Kakiuchi T, Tsukada H, Fukumoto D, Nishiyama S
Central Research Laboratory, Hamamatsu Photonics K. K., Shizuoka, Japan.
Synapse. 2001 Jun 1;40(3):170-9. doi: 10.1002/syn.1039.
Age-related changes in the serotonin transporter (SERT) in the living brains of conscious young (5.9 +/- 1.8 years old) and aged (19.0 +/- 3.3 years old) monkeys (Macaca mulatta) were evaluated in combination with (11)CMcN5652 and its inactive enantiomer (11)CMcN5652 by high-resolution positron emission tomography (PET). For the quantitative analysis of SERT binding in vivo, two serial PET scans with (11)CMcN5652 and (11)CMcN5652 were performed in the same animals in a day and the differences in radioactivities of (11)CMcN5652 vs. (11)CMcN5652 measured from 41-91 min postinjection were calculated as an estimate of specific ligand binding. Higher specific binding of SERT was observed in the thalamus and striatum, regions known to contain high densities of SERT by in vitro assay, with intermediate levels in the pons, hippocampus, cingulate gyrus, and cortical regions and lower levels in the cerebellum in both young and aged monkeys. Almost all regions assayed except the cerebellum showed significant age-related decreases in the specific binding of SERT, which showed reverse correlation with cortisol level in plasma. When the SERT blocker fluvoxamine (1 mg/kg) was administered intravenously 30 min after tracer injection, specific binding of SERT was displaced in both age groups. However, the degree of displacement was more marked in young than in aged monkeys. Cortisol level in plasma was significantly higher in aged than in young animals. These observations demonstrate the usefulness of the combined use of (11)CMcN5652 and (11)CMcN5652 as an indicator for the age-related changes in cortical SERT measured noninvasively by PET. In addition, these observations suggest that the age-related impairment of SERT sensitivity for fluvoxamine might be related to the reduced efficacy of antidepressant therapy in elderly patients with depression.
通过高分辨率正电子发射断层扫描（PET），结合[¹¹C]⁺McN5652及其无活性对映体[¹¹C]⁻McN5652，评估清醒的幼年（5.9±1.8岁）和老年（19.0±3.3岁）恒河猴（猕猴）活体大脑中血清素转运体（SERT）与年龄相关的变化。为了对体内SERT结合进行定量分析，在同一天对同一组动物进行了两次连续的PET扫描，分别注射[¹¹C]⁺McN5652和[¹¹C]⁻McN5652，并计算注射后41 - 91分钟测量的[¹¹C]⁺McN5652与[¹¹C]⁻McN5652放射性差异，作为特异性配体结合的估计值。在丘脑和纹状体中观察到SERT的特异性结合较高，体外分析已知这些区域含有高密度的SERT，在脑桥、海马体、扣带回和皮质区域为中等水平，在幼年和老年猴子的小脑中水平较低。除小脑外，几乎所有检测区域的SERT特异性结合均显示出与年龄相关的显著下降，且与血浆皮质醇水平呈负相关。在注射示踪剂30分钟后静脉注射SERT阻断剂氟伏沙明（1mg/kg），两个年龄组的SERT特异性结合均被取代。然而，幼年猴子的取代程度比老年猴子更明显。老年动物血浆中的皮质醇水平显著高于幼年动物。这些观察结果证明了联合使用[¹¹C]⁺McN5652和[¹¹C]⁻McN5652作为通过PET无创测量皮质SERT与年龄相关变化指标的有效性。此外，这些观察结果表明，SERT对氟伏沙明敏感性与年龄相关的损害可能与老年抑郁症患者抗抑郁治疗疗效降低有关。
