Purpose

Synapse loss is a hallmark of Alzheimer’s disease (AD) and correlates with cognitive decline. The validation of a noninvasive in vivo imaging approach to quantify synapse would greatly facilitate our understanding of AD pathogenesis and assist drug developments for AD. As animal models of neurodegenerative and neuropsychiatric disorders play a critical role in the drug discovery and development process, a robust, objective, and translational method for quantifying therapeutic drug efficacy in animal models will facilitate the drug development process. In this study, we tested the quantification reliability of the SV2A PET tracer, [¹⁸F]SynVesT-1, in a mouse model of AD (APP/PS1) and wild-type controls, and developed a simplified quantification method to facilitate large cohort preclinical imaging studies.

Procedures

We generated nondisplaceable binding potential (BP_ND) and distribution volume ratio (DVR) values using the simplified reference tissue model (SRTM) on the 90-min dynamic PET imaging data, with brain stem and cerebellum as the reference region, respectively. Then, we correlated the standardized uptake value ratio (SUVR)-1 and SUVR averaged from different imaging windows with BP_ND and DVR, using brain stem and cerebellum as the reference region, respectively. We performed homologous competitive binding assay and autoradiographic saturation binding assay using [¹⁸F]SynVesT-1 to calculate the B_max and K_d.

Results

Using brain stem as the reference region, the averaged SUVR-1 from 30 to 60 min postinjection correlated well with the BP_ND calculated using SRTM. Using cerebellum as the reference region, the averaged SUVR from 30 to 60 min postinjection correlated well with the SRTM DVR. From the homologous competitive binding assay and autoradiographic saturation binding assay, the calculated the B_max and K_d were 4.5–18 pmol/mg protein and 9.8–19.6 nM, respectively, for rodent brain tissue.

Conclusions

This simplified SUVR method provides reasonable SV2A measures in APP/PS1 mice and their littermate controls. Our data indicate that, in lieu of a full 90-min dynamic scan, a 30-min static PET scan (from 30 to 60 min postinjection) would be sufficient to provide quantification data on SV2A expression, equivalent to the data generated from kinetic modeling. The methods developed here are readily applicable to the evaluation of therapeutic effects of novel drugs in this rodent model using [¹⁸F]SynVesT-1 and small animal PET.

中文翻译：

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使用 [ 18 F]SynVesT-1 和 PET 成像对啮齿动物大脑中的 SV2A 结合进行量化

目的

突触缺失是阿尔茨海默病 (AD) 的标志，与认知能力下降相关。验证用于量化突触的无创体内成像方法将极大地促进我们对 AD 发病机制的理解，并有助于 AD 的药物开发。由于神经退行性和神经精神疾病的动物模型在药物发现和开发过程中起着关键作用，因此在动物模型中量化治疗药物疗效的稳健、客观和转化方法将促进药物开发过程。在这项研究中，我们测试了 SV2A PET 示踪剂的量化可靠性，[ ¹⁸F]SynVesT-1，在 AD (APP/PS1) 小鼠模型和野生型对照中，开发了一种简化的量化方法，以促进大型队列临床前成像研究。

程序

我们使用简化的参考组织模型 (SRTM) 在 90 分钟的动态 PET 成像数据上生成了不可置换的结合电位 ( BP ND _{)和分布体积比 (DVR) 值，分别以脑干和小脑作为参考区域。}然后，我们将不同成像窗口的标准化摄取值比 (SUVR)-1 和 SUVR 与BP _ND和 DVR 相关联，分别使用脑干和小脑作为参考区域。我们使用 [ ¹⁸ F]SynVesT-1 进行同源竞争性结合测定和放射自显影饱和结合测定以计算B _max和K _d。

结果

使用脑干作为参考区域，注射后 30 至 60 分钟的平均 SUVR-1 与使用 SRTM 计算的BP _ND相关性良好。使用小脑作为参考区域，注射后 30 至 60 分钟的平均 SUVR 与 SRTM DVR 相关性良好。从同源竞争性结合测定和放射自显影饱和结合测定，计算出的啮齿动物脑组织的B _max和K _d分别为 4.5-18 pmol/mg 蛋白质和 9.8-19.6 nM。

结论

这种简化的 SUVR 方法在 APP/PS1 小鼠及其同窝小鼠对照中提供了合理的 SV2A 测量。我们的数据表明，代替完整的 90 分钟动态扫描，30 分钟静态 PET 扫描（注射后 30 至 60 分钟）足以提供 SV2A 表达的量化数据，相当于动力学建模生成的数据. ^{这里开发的方法很容易适用于使用 [ 18} F]SynVesT-1 和小动物 PET评估新型药物在这种啮齿动物模型中的治疗效果。