VMAT2 与新型放射性配体 [18F]FE-DTBZ-d4 在非人灵长类动物中的 PET 成像：与 [11C]DTBZ 和 [18F]FE-DTBZ 的比较,ACS Chemical Neuroscience

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VMAT2 与新型放射性配体 [18F]FE-DTBZ-d4 在非人灵长类动物中的 PET 成像：与 [11C]DTBZ 和 [18F]FE-DTBZ 的比较
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2021-11-23 , DOI: 10.1021/acschemneuro.1c00651
Sangram Nag ₁ , Mahabuba Jahan ₁ , Miklós Tóth ₁ , Ryuji Nakao ₁ , Andrea Varrone ₁ , Christer Halldin ₁

Affiliation

囊泡单胺转运蛋白 2 型 (VMAT2) 被认为负责将单胺吸收到突触末端的囊泡中。两种 VMAT2 放射性配体 [ ¹¹ C]DTBZ 和 [ ¹⁸ F]FP-DTBZ 已用于使用正电子发射断层扫描 (PET) 评估帕金森病 (PD) 中黑质纹状体缺陷的程度。[ ¹⁸ F]FE-DTBZ-d4 是 [ ¹⁸ F]FE-DTBZ 的非氘代类似物，具有相似的成像特性，具有更好的抗脱氟稳定性。因此，[ ¹⁸ F]FE-DTBZ-d4 作为脑中 VMAT2 的成像标记物引起了人们的关注。本研究的目的是研究 [ ^{18 ] 的脑动力学和量化}^{与 [ 11} C]DTBZ 和 [ ¹⁸ F]FE-DTBZ相比，非人灵长类动物 (NHP) 中的 F]FE-DTBZ-d4 。通过一步¹¹ C-甲基化或两步氟 18 亲核取代反应成功地实现了放射性标记。用高效液相色谱（HPLC）分析稳定性和放射化学产率。三只雌性食蟹猴被纳入研究，共进行了 12 次正电子发射断层扫描 (PET) 测量。用每种示踪剂检查每只猴子。此外，用丁苯那嗪 (2.0 mg/kg) 进行了两次预处理和一次置换 PET 测量 [ ¹⁸F]FE-DTBZ-d4。所有 PET 测量均使用高分辨率研究断层扫描 (HRRT) 系统进行。使用梯度放射性高效液相色谱法测量猴血浆中的放射性代谢物。[ ¹⁸ F]FE-DTBZ-d4 (SUV: 4.28 ± 1.01) 显示出比 [ ¹⁸ F]FE-DTBZ (SUV: 3.43 ± 0.54) 和 [ ¹¹ C]DTBZ (SUV: 3.06 ± 0.32)更高的脑摄取和更快的冲洗。^{[ 18} F]FE-DTBZ-d4在不同脑区（壳核：5.5 ± 1.4；尾状核：4.4 ± 1.1；中脑：1.4 ± 0.4）的结合电位（BP _ND）值高于[ ¹¹ C]DTBZ和 [ ¹⁸ F]FE-DTBZ。^{与 [ 11}相比， [ ¹⁸ F]FE-DTBZ 在血浆中的放射性代谢更快C]DTBZ 和 [ ¹⁸ F]FE-DTBZ-d4。[ ¹⁸ F]FE-DTBZ-d4 是一种适用于定量非人类灵长类动物大脑中 VMAT2 的放射性配体，具有比 [ ¹¹ C]DTBZ 和 [ ¹⁸ F]FE-DTBZ 更好的成像特性。初步比较表明，与非氘代类似物相比，[ ¹⁸ F]FE-DTBZ-d4 具有更高的抗脱氟稳定性。

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PET Imaging of VMAT2 with the Novel Radioligand [18F]FE-DTBZ-d4 in Nonhuman Primates: Comparison with [11C]DTBZ and [18F]FE-DTBZ

The vesicular monoamine transporter type 2 (VMAT2) is believed to be responsible for the uptake of monoamines into the vesicles of the synaptic terminals. Two VMAT2 radioligands [¹¹C]DTBZ and [¹⁸F]FP-DTBZ have been used to assess the degree of nigrostriatal deficit in Parkinson’s disease (PD) using positron emission tomography (PET). [¹⁸F]FE-DTBZ-d4, the nondeuterated analogue of [¹⁸F]FE-DTBZ showed similar imaging properties with better stability against defluorination. Therefore, [¹⁸F]FE-DTBZ-d4 draws attention to be investigated as an imaging marker for VMAT2 in the brain. The aim of this study was to investigate the brain kinetics and quantification of [¹⁸F]FE-DTBZ-d4 in nonhuman primates (NHPs), with comparison to [¹¹C]DTBZ and [¹⁸F]FE-DTBZ. Radiolabeling was successfully achieved either by one-step ¹¹C-methylation or by a two-step fluorine-18 nucleophilic substitution reaction. The stability and radiochemical yield were analyzed with high-performance liquid chromatography (HPLC). Three female cynomolgus monkeys were included in the study and underwent a total of 12 positron emission tomography (PET) measurements. Each monkey was examined with each tracer. In addition, two pretreatment and one displacement PET measurements with tetrabenazine (2.0 mg/kg) were performed for [¹⁸F]FE-DTBZ-d4. All PET measurements were conducted using a high-resolution research tomograph (HRRT) system. Radiometabolites were measured in monkey plasma using gradient radio-HPLC. [¹⁸F]FE-DTBZ-d4 (SUV: 4.28 ± 1.01) displayed higher brain uptake compared to both [¹⁸F]FE-DTBZ (SUV: 3.43 ± 0.54) and [¹¹C]DTBZ (SUV: 3.06 ± 0.32) and faster washout. Binding potential (BP_ND) values of [¹⁸F]FE-DTBZ-d4 in different brain regions (putamen: 5.5 ± 1.4; caudate: 4.4 ± 1.1; midbrain: 1.4 ± 0.4) were higher than those of [¹¹C]DTBZ and [¹⁸F]FE-DTBZ. [¹⁸F]FE-DTBZ showed faster radiometabolism in plasma compared to [¹¹C]DTBZ and [¹⁸F]FE-DTBZ-d4. [¹⁸F]FE-DTBZ-d4 is a suitable radioligand for quantification of VMAT2 in the nonhuman primate brain, with better imaging properties than [¹¹C]DTBZ and [¹⁸F]FE-DTBZ. A preliminary comparison suggests that [¹⁸F]FE-DTBZ-d4 has increased stability against defluorination compared to the nondeuterated analogue.

更新日期：2021-12-15

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