Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110, USA.
J Med Chem. 2013 Aug 8;56(15):6216-33. doi: 10.1021/jm400664x. Epub 2013 Jul 18.
To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALogD values between 0.53 and 3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k, and 24a-b) displayed high affinity for VAChT (Ki = 0.93-18 nM for racemates) and moderate to high selectivity for VAChT over σ1 and σ2 receptors (Ki = 44-4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[(11)C]24b (Ki = 0.78 nM for VAChT, 1200-fold over σ receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[(11)C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain.
为了鉴定对囊泡型乙酰胆碱转运体（VAChT）具有高活性和选择性的合适亲脂性化合物，将杂芳环或苯基引入到 VAChT 配体的含羰基骨架中。合成了 20 种 ALogD 值在 0.53 到 3.2 之间的新化合物，并对其体外结合亲和力进行了测定。其中 6 种（19a、19e、19g、19k 和 24a-b）对 VAChT 具有高亲和力（对映异构体的 Ki 值为 0.93-18 nM），对 VAChT 相对于 σ1 和 σ2 受体具有中等至高的选择性（Ki 值为 44-4400 倍）。这些化合物具有甲基或氟取代基，为掺入 PET 放射性同位素 C-11 或 F-18 提供了位置。化合物（-）-[(11)C]24b（对 VAChT 的 Ki 值为 0.78 nM，相对于 σ 受体的选择性为 1200 倍）在大鼠和非人灵长类动物体内成功合成并进行了评估。数据表明，（-）-[(11)C]24b 在纹状体中的结合最高，并且在大脑中有良好的药代动力学特性。
