Center for Radiopharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich (Swiss Federal Institute of Technology), Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland.
Bioorg Med Chem. 2012 May 1;20(9):2889-96. doi: 10.1016/j.bmc.2012.03.024. Epub 2012 Mar 17.
The histamine H(3) receptor (H(3)R) plays a role in cognition and memory processes and is implicated in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. In vivo studies of the H(3)R occupancy using a radiolabeled PET tracer would be very useful for CNS drug discovery and development. We report here the radiosynthesis, in vitro and in vivo evaluation of a novel (18)F-labeled high-affinity H(3)R antagonist (18)F-ST889. The radiosynthesis was accomplished via nucleophilic substitution of the mesylate leaving group with a radiochemical yield of 8-20%, radiochemical purity >99%, and specific radioactivity > 65 GBq/μmol. (18)F-ST889 exhibited high in vivo stability and rather low lipophilicity (logD(7.4)=0.35 ± 0.09). In vitro autoradiography showed specific binding in H(3)R-rich brain regions such as striatum and cortex. However, in vivo PET imaging of the rat brain with (18)F-ST889 was not successful. Possible reasons are discussed.
组胺 H(3)受体（H(3)R）在认知和记忆过程中发挥作用，并与包括阿尔茨海默病、精神分裂症和发作性睡病在内的多种神经紊乱相关。使用放射性标记的 PET 示踪剂进行体内 H(3)R 占有率研究对于中枢神经系统药物的发现和开发非常有用。我们在此报告了一种新型（18）F 标记的高亲和力 H(3)R 拮抗剂（18）F-ST889 的放射合成、体外和体内评估。该放射性合成是通过甲磺酸酯离去基团的亲核取代来完成的，放射化学产率为 8-20%，放射化学纯度>99%，比活度>65GBq/μmol。（18）F-ST889 表现出较高的体内稳定性和较低的亲脂性（logD(7.4)=0.35 ± 0.09）。体外放射自显影显示（18）F-ST889 在富含 H(3)R 的脑区（如纹状体和皮质）具有特异性结合。然而，（18）F-ST889 对大鼠脑的体内 PET 成像并不成功。讨论了可能的原因。
