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Positron Emission Tomography Assessment of the Intranasal Delivery Route for Orexin A
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2017-11-07 00:00:00 , DOI: 10.1021/acschemneuro.7b00357
Genevieve C. Van de Bittner 1 , Kyle C. Van de Bittner 1 , Hsiao-Ying Wey 1 , Wayne Rowe 2 , Ram Dharanipragada 2 , Xiaoyou Ying 3 , William Hurst 2 , Andrew Giovanni 2 , Kim Alving 4 , Anurag Gupta 3 , John Hoekman 5 , Jacob M. Hooker 1
Affiliation  

Intranasal drug delivery is a noninvasive drug delivery route that can enhance systemic delivery of therapeutics with poor oral bioavailability by exploiting the rich microvasculature within the nasal cavity. The intranasal delivery route has also been targeted as a method for improved brain uptake of neurotherapeutics, with a goal of harnessing putative, direct nose-to-brain pathways. Studies in rodents, nonhuman primates, and humans have pointed to the efficacy of intranasally delivered neurotherapeutics, while radiolabeling studies have analyzed brain uptake following intranasal administration. In the present study, we employed carbon-11 radioactive methylation to assess the pharmacokinetic mechanism of intranasal delivery of Orexin A, a native neuropeptide and prospective antinarcoleptic drug that binds the orexin receptor 1. Using physicochemical and pharmacological analysis, we identified the methylation sites and confirmed the structure and function of methylated Orexin A (CH3-Orexin A) prior to monitoring its brain uptake following intranasal administration in rodent and nonhuman primate. Through positron emission tomography (PET) imaging of [11C]CH3-Orexin A, we determined that the brain exposure to Orexin A is poor after intranasal administration. Additional ex vivo analysis of brain uptake using [125I]Orexin A indicated intranasal administration of Orexin A affords similar brain uptake when compared to intravenous administration across most brain regions, with possible increased brain uptake localized to the olfactory bulbs.

中文翻译:

正电子发射断层扫描评估食欲素A的鼻腔内递送途径

鼻内药物输送是一种非侵入性药物输送途径,可以通过利用鼻腔内丰富的微脉管系统来增强口服生物利用度较差的治疗剂的全身输送。鼻内递送途径也已经被作为改善神经治疗剂的大脑摄取的方法的目标,其目的是利用假定的直接的鼻-脑途径。在啮齿动物,非人类灵长类动物和人类中进行的研究指出了鼻内给药的神经疗法的功效,而放射性标记研究则对鼻内给药后的大脑摄取进行了分析。在本研究中,我们使用了碳11放射性甲基化来评估Orexin A的鼻内递送药代动力学机制,该蛋白是一种与Orexin受体1结合的天然神经肽和前瞻性抗麻醉药。3- Orexin A)在啮齿动物和非人类灵长类动物鼻内给药后监测其脑摄取之前。通过[ 11 C] CH 3 -Orexin A的正电子发射断层扫描(PET)成像,我们确定鼻内给药后脑对Orexin A的暴露不良。使用[ 125 I] Orexin A进行的脑部吸收的其他离体分析表明,与大多数大脑区域的静脉内给药相比,鼻内给予Orexin A可获得相似的脑部吸收,可能是嗅球局部吸收了更多的脑。
更新日期:2017-11-07
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