Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University of Tübingen, Tübingen, Germany.
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University of Tübingen, Tübingen, Germany
J Nucl Med. 2016 Jan;57(1):115-21. doi: 10.2967/jnumed.115.163683. Epub 2015 Oct 29.
Serotonin, or 5-hydroxytryptamine (5-HT), plays a key role in the central nervous system and is involved in many essential neurologic processes such as mood, social behavior, and sleep. The serotonin transporter ligand (11)C-3-amino-4(2-dimethylaminomethyl-phenylsufanyl)-benzonitrile ((11)C-DASB) has been used to determine nondisplaceable binding potential (BPND), which is defined as the quotient of the available receptor density (Bavail) and the apparent equilibrium dissociation rate constant (1/appKD) under in vivo conditions. Because of the increasing number of animal models of human diseases, there is a pressing need to evaluate the applicability of (11)C-DASB to rats and mice. Here, we assessed the feasibility of using (11)C-DASB for quantification of serotonin transporter (SERT) density and affinity in vivo in rats and mice.
Rats and mice underwent 4 PET scans with increasing doses of the unlabeled ligand to calculate Bavail and appKD using the multiple-ligand concentration transporter assay. An additional PET scan was performed to calculate test-retest reproducibility and reliability. BPND was calculated using the simplified reference tissue model, and the results for different reference regions were compared.
Displaceable binding of (11)C-DASB was found in all brain regions of both rats and mice, with the highest binding being in the thalamus and the lowest in the cerebellum. In rats, displaceable binding was largely reduced in the cerebellar cortex, which in mice was spatially indistinguishable from cerebellar white matter. Use of the cerebellum with fully saturated binding sites as the reference region did not lead to reliable results. Test-retest reproducibility in the thalamus was more than 90% in both mice and rats. In rats, Bavail, appKD, and ED50 were 3.9 ± 0.4 pmol/mL, 2.2 ± 0.4 nM, and 12.0 ± 2.6 nmol/kg, respectively, whereas analysis of the mouse measurements resulted in inaccurate fits due to the high injected tracer mass.
Our data showed that in rats, (11)C-DASB can be used to quantify SERT density with good reproducibility. BPND agreed with the distribution of SERT in the rat brain. It remains difficult to estimate quantitative parameters accurately from mouse measurements because of the high injected tracer mass and underestimation of the binding parameters due to high displaceable binding in the reference region.
探讨在大鼠和小鼠体内使用（11）C-DASB 进行 5-羟色胺转运体（SERT）密度和亲和力定量的可行性。
大鼠和小鼠分别进行了 4 次正电子发射断层扫描（PET），采用多配体浓度转运体测定法计算 Bavail 和 appKD。另外进行了 1 次 PET 扫描以计算测试-重测的可重复性和可靠性。采用简化参考组织模型计算 BPND，并比较不同参考区的结果。
在大鼠和小鼠的所有脑区均发现（11）C-DASB 的可置换结合，其中丘脑的结合最高，小脑的结合最低。在大鼠中，小脑皮质的可置换结合显著降低，而在小鼠中，其与小脑白质难以区分。使用完全饱和结合的小脑作为参考区并不能得到可靠的结果。在大鼠和小鼠的丘脑内，测试-重测的可重复性均超过 90%。在大鼠中，Bavail、appKD 和 ED50 分别为 3.9±0.4 pmol/mL、2.2±0.4 nM 和 12.0±2.6 nmol/kg，而对小鼠测量结果的分析由于注入示踪剂的质量高而导致拟合不准确。
本研究数据表明，在大鼠中，（11）C-DASB 可用于定量 SERT 密度，且具有良好的可重复性。BPND 与大鼠脑内 SERT 的分布一致。由于注入示踪剂的质量高，以及由于参考区的可置换结合较高而低估了结合参数，因此仍难以从小鼠测量中准确估计定量参数。
