新型5-羟色胺5-HT1A受体放射性配体18F标记的美法韦在啮齿动物中的合成、生物学评价及在非人灵长类动物中的PET成像

Synthesis and biologic evaluation of a novel serotonin 5-HT1A receptor radioligand, 18F-labeled mefway, in rodents and imaging by PET in a nonhuman primate.

作者信息

Saigal Neil, Pichika Rama, Easwaramoorthy Balasubramaniam, Collins Daphne, Christian Bradley T, Shi Bingzhi, Narayanan Tanjore K, Potkin Steven G, Mukherjee Jogeshwar

机构信息

Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, California 92697-3960, USA.

出版信息

J Nucl Med. 2006 Oct;47(10):1697-706.

PMID:17015907

Abstract

UNLABELLED

Serotonin 5-HT1A receptors have been implicated in disorders of the central nervous system and, therefore, are being studied by PET. Efforts are under way to improve in vivo stability of 5-HT1A agents currently in human use (11C-labeled N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl)cyclohexanecarboxamide [11C-WAY-100635], 4-(2'-methoxyphenyl)-1-[2'-(N-2''-pyridinyl)-p-18F-fluorobenzamido]ethylpiperazine [18F-MPPF], and 18F-labeled trans-4-fluoro-N-(2-[4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-N-(2-pyridyl)cyclohexanecarboxamide [18F-FCWAY]). We have synthesized N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(4-18F-fluoromethylcyclohexane)carboxamide (18F-mefway), which contains a 18F on a primary carbon to make the compound more stable to defluorination.

METHODS

Radiosynthesis of 18F-mefway was performed in a single tosylate for 18F-fluoride exchange. In vitro binding studies on rat brain slices using 18F-mefway were read on a phosphor imager. Monkey PET studies were performed on a whole-body PET scanner.

RESULTS

Binding affinity (inhibitory concentration of 50% [IC50]) of mefway was 26 nmol/L and was comparable to that of WAY-100635, 23 nmol/L. Yields of 18F-mefway were 20%-30% in specific activities of 74-111 GBq/micromol at the end of synthesis. In vitro binding of 18F-mefway in the hippocampus (Hp), colliculus (Co), cortex (Ctx), and other brain regions-with limited binding in the cerebellum (Cer)--was observed, with ratios of Hp/Cer = 82.3, Co/Cer = 45.8, and Ctx/Cer = 40. Serotonin displaced 18F-mefway from various brain regions with IC50 values in the range of 169-243 nmol/L. PET studies in a rhesus monkey showed 18F-mefway binding in the fontal cortex (FC), temporal cortex (TC) including hippocampus, raphe (Rp), and other brain regions, with ratios of FC/Cer = 9.0, TC/Cer = 10, and Rp/Cer = 3.3. Plasma analysis indicated the presence of approximately 30% of 18F-mefway at 150-180 min after injection.

CONCLUSION

The high ratios in specific brain regions such as the hippocampus suggest that 18F-mefway has potential as a PET agent for 5HT1A receptors.

摘要

未标注

血清素5-HT1A受体与中枢神经系统疾病有关，因此正通过正电子发射断层扫描（PET）进行研究。目前正在努力提高目前用于人体的5-HT1A药物（11C标记的N-(2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基-N-(2-吡啶基)环己烷甲酰胺[11C-WAY-100635]、4-(2'-甲氧基苯基)-1-[2'-(N-2''-吡啶基)-p-18F-氟苯甲酰胺基]乙基哌嗪[18F-MPPF]和18F标记的反式-4-氟-N-(2-[4-(2-甲氧基苯基)哌嗪-1-基)乙基]-N-(2-吡啶基)环己烷甲酰胺[18F-FCWAY]）的体内稳定性。我们合成了N-{2-[4-(2-甲氧基苯基)哌嗪基]乙基}-N-(2-吡啶基)-N-(4-18F-氟甲基环己烷)甲酰胺（18F-美法韦），其在伯碳上含有18F，使该化合物对脱氟更稳定。

方法

18F-美法韦的放射性合成在单个甲苯磺酸盐中进行18F-氟化物交换。使用18F-美法韦对大鼠脑切片进行的体外结合研究在磷光成像仪上读取。在全身PET扫描仪上对猴子进行PET研究。

结果

美法韦的结合亲和力（50%抑制浓度[IC50]）为26 nmol/L，与WAY-100635的23 nmol/L相当。合成结束时，18F-美法韦的产率为20%-30%，比活度为74-111 GBq/μmol。观察到18F-美法韦在海马体（Hp）、丘脑中脑（Co）、皮质（Ctx）和其他脑区的体外结合——在小脑（Cer）中的结合有限——Hp/Cer = 82.3、Co/Cer = 45.8和Ctx/Cer = 40。血清素从各个脑区取代18F-美法韦，IC50值在169-243 nmol/L范围内。对恒河猴的PET研究显示18F-美法韦在额叶皮质（FC）、包括海马体的颞叶皮质（TC）、中缝（Rp）和其他脑区有结合，FC/Cer = 9.0、TC/Cer = 10和Rp/Cer = 3.3。血浆分析表明注射后第150-180分钟存在约30%的18F-美法韦。