Nguyen V H, Mardon K, Kassiou M, Christie M D
Department of Pharmacology, The University of Sydney, NSW, Australia.
Nucl Med Biol. 1999 Feb;26(2):209-15. doi: 10.1016/s0969-8051(98)00095-x.
N-(4-phenylbutyl)-3-hydroxy-4-azahexacyclo[5.4.1.0(2,6).0(3, 10).0(5,9) .0(8,11)]dodecane (ANSTO-14) showed the highest activity for the sigma 1 site (Ki = 9.4 nM) and 19-fold sigma 1/sigma 2 selectivity. The present study showed that [3H]ANSTO-14 binds to a single high-affinity site in guinea pig brain membranes with an equilibrium Ki of 8.0 +/- 0.3 nM, in good agreement with the kinetic studies (Kd = 13.3 +/- 5.4 nM, n = 4), and a Bmax of 3.199 +/- 105 fmol/mg protein (n = 4). The in vivo biodistribution of [3H]ANSTO-14 showed a high uptake in the diencephalon. Pretreatment of rats with sigma ligands including (+)-pentazocine (sigma 1), ANSTO-14 (sigma 1), and DTG (sigma 1 and sigma 2) did not significantly reduce radiotracer uptake in the brain, but did in the spleen. A labelled metabolite was found in the liver and brain. Due to its insensitivity to sigma ligands, the accumulation of [3H]ANSTO-14 in the brain indicates high nonspecific binding. Therefore, [3H]ANSTO-14 is a suitable ligand for labelling sigma 1 sites in vitro but is not suitable for brain imaging of sigma binding sites in vivo.
N-(4-苯基丁基)-3-羟基-4-氮杂十六环[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]十二烷（ANSTO-14）对σ1位点表现出最高活性（Ki = 9.4 nM），且具有19倍的σ1/σ2选择性。本研究表明，[3H]ANSTO-14与豚鼠脑膜中的单一高亲和力位点结合，平衡解离常数Ki为8.0±0.3 nM，与动力学研究结果（Kd = 13.3±5.4 nM，n = 4）吻合良好，最大结合量Bmax为3.199±105 fmol/mg蛋白（n = 4）。[3H]ANSTO-14的体内生物分布显示，间脑中摄取量较高。用包括(+)-喷他佐辛（σ1）、ANSTO-14（σ1）和DTG（σ1和σ2）在内的σ配体预处理大鼠，并未显著降低脑中放射性示踪剂的摄取，但脾中的摄取量降低。在肝脏和脑中发现了一种标记代谢物。由于其对σ配体不敏感，[3H]ANSTO-14在脑中的积累表明存在高非特异性结合。因此，[3H]ANSTO-14是体外标记σ1位点的合适配体，但不适用于体内σ结合位点的脑成像。
