Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
J Nucl Med. 2010 Nov;51(11):1763-70. doi: 10.2967/jnumed.109.074021. Epub 2010 Oct 18.
PET brain imaging of the serotonin 2A (5-hydroxytryptamine 2A, or 5-HT(2A)) receptor has been widely used in clinical studies, and currently, several well-validated radiolabeled antagonist tracers are used for in vivo imaging of the cerebral 5-HT(2A) receptor. Access to 5-HT(2A) receptor agonist PET tracers would, however, enable imaging of the active, high-affinity state of receptors, which may provide a more meaningful assessment of membrane-bound receptors. In this study, we radiolabel the high-affinity 5-HT(2A) receptor agonist 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-[(11)C-OCH(3)]methoxybenzyl)ethanamine ((11)C-CIMBI-5) and investigate its potential as a PET tracer.
The in vitro binding and activation at 5-HT(2A) receptors by CIMBI-5 was measured with binding and phosphoinositide hydrolysis assays. Ex vivo brain distribution of (11)C-CIMBI-5 was investigated in rats, and PET with (11)C-CIMBI-5 was conducted in pigs.
In vitro assays showed that CIMBI-5 was a high-affinity agonist at the 5-HT(2A) receptor. After intravenous injections of (11)C-CIMBI-5, ex vivo rat studies showed a specific binding ratio of 0.77 ± 0.07 in the frontal cortex, which was reduced to cerebellar levels after ketanserin treatment, thus indicating that (11)C-CIMBI-5 binds selectively to the 5-HT(2A) receptor in the rat brain. The PET studies showed that the binding pattern of (11)C-CIMBI-5 in the pig brain was in accordance with the expected 5-HT(2A) receptor distribution. (11)C-CIMBI-5 gave rise to a cortical binding potential of 0.46 ± 0.12, and the target-to-background ratio was similar to that of the widely used 5-HT(2A) receptor antagonist PET tracer (18)F-altanserin. Ketanserin treatment reduced the cortical binding potentials to cerebellar levels, indicating that in vivo (11)C-CIMBI-5 binds selectively to the 5-HT(2A) receptor in the pig brain.
(11)C-CIMBI-5 showed a cortex-to-cerebellum binding ratio equal to the widely used 5-HT(2A) antagonist PET tracer (18)F-altanserin, indicating that (11)C-CIMBI-5 has a sufficient target-to-background ratio for future clinical use and is displaceable by ketanserin in both rats and pigs. Thus, (11)C-CIMBI-5 is a promising tool for investigation of 5-HT(2A) agonist binding in the living human brain.
评估新型高亲和力 5-羟色胺 2A（5-HT2A）受体激动剂 [11C]CIMBI-5 作为正电子发射断层扫描（PET）示踪剂的可行性。
采用放射性配体结合和磷酸肌醇水解测定方法，检测 CIMBI-5 与 5-HT2A 受体的体外结合和激活作用。在大鼠体内研究 [11C]CIMBI-5 的脑外分布，并在猪体内进行 [11C]CIMBI-5 的 PET 研究。
体外实验表明，CIMBI-5 是一种高亲和力的 5-HT2A 受体激动剂。静脉注射 [11C]CIMBI-5 后，大鼠脑外研究显示额皮质的特异性结合比为 0.77±0.07，用酮色林处理后降低至小脑水平，提示 [11C]CIMBI-5 选择性结合大鼠脑内的 5-HT2A 受体。PET 研究显示，[11C]CIMBI-5 在猪脑内的结合模式与预期的 5-HT2A 受体分布一致。[11C]CIMBI-5 引起皮质结合势为 0.46±0.12，靶背比与广泛使用的 5-HT2A 受体拮抗剂 PET 示踪剂 [18F]altanserin 相似。酮色林处理后皮质结合势降低至小脑水平，提示 [11C]CIMBI-5 选择性结合猪脑内的 5-HT2A 受体。
[11C]CIMBI-5 显示与广泛使用的 5-HT2A 拮抗剂 PET 示踪剂 [18F]altanserin 相当的皮质/小脑结合比，表明 [11C]CIMBI-5 具有足够的靶背比，可用于未来的临床研究，且在大鼠和猪体内均可被酮色林置换。因此，[11C]CIMBI-5 是研究活体人脑内 5-HT2A 激动剂结合的一种很有前途的工具。
