Vesamicol receptor mapping of brain cholinergic neurons with radioiodine-labeled positional isomers of benzovesamicol
Vesamicol receptor mapping of brain cholinergic neurons with radioiodine-labeled positional isomers of benzovesamicol
复制标题
DOI：
10.1021/jm9507486
复制
发表时间：
1996-08-16
影响因子：
7.3
通讯作者：
Wieland, DM
中科院分区：
文献类型：
--
作者：
Jung, YW;Frey, KA;Wieland, DM
阿尔茨海默病的特征是进行性脑胆碱能神经元变性。苯并维沙考的放射性示踪剂类似物以高亲和力与位于乙酰胆碱储存囊泡摄取转运蛋白上的维沙考受体结合，可以提供胆碱能神经元完整性的体内标记。合成了外消旋碘苯并维沙考的五种位置异构体（4'-、5-、6-、7-和8-IBVM），用碘125进行交换标记，并评估其可能作为中枢胆碱能神经元的体内标记物。只有两种异构体，5-IBVM (5) 和 6-IBVM (10)，在小鼠大脑中的分布模式与胆碱能神经支配一致：纹状体远大于海马大于或等于皮质 > 下丘脑远大于小脑。纹状体、皮质和海马的 5-IBVM (5) 24 小时组织与小脑浓度比率比 6-IBVM (10) 的相应比率高 3-4 倍。 8-IBVM (16) 和 4'-IBVM (17) 在所检查的任何大脑区域中均未表现出选择性保留。在心脏中，只有 5-IBVM (5) 表现出与高外周胆碱能神经元选择性一致的心房与心室浓度比。 7-IBVM (14) 异构体表现出异常的大脑分布模式，其特征是在五个大脑区域（尤其是小脑）中的高且长时间的保留。在一系列 26 种不同的生物测定中筛选了该异构体的结合情况； 7-IBVM (14) 仅对 σ 受体表现出亲和力，IC50 约为 30 nM。药物阻断研究表明 7-IBVM (14) 的大脑滞留反映了与 vesamicol 和 sigma 受体的高亲和力结合。使用大鼠皮质匀浆进行的竞争性结合研究得出，5-IBVM (5) 与维沙米考受体结合的 IC50 值为 2.5 nM，6-IBVM (10) 为 4.8 nM，7-IBVM (14) 为 3.5 nM。注射 (-)-5-[I-123]IBVM ((-)-[I-123]5) 后，大鼠脑的离体放射自显影清晰地描绘出富含胆碱能的小区域，如基底外侧杏仁核、脚间核和面核。除皮质外，4 小时时的 (-)-5-[I-123]IBVM((I-123)5) 区域脑水平与内源性胆碱乙酰转移酶水平呈相关性 (r(2) = 0.99)。结论：小鼠大脑中胆碱能神经末梢的 Vesamicol 受体图谱可以通过 5-IBVM (5) 实现，而通过 6-IBVM (10) 则不太稳健，而 7-IBVM (14) 的大脑定位反映了与 Vesamicol 和 sigma 受体的高亲和力结合。
Alzheimer's disease is characterized by progressive cerebral cholinergic neuronal degeneration. Radiotracer analogs of benzovesamicol, which bind with high affinity to the vesamicol receptor located on the uptake transporter of acetylcholine storage vesicles, may provide an in vivo marker of cholinergic neuronal integrity. Five positional isomers of racemic iodobenzovesamicol (4'-, 5-, 6-, 7-, and 8-IBVM) were synthesized, exchange-labeled with iodine-125, and evaluated as possible in vivo markers for central cholinergic neurons. Only two isomers, 5-IBVM (5) and 6-IBVM (10), gave distribution patterns in mouse brain consistent with cholinergic innervation: striatum much greater than hippocampus greater than or equal to cortex > hypothalamus much greater than cerebellum. The 24-h tissue-to-cerebellum concentration ratios for 5-IBVM (5) were 3-4-fold higher for striatum, cortex, and hippocampus than the respective ratios for 6-IBVM (10). Neither 8-IBVM (16) nor 4'-IBVM (17) exhibited selective retention in any of the brain regions examined. In the heart, only 5-IBVM (5) exhibited an atria-to-ventricles concentration ratio consistent with high peripheral cholinergic neuronal selectivity. The 7-IBVM (14) isomer exhibited an anomalous brain distribution pattern, marked by high and prolonged retention in the five brain regions, most notably the cerebellum. This isomer was screened for binding in a series of 26 different biological assays; 7-IBVM (14) exhibited affinity only for the sigma-receptor with an IC50 of similar to 30 nM. Drug-blocking studies suggested that brain retention of 7-IBVM (14) reflects high-affinity binding to both vesamicol and sigma-receptors. Competitive binding studies using rat cortical homogenates gave IC50 values for binding to the vesamicol receptor of 2.5 nM for 5-IBVM (5), 4.8 nM for 6-IBVM (10), and 3.5 nM for 7-IBVM (14). Ex vivo autoradiography of rat brain after injection of (-)-5-[I-123]IBVM ((-)-[I-123]5) clearly delineated small cholinergic-rich areas such as basolateral amygdala, interpeduncular nucleus, and facial nuclei. Except for cortex, regional brain levels of (-)-5-[I-123]IBVM((I-123)5) at 4 h exhibited correlation (r(2) = 0.99) with endogenous levels of choline acetyltransferase. Conclusion: Vesamicol receptor mapping of cholinergic nerve terminals in murine brain can be achieved with 5-IBVM (5) and less robustly with 6-IBVM (10), whereas the brain localization of 7-IBVM (14) reflects high-affinity binding to both vesamicol and sigma-receptors.