Synthesis and Evaluation of [11C]SB207145 as the First In Vivo Serotonin 5-HT4 Receptor Radioligand for PET Imaging in Man
Synthesis and Evaluation of [11C]SB207145 as the First In Vivo Serotonin 5-HT4 Receptor Radioligand for PET Imaging in Man
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DOI：
10.2174/1874471010801020110
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发表时间：
2008-01-01
影响因子：
2.3
通讯作者：
Gunn, R.
中科院分区：
文献类型：
--
作者：
Gee, A. D.;Martarello, L.;Gunn, R.
这项工作的目的是开发一种PET放射性示踪剂，这将使使用正电子发射断层扫描（PET）的人的中枢5-羟色胺5-HT 4受体的研究。开发了一种用于标记SB 207145的程序，SB 207145是一种有效的和选择性的5-HT 4拮抗剂，具有短寿命的正电子发射放射性核素C-11。相应的去甲基化合物与C-11-甲基碘烷基化得到[C-11] SB 207145，放射化学产率为50 - 60%（衰变校正到回旋加速器轰击结束），比活度>50 GBq/μ mol，放射化学纯度大于95%。猪的PET研究显示，[C-11] SB 207145迅速进入大脑，在给药后10 - 20分钟达到峰值浓度，随后从组织中洗脱。在人体中，示踪剂的组织动力学较慢，在给药后30 - 60分钟达到峰值组织浓度。在这两个物种中，观察到的区域脑浓度的等级顺序为纹状体>丘脑>皮质区域>小脑，与体外研究中5-HT 4受体的已知分布和浓度一致。在猪中，给予0.5 mg/kg SB 207040（一种选择性5-HT 4拮抗剂）后，[C-11] SB 207145的特异性结合降低至皮质水平，表明5-HT 4受体群体具有饱和性。总之，描述了一种新的PET放射性配体，其使得首次使用PET在人体中研究5-HT 4受体成为可能。
The aim of this work was to develop a PET radiotracer which would enable the study of central serotonin 5-HT4 receptors in man using positron emission tomography (PET). A procedure was developed for labelling SB207145, a potent and selective 5-HT4 antagonist, with the short-lived positron emitting radionuclide C-11. Alkylation of the corresponding desmethyl compound with C-11-methyl iodide afforded [C-11] SB207145 in 50 60 % radiochemical yield (decay corrected to end of cyclotron bombardment), specific activities of >50 GBq/mu mole and radiochemical purities greater than 95%. PET studies in pig showed [C-11] SB207145 rapidly entered the brain reaching peak concentrations at 10 - 20 mins post administration, followed by washout from tissue. In humans the tissue kinetics of the tracer was slower, reaching peak tissue concentrations at 30 - 60 mins post administration. In both species, the observed rank order of regional brain concentrations was striatum > thalamus > cortical regions > cerebellum, consistent with the known distribution and concentration of 5-HT4 receptors from in vitro studies. In pig, on administration of 0.5 mg/kg SB207040, a selective 5-HT4 antagonist, the specific binding of [C-11] SB207145 was reduced to level of the cortex, demonstrating saturability of the 5-HT4 receptor population. In conclusion, a new PET radioligand is described which enables the study of 5-HT4 receptors in vivo in humans for the first time using PET.