Preclinical PET Studies of [11C]UCB-J Binding in Minipig Brain.,Molecular Imaging and Biology

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Preclinical PET Studies of [11C]UCB-J Binding in Minipig Brain.
Molecular Imaging and Biology ( IF 3.1 ) Pub Date : 2020-06-08 , DOI: 10.1007/s11307-020-01506-8
Majken Borup Thomsen ₁ , Anna Christina Schacht ₁ , Aage Kristian Olsen Alstrup ₁ , Jan Jacobsen ₁ , Thea Pinholt Lillethorup ₁ , Simone Larsen Bærentzen _{1,

2} , Ove Noer ₁ , Dariusz Orlowski ₃ , Betina Elfving ₂ , Heidi Kaastrup Müller ₂ , David J Brooks _{1,

4} , Anne M Landau _{1,

2}

Affiliation

Purpose

Loss of neuronal synapse function is associated with a number of brain disorders. The [¹¹C]UCB-J positron emission tomography (PET) tracer allows for in vivo examination of synaptic density, as it binds to synaptic vesicle glycoprotein 2A (SV2A) expressed in presynaptic terminals. Here, we characterise [¹¹C]UCB-J imaging in Göttingen minipigs.

Procedures

Using PET imaging, we examined tracer specificity and compared kinetic models. We explored the use of a standard blood curve and centrum semiovale white matter as a reference region. We compared in vivo [¹¹C]UCB-J PET imaging to in vitro autoradiography, Western blotting and real-time quantitative polymerase chain reaction.

Results

The uptake kinetics of [¹¹C]UCB-J could be described using a 1-tissue compartment model and blocking of SV2A availability with levetiracetam showed dose-dependent specific binding. Population-based blood curves resulted in reliable [¹¹C]UCB-J binding estimates, while it was not possible to use centrum semiovale white matter as a non-specific reference region. Brain [¹¹C]UCB-J PET signals correlated well with [³H]UCB-J autoradiography and SV2A protein levels.

Conclusions

[¹¹C]UCB-J PET is a valid in vivo marker of synaptic density in the minipig brain, with binding values close to those reported for humans. Minipig models of disease could be valuable for investigating the efficacy of putative neuroprotective agents for preserving synaptic function in future non-invasive, longitudinal studies.

中文翻译：

小型猪脑中 [11C]UCB-J 结合的临床前 PET 研究。

目的

神经元突触功能的丧失与许多脑部疾病有关。[ ¹¹ C] UCB-J 正电子发射断层扫描 (PET) 示踪剂允许体内检查突触密度，因为它与突触前末端表达的突触囊泡糖蛋白 2A (SV2A) 结合。在这里，我们表征了哥廷根小型猪的[ ¹¹ C] UCB-J 成像。

程序

我们使用 PET 成像检查了示踪剂的特异性并比较了动力学模型。我们探索了使用标准血液曲线和半卵圆中心白质作为参考区域。我们将体内[ ¹¹ C] UCB-J PET 成像与体外放射自显影、蛋白质印迹和实时定量聚合酶链反应进行了比较。

结果

[ ¹¹ C]UCB-J的摄取动力学可以使用 1 组织隔室模型进行描述，并且用左乙拉西坦阻断 SV2A 的可用性显示出剂量依赖性的特异性结合。基于人群的血液曲线导致可靠的 [ ¹¹ C] UCB-J 结合估计，而不能使用半卵圆中心白质作为非特异性参考区域。脑[ ¹¹ C]UCB-J PET 信号与[ ³ H]UCB-J 放射自显影和SV2A 蛋白水平相关。