Ito H, Nyberg S, Halldin C, Lundkvist C, Farde L
Karolinska Institutet and Department of Clinical Neuroscience, Karolinska Hospital, Stockholm, Sweden.
J Nucl Med. 1998 Jan;39(1):208-14.
Serotonergic 5-HT2A receptors are of central interest in the complex pathophysiology of schizophrenia. These receptors have also been proposed as putative targets for atypical antipsychotic drugs. Suitable radioligands for 5-HT2A receptors are required to evaluate this hypothesis in vivo with PET. MDL 100,907 is a highly selective 5-HT2A receptor antagonist that is currently being developed as a potential antipsychotic drug. We have previously reported on the preparation of [11C]MDL 100,907 and initial characterization of [11C]MDL 100,907 binding in the monkey brain. In this preliminary PET study, the regional distribution and binding kinetics of [11C]MDL 100,907 were examined in healthy men.
A PET examination was performed in each of three subjects after intravenous injection of [11C]MDL 100,907. The metabolite-corrected arterial input function was used in a kinetic analysis according to the standard three-compartment model.
The highest radioactivity concentration was observed in the neocortex, whereas radioactivity was lower in the cerebellum, pons, thalamus, striatum and white matter. The binding potential (BP) in the neocortical regions was 4-6 times higher, whereas BP in the striatum was slightly higher than that in the cerebellum, demonstrating a regional distribution in good agreement with 5-HT2A receptor densities measured in vitro. The BP in the cerebellum was small but not negligible.
This preliminary study suggests that [11C]MDL 100,907 is a suitable PET radioligand for studies on 5-HT2A receptors in man. The high selectivity of MDL 100,907 represents a major advantage as compared to presently available radioligands with poor selectivity. Thus, [11C]MDL 100,907 is recommended in the future for PET studies in healthy subjects and schizophrenic patients, including the determination of drug-induced 5-HT2A receptor occupancy.
血清素能5-HT2A受体在精神分裂症复杂的病理生理学中备受关注。这些受体也被认为是非典型抗精神病药物的潜在靶点。需要合适的5-HT2A受体放射性配体来通过正电子发射断层扫描（PET）在体内评估这一假设。MDL 100,907是一种高度选择性的5-HT2A受体拮抗剂，目前正作为一种潜在的抗精神病药物进行研发。我们之前曾报道过[11C]MDL 100,907的制备以及[11C]MDL 100,907在猴脑中结合的初步特征。在这项初步的PET研究中，对健康男性体内[11C]MDL 100,907的区域分布和结合动力学进行了研究。
在静脉注射[11C]MDL 100,907后，对三名受试者分别进行了PET检查。根据标准的三室模型，在动力学分析中使用了代谢物校正的动脉输入函数。
在新皮质中观察到最高的放射性浓度，而在小脑、脑桥、丘脑、纹状体和白质中的放射性较低。新皮质区域的结合潜能（BP）高出4 - 6倍，而纹状体中的BP略高于小脑中的BP，显示出与体外测量的5-HT2A受体密度良好一致的区域分布。小脑中的BP较小但并非可忽略不计。
这项初步研究表明，[11C]MDL 100,907是用于人体5-HT2A受体研究的合适PET放射性配体。与目前选择性较差的放射性配体相比，MDL 100,907的高选择性是一个主要优势。因此，未来建议在健康受试者和精神分裂症患者中使用[11C]MDL 100,907进行PET研究，包括测定药物诱导的5-HT2A受体占有率。
