Blin J, Sette G, Fiorelli M, Bletry O, Elghozi J L, Crouzel C, Baron J C
Service Hospitalier Frédéric Joliot, CEA, Hôpital d'Orsay, France.
J Neurochem. 1990 May;54(5):1744-54. doi: 10.1111/j.1471-4159.1990.tb01229.x.
Following previous validation in baboons, we have studied the characteristics of [18F]setoperone as a radioligand for investigating serotonergic 5-hydroxytryptamine2 (5-HT2) receptors in the normal, unmedicated human brain with positron emission tomography (PET); subjects orally pretreated with therapeutic amounts of ketanserin, sulpiride, or prazosin were also studied to evaluate the specificity and sensitivity of [18F]setoperone brain specific binding. In controls (n = 10), the tracer showed a clear-cut retention in both frontal cortex and striatum (known to contain a high density of 5-HT2 receptors) relative to cerebellum (known to be devoid of 5-HT2 receptors). In the seven young controls (20-39 years old), the frontal cortex/cerebellum and striatum/cerebellum ratios increased during the first hour to reach similar values of 2.53 +/- 0.12 and 2.38 +/- 0.11 (mean +/- SEM), respectively, and were essentially stable during the second hour. Pretreatment with ketanserin (a 5-HT2 blocker) significantly reduced the frontal cortex/cerebellum ratio to 0.7-1.0 at 65 min, whereas the striatum/cerebellum ratio was significantly, but only partially, reduced. During sulpiride treatment (a D2 blocker), the frontal cortex/cerebellum ratio was not altered, whereas the striatum/cerebellum ratio was significantly, but only partially, reduced. With prazosin pretreatment (an alpha 1-adrenergic blocker), neither the frontal cortex/cerebellum nor the striatum/cerebellum ratio was modified. These data in humans with PET demonstrate that [18F]setoperone labels with high sensitivity and selectivity 5-HT2 receptors in the frontal cortex; in striata, however, binding is to both 5-HT2 and D2 receptors. The deproteinated-to-whole plasma radio-activity concentration ratio increased with time following injection. The mean percentage of intact [18F]setoperone, in deproteinated plasma, was 82, 74, 53, 45, 30, and 22% at 5, 10, 20, 30, 60, and 110 min following injection, respectively. These data indicate that [18F]setoperone (a) is significantly bound to plasma proteins and (b) is significantly metabolized into several labeled metabolites that are much more hydrophilic than setoperone and, hence, presumably do not cross the blood-brain barrier. These results suggest the suitability of [18F]setoperone data for modeling of 5-HT2 receptor binding in brain.
在先前对狒狒进行验证之后，我们研究了[18F]司托哌隆作为放射性配体的特性，以通过正电子发射断层扫描（PET）研究正常、未用药的人脑血清素能5-羟色胺2（5-HT2）受体；还对口服治疗剂量的酮色林、舒必利或哌唑嗪进行预处理的受试者进行了研究，以评估[18F]司托哌隆脑特异性结合的特异性和敏感性。在对照组（n = 10）中，相对于小脑（已知不含5-HT2受体），该示踪剂在额叶皮质和纹状体（已知含有高密度的5-HT2受体）中均显示出明显的滞留。在7名年轻对照组（20 - 39岁）中，额叶皮质/小脑和纹状体/小脑比值在第一个小时内增加，分别达到相似的值2.53±0.12和2.38±0.11（平均值±标准误），并且在第二个小时内基本稳定。用酮色林（一种5-HT2阻滞剂）预处理后，在65分钟时额叶皮质/小脑比值显著降低至0.7 - 1.0，而纹状体/小脑比值虽有显著降低，但只是部分降低。在舒必利治疗（一种D2阻滞剂）期间，额叶皮质/小脑比值未改变，而纹状体/小脑比值显著降低，但只是部分降低。用哌唑嗪预处理（一种α1 - 肾上腺素能阻滞剂）后，额叶皮质/小脑和纹状体/小脑比值均未改变。这些在人体通过PET获得的数据表明，[18F]司托哌隆在额叶皮质中以高灵敏度和选择性标记5-HT2受体；然而，在纹状体中，结合的是5-HT2和D2受体。注射后脱蛋白血浆与全血浆放射性浓度比值随时间增加。注射后5、10、20、30、60和110分钟时，脱蛋白血浆中完整的[18F]司托哌隆的平均百分比分别为82%、74%、53%、45%、30%和22%。这些数据表明，[18F]司托哌隆（a）与血浆蛋白有显著结合，（b）被显著代谢为几种标记代谢物，这些代谢物比司托哌隆亲水性强得多，因此可能无法穿过血脑屏障。这些结果表明[18F]司托哌隆的数据适用于脑内5-HT2受体结合的建模。
