Radiosynthesis and biodistribution of a histamine H₃ receptor antagonist 4-[3-(4-piperidin-1-yl-but-1-ynyl)-[¹¹C]benzyl]-morpholine: evaluation of a potential PET ligand

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• 作者：Anu J. Airaksinen ; Jill A. Jablonowski ; Margreet van der Mey ; Ann J. Barbier ; Rob P. Klok ; Joost Verbeek ; Robert Schuit ; Jacobus D.M. Herscheid ; Josee E. Leysen ; Nicholas I. Carruthers et al.
• 关键词：Histamine H₃ receptor ; Antagonist ; Brain ; Biodistribution ; Autoradiography ; PET ligand
• 刊名：Nuclear Medicine and Biology
• 出版年：2006
• 出版时间：August 2006
• 年：2006
• 卷：33
• 期：6
• 页码：801-810
• 全文大小：526 K

文摘

The potent histamine H₃ receptor antagonist JNJ-10181457 (1) was successfully labeled with ¹¹C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28±8 % ) and high specific radioactivity (56±26 GBq/μmol). The binding of [¹¹C]1 to H₃ receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [¹¹C]1 in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H₃ antagonists, JNJ-5207852 (2) and unlabeled Compound (1), in a concentration-dependent manner. The biodistribution of [¹¹C]1 in rats was measured at 5, 10, 30 and 60 min. The uptake of [¹¹C]1 in regions rich in H₃ receptors was highest at 30 min, giving 0.98 % , 1.41 % , 1.28 % and 1.72 % dose/g for the olfactory bulb, hippocampus, striatum and cerebral cortex, respectively. However, the binding of [¹¹C]1 in the rat brain could not be blocked by pretreatment with either Compound (2) (30 min or 24 h pretreatment) or cold Compound (1) (30-min pretreatment). The biodistribution of [¹¹C]1 in a second species (Balb/c mice) showed a higher overall uptake of the radioligand with an average brain uptake of 8.9 % dose/g. In C57BL/6-H₃(−/−) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [¹¹C]1 could not specifically label H₃ receptors in rodent brain in vivo. Possible causes are discussed.