for dopaminergic neurodegeneration. In this study, by using in vivo microPET imaging with a VMAT2 radioligand [F]fluoropropyl-(+)-dihydrotetrabenazine ([F]FP-(+)-DTBZ), we investigated the enhanced role of inhibiting VMAT2 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced loss of dopaminergic neurons.
The (+)-α-dihydrotetrabenazine ((+)-DTBZ, an inhibitor of VMAT2, 5 mg/kg), or MPTP (low dose (ld): 10 mg/kg, high dose (hd): 30 mg/kg) or both of them were intraperitoneally injected into C57BL/6 mice for 5 or 10 consecutive days. MicroPET imaging with [F]FP-(+)-DTBZ was performed to test the dopaminergic neuronal integrity. [F]FP-(+)-DTBZ uptake in striatum was quantified as standardized uptake value (SUV). The pathological changes in the striata and substantia nigra were confirmed by measuring the DA contents and immunohistochemical staining of tyrosine hydroxylase (TH).
In vivo imaging results showed that the striatal SUVs of both DTBZ&MPTP and MPTP groups were substantially declined compared to the baseline. Moreover, the striatal uptakes of [F]FP-(+)-DTBZ in DTBZ&MPTP and MPTP groups were obviously lower than the control, DTBZ group and MPTP group. Notably, the decrease of the striatal uptake in the DTBZ&MPTP/10d group was more serious than the DTBZ&MPTP/5d group and comparable to the MPTP group. Consistently, the ratios of DA metabolites to DA in DTBZ&MPTP/10d and MPTP mice were significantly increased. The correlation analysis showed that SUVs were highly correlated to the striatal dopaminergic fiber density and TH-positive dopaminergic neuron number in the substantia nigra.
MicroPET brain imaging with [F]FP-(+)-DTBZ noninvasively revealed that (+)-DTBZ co-administration significantly aggravated the neurotoxicity of MPTP to dopaminergic neurons, suggesting that inhibition of VMAT2 may be related to the pathogenesis of PD and tracing VMAT2 activity with PET imaging is of potential value in monitoring PD progression.
囊泡单胺转运体 2（VMAT2）与 PD 的风险相关。据报道，VMAT2 水平的遗传降低会增加多巴胺能神经退行性变的易感性。在这项研究中，我们使用 VMAT2 放射性配体 [F]氟丙基-（+）-二氢四苯并嗪（[F] FP-（+）-DTBZ）的体内 microPET 成像，研究了抑制 VMAT2 在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的多巴胺能神经元损失中的增强作用。
（+）-α-二氢四苯并嗪（（+）-DTBZ，VMAT2 抑制剂，5mg/kg）或 MPTP（低剂量（ld）：10mg/kg，高剂量（hd）：30mg/kg）或两者连续 5 或 10 天腹腔注射到 C57BL/6 小鼠中。使用 [F] FP-（+）-DTBZ 进行 microPET 成像以测试多巴胺能神经元的完整性。纹状体中的 [F] FP-（+）-DTBZ 摄取被量化为标准化摄取值（SUV）。通过测量多巴胺含量和酪氨酸羟化酶（TH）的免疫组织化学染色，确认纹状体和黑质中的病理变化。
体内成像结果表明，与基线相比，DTBZ&MPTP 和 MPTP 组的纹状体 SUV 均明显下降。此外，DTBZ&MPTP 和 MPTP 组纹状体中 [F] FP-（+）-DTBZ 的摄取明显低于对照组、DTBZ 组和 MPTP 组。值得注意的是，DTBZ&MPTP/10d 组纹状体摄取的减少比 DTBZ&MPTP/5d 组更严重，与 MPTP 组相当。同样，DTBZ&MPTP/10d 和 MPTP 小鼠的 DA 代谢物与 DA 的比值显著增加。相关性分析表明，SUV 与纹状体多巴胺能纤维密度和黑质中 TH 阳性多巴胺能神经元数量高度相关。
使用 [F] FP-（+）-DTBZ 的 microPET 脑成像非侵入性地显示，（+）-DTBZ 联合给药显着加重了 MPTP 对多巴胺能神经元的神经毒性，表明抑制 VMAT2 可能与 PD 的发病机制有关，使用 PET 成像追踪 VMAT2 活性在监测 PD 进展方面具有潜在价值。
