Jaya Prabhakaran, Christine DeLorenzo, Francesca Zanderigo, Gitte M Knudsen, Nic Gilling, Mali Pratap, Matthew J Jorgensen, James Daunais, Jay R Kaplan, Ramin V Parsey, J John Mann, Dileep Kumar
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We compared the in vivo binding of [11C]CIMBI-5, a 5-HT2AR agonist, and of the antagonist [11C]M100907, in monkeys and baboons.</p><p><strong>Methods: </strong>[11C]CIMBI-5 and [11C]M100907 baseline PET scans were performed in anesthetized male baboons (n=2) and male vervet monkeys (n=2) with an ECAT EXACT HR+ and GE 64-slice PET/CT Discovery VCT scanners. Blocking studies were performed in vervet monkeys by pretreatment with MDL100907 (0.5 mg/kg, i.v.) 60 minutes prior to the scan. Regional distribution volumes and binding potentials were calculated for each ROI using the likelihood estimation in graphical analysis and Logan plot, with either plasma input function or reference region as input, and simplified reference tissue model approaches.</p><p><strong>Results: </strong>PET imaging of [11C]CIMBI-5 in baboons and monkeys showed the highest binding in 5-HT2AR-rich cortical regions, while the lowest binding was observed in cerebellum, consistent with the expected distribution of 5-HT2AR. Very low free fractions and rapid metabolism were observed for [11C]CIMBI-5 in baboon plasma. Binding potential values for [11C]CIMBI-5 were 25-33% lower than those for [11C]MDL100907 in the considered brain regions.</p><p><strong>Conclusion: </strong>The lower binding potential of [11C]CIMBI-5 in comparison to [11C]MDL100907 is likely due to the preferential binding of the former to the high affinity site in vivo in contrast to the antagonist, [11C]MDL100907, which binds to both high and low affinity sites.</p>","PeriodicalId":48320,"journal":{"name":"Harvard Law Review","volume":"67 1","pages":"352-364"},"PeriodicalIF":3.5000,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453972/pdf/","citationCount":"0","resultStr":"{\"title\":\"In vivo PET Imaging of [11C]CIMBI-5, a 5-HT2AR Agonist Radiotracer in Nonhuman Primates.\",\"authors\":\"Jaya Prabhakaran, Christine DeLorenzo, Francesca Zanderigo, Gitte M Knudsen, Nic Gilling, Mali Pratap, Matthew J Jorgensen, James Daunais, Jay R Kaplan, Ramin V Parsey, J John Mann, Dileep Kumar\",\"doi\":\"10.18433/jpps30329\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>5-HT2AR exists in high and low affinity states. 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引用次数: 0
摘要
目的:5-HT2AR 存在高亲和力和低亲和力两种状态。激动剂 PET 示踪剂可测量与活跃的高亲和力位点的结合,从而提供与受体功能相关的测量。迄今为止,关于 5-HT2AR 激动剂与拮抗剂示踪剂的体内比较数据有限,这些数据被用作测量该受体高亲和力和低亲和力状态的原理验证。我们比较了 5-HT2AR 激动剂[11C]CIMBI-5 和拮抗剂[11C]M100907 在猴子和狒狒体内的结合情况。方法:使用 ECAT EXACT HR+ 和 GE 64 片 PET/CT Discovery VCT 扫描仪对麻醉的雄性狒狒(n=2)和雄性绒猴(n=2)进行[11C]CIMBI-5 和 [11C]M100907 基线 PET 扫描。在扫描前 60 分钟用 MDL100907(0.5 毫克/千克,静脉注射)对疣猴进行阻断研究。利用图形分析中的似然估计和 Logan 图,以血浆输入函数或参考区域作为输入,并采用简化的参考组织模型方法计算每个 ROI 的区域分布容积和结合电位:狒狒和猴子的[11C]CIMBI-5 PET 成像显示,在 5-HT2AR 丰富的皮质区域结合率最高,而在小脑观察到的结合率最低,这与 5-HT2AR 的预期分布一致。在狒狒血浆中,[11C]CIMBI-5 的游离部分非常低,而且代谢速度很快。在所考虑的脑区中,[11C]CIMBI-5 的结合潜能值比[11C]MDL100907 低 25-33%:结论:与[11C]MDL100907相比,[11C]CIMBI-5的结合电位较低,这可能是由于前者在体内更倾向于与高亲和力位点结合,而拮抗剂[11C]MDL100907则同时与高亲和力和低亲和力位点结合。
In vivo PET Imaging of [11C]CIMBI-5, a 5-HT2AR Agonist Radiotracer in Nonhuman Primates.
Purpose: 5-HT2AR exists in high and low affinity states. Agonist PET tracers measure binding to the active high affinity site and thus provide a functionally relevant measure of the receptor. Limited in vivo data have been reported so far for a comparison of agonist versus antagonist tracers for 5-HT2AR used as a proof of principle for measurement of high and low affinity states of this receptor. We compared the in vivo binding of [11C]CIMBI-5, a 5-HT2AR agonist, and of the antagonist [11C]M100907, in monkeys and baboons.
Methods: [11C]CIMBI-5 and [11C]M100907 baseline PET scans were performed in anesthetized male baboons (n=2) and male vervet monkeys (n=2) with an ECAT EXACT HR+ and GE 64-slice PET/CT Discovery VCT scanners. Blocking studies were performed in vervet monkeys by pretreatment with MDL100907 (0.5 mg/kg, i.v.) 60 minutes prior to the scan. Regional distribution volumes and binding potentials were calculated for each ROI using the likelihood estimation in graphical analysis and Logan plot, with either plasma input function or reference region as input, and simplified reference tissue model approaches.
Results: PET imaging of [11C]CIMBI-5 in baboons and monkeys showed the highest binding in 5-HT2AR-rich cortical regions, while the lowest binding was observed in cerebellum, consistent with the expected distribution of 5-HT2AR. Very low free fractions and rapid metabolism were observed for [11C]CIMBI-5 in baboon plasma. Binding potential values for [11C]CIMBI-5 were 25-33% lower than those for [11C]MDL100907 in the considered brain regions.
Conclusion: The lower binding potential of [11C]CIMBI-5 in comparison to [11C]MDL100907 is likely due to the preferential binding of the former to the high affinity site in vivo in contrast to the antagonist, [11C]MDL100907, which binds to both high and low affinity sites.
期刊介绍:
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