Airaksinen Anu J, Jablonowski Jill A, van der Mey Margreet, Barbier Ann J, Klok Rob P, Verbeek Joost, Schuit Robert, Herscheid Jacobus D M, Leysen Josee E, Carruthers Nicholas I, Lammertsma Adriaan A, Windhorst Albert D
Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Nucl Med Biol. 2006 Aug;33(6):801-10. doi: 10.1016/j.nucmedbio.2006.05.008.
The potent histamine H(3) receptor antagonist JNJ-10181457 (1) was successfully labeled with (11)C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28+/-8%) and high specific radioactivity (56+/-26 GBq/mumol). The binding of [(11)C]1 to H(3) receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [(11)C]1 in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H(3) antagonists, JNJ-5207852 (2) and unlabeled Compound (1), in a concentration-dependent manner. The biodistribution of [(11)C]1 in rats was measured at 5, 10, 30 and 60 min. The uptake of [(11)C]1 in regions rich in H(3) 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 [(11)C]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 [(11)C]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-H(3)(-/-) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [(11)C]1 could not specifically label H(3) receptors in rodent brain in vivo. Possible causes are discussed.
强效组胺H(3)受体拮抗剂JNJ - 10181457（1）通过一种新型的一锅法反应序列成功地用(11)C标记，化学产率高（衰变校正产率，28±8%）且比活度高（56±26 GBq/μmol）。在大鼠脑内体外以及大鼠和小鼠体内研究了[(11)C]1与H(3)受体的结合。[(11)C]1在大鼠冠状脑切片中的体外结合显示在纹状体中有高结合，并且这种结合被组胺以及两种已知的H(3)拮抗剂JNJ - 5207852（2）和未标记的化合物（1）以浓度依赖性方式阻断。在5、10、30和60分钟时测量了[(11)C]1在大鼠体内的生物分布。[(11)C]1在富含H(3)受体区域的摄取在30分钟时最高，嗅球、海马体、纹状体和大脑皮层的摄取量分别为0.98%、1.41%、1.28%和1.72%剂量/克。然而，用化合物（2）（30分钟或24小时预处理）或冷化合物（1）（30分钟预处理）预处理均不能阻断[(11)C]1在大鼠脑中的结合。[(11)C]1在第二个物种（Balb/c小鼠）中的生物分布显示放射性配体的总体摄取较高，平均脑摄取量为8.9%剂量/克。在C57BL/6 - H(3)(-/-)基因敲除小鼠中也观察到较高的脑摄取。还进行了代谢物分析和血浆蛋白结合分析。似乎[(11)C]1在体内不能特异性标记啮齿动物脑中的H(3)受体。讨论了可能原因。
