Letchworth S R, Smith H R, Porrino L J, Bennett B A, Davies H M, Sexton T, Childers S R
Department of Physiology and Pharmacology, Center for the Neurobiological Investigation of Drug Abuse, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
J Pharmacol Exp Ther. 2000 May;293(2):686-96.
PTT (2beta-propanoyl-3beta-[4-tolyl] tropane) is a tropane analog relatively selective for dopamine transporters in binding and uptake assays in vitro, with long-acting psychostimulant properties in vivo. To explore its utility in binding to dopamine transporters, [(3)H]PTT was synthesized and assayed for binding in rat striatal membranes and by in vitro autoradiography. In membranes, binding of [(3)H]PTT was saturable to a single class of binding sites with a K(D) value of 3 nM. The pharmacology of [(3)H]PTT binding in striatal membranes was consistent with that of a ligand selective for dopamine transporters, with dopamine-selective compounds being significantly more potent in displacing [(3)H]PTT binding than those for 5-HT or norepinephrine transporters. Although the ability of various transporter inhibitors to displace both [(125)I]RTI-55 and [(3)H]PTT binding correlated significantly with each other, there was a better correlation of inhibitor potencies versus [(3)H]PTT binding and dopamine uptake than versus [(125)I]RTI-55 binding and dopamine uptake. The differences in correlations were most noticeable for compounds relatively selective at the 5-hydroxytryptamine (serotonin) transporter. The autoradiographic distribution of [(3)H]PTT binding in coronal sections was consistent with the known distribution of the dopamine transporter, with high levels of binding evident in caudate nucleus, nucleus accumbens, and olfactory tubercle. Moderate densities of [(3)H]PTT binding were also observed in substantia nigra pars compacta, and ventral tegmental area, as well as in the anterior cingulate cortex and portions of the hypothalamus. In addition, nonspecific binding was less than 5% of total binding. Thus, [(3)H]PTT provides an accurate and convenient marker for the dopamine transporter.
PTT（2β-丙酰基-3β-[4-甲苯基]托烷）是一种托烷类似物，在体外结合和摄取试验中对多巴胺转运体具有相对选择性，在体内具有长效精神兴奋特性。为了探索其与多巴胺转运体结合的效用，合成了[³H]PTT，并在大鼠纹状体膜中通过体外放射自显影法进行结合测定。在膜中，[³H]PTT与一类单一的结合位点的结合是可饱和的，K(D)值为3 nM。[³H]PTT在纹状体膜中结合的药理学特性与对多巴胺转运体具有选择性的配体一致，多巴胺选择性化合物在取代[³H]PTT结合方面比5-羟色胺或去甲肾上腺素转运体的化合物更有效。尽管各种转运体抑制剂取代[¹²⁵I]RTI-55和[³H]PTT结合的能力彼此显著相关，但抑制剂效力与[³H]PTT结合和多巴胺摄取的相关性比对[¹²⁵I]RTI-55结合和多巴胺摄取的相关性更好。对于在5-羟色胺（血清素）转运体上相对有选择性的化合物，相关性差异最为明显。[³H]PTT结合在冠状切片中的放射自显影分布与多巴胺转运体的已知分布一致，在尾状核、伏隔核和嗅结节中可见高水平的结合。在黑质致密部、腹侧被盖区以及前扣带回皮质和下丘脑部分也观察到中等密度的[³H]PTT结合。此外，非特异性结合小于总结合的5%。因此，[³H]PTT为多巴胺转运体提供了一种准确且方便的标记物。
