辐射合成和临床前评价[11 c] prucalopride作为一个潜在的兴奋剂宠物5-HT4受体的配体。
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辐射合成和临床前评价[11 c] prucalopride作为一个潜在的兴奋剂宠物5-HT4受体的配体。
EJNMMI研究》2013年4月4;3 (1):24。doi: 10.1186 / 2191 - 219 x - 3 - 24。
- PubMed ID
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23557209 (在PubMed]
- 文摘
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背景:5 -羟色胺受体5-HT4 (5-HT4-R)受体激动剂的潜在治疗药物enterokinetic和认知障碍和销售用于治疗便秘。本研究的目的是开发一个兴奋剂正电子发射断层扫描(PET)配体以标签激活g蛋白耦合5-HT4-R外围和中央组织。为此prucalopride,选择性5-HT4-R受体激动剂的高亲和性,被选中。方法:[11 c] Prucalopride从c[11]合成了甲基triflate和desmethyl Prucalopride,及其LogDoct pH7.4决心。三个不同的研究进行管理IV (11 c)在雄性老鼠prucalopride: (1) biodistribution放射性测量体外;(2)动力学大脑区域和周边器官的辐射水平评估基线条件下体内并与tariquidar预处理后,22外排泵抑制剂;和(3)在体内的稳定性(11 c) prucalopride在血浆和脑提取物体外检查使用高效液相色谱法。结果:c [11] Prucalopride在优化条件下合成了收益率为21% + / - 4%(衰变修正)和放射化学纯度(> 99%),其LogDoct pH7.4是0.87。体外与c [11] prucalopride biodistribution研究老鼠表现出非常低水平的放射性物质在大脑(ID.g-1最大0.13%)和十倍的水平在某些外围组织。宠物研究证实大脑非常低水平的放射性基线条件下; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut. CONCLUSION: [11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. In humans, further investigation of [11C]prucalopride for imaging the active state of 5-HT4-R is worthwhile, in view of the therapeutic applications of 5-HT4 agonists for treatment of gastrointestinal motility disorders.
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