Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
School of Chemistry, University of Sydney, Sydney, Australia.
Sci Rep. 2018 Apr 26;8(1):6580. doi: 10.1038/s41598-018-24814-0.
The P2X receptor plays a significant role in microglial activation, and as a potential drug target, the P2X receptor is also an interesting target in positron emission tomography. The current study aimed at the development and evaluation of a potent tracer targeting the P2X receptor, to which end four adamantanyl benzamide analogues with high affinity for the human P2X receptor were labelled with carbon-11. All four analogues could be obtained in excellent radiochemical yield and high radiochemical purity and molar activity, and all analogues entered the rat brain. [C]SMW139 showed the highest metabolic stability in rat plasma, and showed high binding to the hP2X receptor in vivo in a hP2X receptor overexpressing rat model. Although no significant difference in binding of [C]SMW139 was observed between post mortem brain tissue of Alzheimer's disease patients and that of healthy controls in in vitro autoradiography experiments, [C]SMW139 could be a promising tracer for P2X receptor imaging using positron emission tomography, due to high receptor binding in vivo in the hP2X receptor overexpressing rat model. However, further investigation of both P2X receptor expression and binding of [C]SMW139 in other neurological diseases involving microglial activation is warranted.
P2X 受体在小胶质细胞激活中发挥重要作用，作为潜在的药物靶点，P2X 受体也是正电子发射断层扫描中的一个有趣靶点。本研究旨在开发和评估一种针对 P2X 受体的有效示踪剂，为此，我们用碳-11 标记了 4 种对人 P2X 受体具有高亲和力的金刚烷苯甲酰胺类似物。所有 4 种类似物都可以以优异的放射化学产率和高放射化学纯度和摩尔活性获得，并且所有类似物都进入了大鼠脑内。[C]SMW139 在大鼠血浆中的代谢稳定性最高，在 hP2X 受体过表达大鼠模型中体内显示出对 hP2X 受体的高结合。尽管在体外放射自显影实验中，阿尔茨海默病患者死后脑组织与健康对照者之间 [C]SMW139 的结合没有明显差异，但由于在 hP2X 受体过表达大鼠模型中体内具有高受体结合，[C]SMW139 仍可能成为使用正电子发射断层扫描进行 P2X 受体成像的有前途的示踪剂。然而，需要进一步研究 [C]SMW139 在涉及小胶质细胞激活的其他神经疾病中的 P2X 受体表达和结合。
