Zea-Ponce Yolanda, Kegeles Lawrence S, Guo Ningning, Raskin Leonid, Bakthavachalam Venkatesalu, Laruelle Marc
Departments of Psychiatry and Radiology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Nucl Med Biol. 2002 Jul;29(5):575-83. doi: 10.1016/s0969-8051(02)00306-2.
Our goal was to synthesize with high specific activity R(-)-1-(2,5-Dimethoxy-4-[123I]iodophenyl)-2-aminopropane [R(-)[123I]DOI], an in vitro potent and selective 5-HT(2A/2C) serotonin agonist, and study in vivo its plasma pharmacokinetics and brain distribution in baboon by SPECT. The purpose was to evaluate this radiotracer as a potential tool in discerning the role of the agonist high affinity state of 5-HT(2) receptors in depression and other neurological disorders. The radiotracer was prepared by electrophilic radioiodination of the N-trifluoroacetyl precursor of R(-)-1-(2,5-Dimethoxyphenyl)-2-aminopropane [R(-)DMA-TFA] with high-purity sodium [123I]iodide in the presence of chloramine-T, followed by amino deprotection with KOH in isopropanol (labeling yield: 73%, radiochemical yield: 62%, radiochemical purity: 99%). In vivo studies in baboon showed high accumulation of radioactivity in thalamus, the frontoparietal cortex, temporal, occipital and the striatum regions, with slightly lower accumulation in the midbrain and cerebellum. Ketanserin did not displaced the radioactivity in any of these brain regions. Plasma metabolite analysis was performed using methanol protein precipitation, the methanol fractions contained from 68% to 92% of the mixture of a labeled metabolite and parent compound. The recovery coefficient of unmetabolized R(-)[123I]DOI was 68%. The percent parent compound present in the extracted fraction, measured by HPLC, decreased gradually with time from 99.8% to 0.3% still present after 4.7 hours post injection whereas the percentage of the only one detected metabolite increased conversely. Free fraction determination (f(1)), was 31 +/- 0.9% (n = 3). For comparison purposes, ex-vivo brain distribution, displacement and metabolite analysis was also carried out in rodents. Although R(-)[123I]DOI displayed good brain uptake and localized in serotonergic areas of the brain, its target to non target ratio and its insensitivity to ketanserin displacement suggest high nonspecific uptake, therefore non potentially useful as brain imaging radiotracer for visualization of the agonist high-affinity state of 5-HT(2A) receptors and for visualizing 5-HT(2C) receptors by SPECT.
我们的目标是高比活度合成R(-)-1-(2,5-二甲氧基-4-[123I]碘苯基)-2-氨基丙烷[R(-)[123I]DOI]，一种体外强效且选择性的5-HT(2A/2C)血清素激动剂，并通过单光子发射计算机断层扫描（SPECT）研究其在狒狒体内的血浆药代动力学和脑部分布。目的是评估这种放射性示踪剂作为一种潜在工具，以辨别5-HT(2)受体激动剂高亲和力状态在抑郁症和其他神经疾病中的作用。该放射性示踪剂是通过在氯胺-T存在下，用高纯度[123I]碘化钠对R(-)-1-(2,5-二甲氧基苯基)-2-氨基丙烷[R(-)DMA-TFA]的N-三氟乙酰基前体进行亲电放射性碘化制备的，随后在异丙醇中用氢氧化钾进行氨基脱保护（标记产率：73%，放射化学产率：62%，放射化学纯度：99%）。在狒狒体内的研究表明，放射性在丘脑、额顶叶皮质、颞叶、枕叶和纹状体区域有高度积累，在中脑和小脑中的积累略低。酮色林在这些脑区中均未使放射性移位。血浆代谢物分析采用甲醇蛋白沉淀法进行，甲醇馏分中含有标记代谢物和母体化合物混合物的68%至92%。未代谢的R(-)[123I]DOI的回收系数为68%。通过高效液相色谱法测定，提取物中母体化合物的百分比随时间从99.8%逐渐下降，注射后4.7小时仍有0.3%存在，而唯一检测到的代谢物的百分比则相反增加。游离分数测定（f(1)）为31±0.9%（n = 3）。为作比较，还在啮齿动物中进行了离体脑部分布、移位和代谢物分析。尽管R(-)[123I]DOI在脑中摄取良好且定位于脑的血清素能区域，但其靶标与非靶标比值以及对酮色林移位的不敏感性表明存在高非特异性摄取，因此作为用于通过SPECT可视化5-HT(2A)受体激动剂高亲和力状态和可视化5-HT(2C)受体的脑成像放射性示踪剂可能没有用处。
