Hall H, Farde L, Halldin C, Lundkvist C, Sedvall G
Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm, Sweden.
Synapse. 2000 Dec 15;38(4):421-31. doi: 10.1002/1098-2396(20001215)38:4<421::AID-SYN7>3.0.CO;2-X.
M100907 (MDL 100907, R-(+)-alpha-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol++ +) is a new selective antagonist of 5-HT(2A) receptors. The compound has been labeled with (11)C and proved useful for in vivo studies of 5-HT(2A) receptors using positron emission tomography (PET). In the present study the distribution of 5-HT(2A) receptors was examined in the postmortem human brain using whole hemisphere autoradiography and [(3)H]M100907 and [(11)C]M100907. The autoradiograms showed very dense binding to all neocortical regions, whereas the hippocampus was only weakly labeled with [(3)H]M100907. Other central brain regions, such as the basal ganglia and thalamus, showed low [(3)H]M100907 binding, reflecting low densities of 5-HT(2A) receptors. The cerebellum or structures of the brain stem were virtually devoid of 5-HT(2A) receptors. [(11)C]M100907 gave images qualitatively similar to those of [(3)H]M100907, although with lower spatial resolution. The labeling of human 5-HT(2A) receptors with [(3)H]M100907 was inhibited by the addition of the 5-HT(2A) receptor blockers ketanserin or SCH 23390 (10 microM), leaving a very low background of nonspecific binding. The 5-HT(1A) receptor antagonist WAY-100635 and the D(2)-dopamine receptor antagonist raclopride had no effect on the binding of [(3)H]M100907. The selective labeling of 5-HT(2A) receptors with [(3)H]M100907 clearly shows that this compound is suitable for further studies of the human 5-HT(2A) receptor subtype in vitro. The in vitro autoradiography of the distribution of 5-HT(2A) receptors obtained with radiolabeled M100907 provides detailed qualitative and quantitative information on the distribution of 5-HT(2A)-receptors in the human brain as well as reference information for the interpretation of previous initial results at much lower resolution in humans in vivo with PET and [(11)C]M100907.
M100907（MDL 100907，R-(+)-α-(2,3 - 二甲氧基苯基)-1-[2-(4 - 氟苯基)乙基]-4 - 哌啶甲醇）是一种新型的5 - HT(2A)受体选择性拮抗剂。该化合物已用(11)C标记，并被证明可用于使用正电子发射断层扫描（PET）对5 - HT(2A)受体进行体内研究。在本研究中，使用全脑半球放射自显影术以及[(3)H]M100907和[(11)C]M100907，对死后人类大脑中5 - HT(2A)受体的分布进行了检测。放射自显影片显示，在所有新皮质区域均有非常密集的结合，而海马体仅被[(3)H]M100907轻度标记。其他中枢脑区，如基底神经节和丘脑，显示出较低的[(3)H]M100907结合，这反映了5 - HT(2A)受体的低密度。小脑或脑干结构几乎没有5 - HT(2A)受体。[(11)C]M100907所生成的图像在质量上与[(3)H]M100907的图像相似，尽管空间分辨率较低。加入5 - HT(2A)受体阻滞剂酮色林或SCH 23390（10 microM）可抑制[(3)H]M100907对人类5 - HT(2A)受体的标记，仅留下非常低的非特异性结合背景。5 - HT(1A)受体拮抗剂WAY - 100635和D(2)-多巴胺受体拮抗剂雷氯必利对[(3)H]M100907的结合没有影响。[(3)H]M100907对5 - HT(2A)受体的选择性标记清楚地表明，该化合物适用于进一步在体外研究人类5 - HT(2A)受体亚型。用放射性标记的M100907获得的5 - HT(2A)受体分布的体外放射自显影术，提供了关于5 - HT(2A)受体在人类大脑中分布的详细定性和定量信息，以及用于解释先前在人类体内使用PET和[(11)C]M100907以低得多的分辨率获得的初步结果的参考信息。
