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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 (CH 3 -Orexin A) prior to monitoring its brain uptake following intranasal administration in rodent and nonhuman primate. Through positron emission tomography (PET) imaging of [ 11 C]CH 3 -Orexin A, we determined that the brain exposure to Orexin A is poor after intranasal administration. Additional ex vivo analysis of brain uptake using [ 125 I]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.

According to the structure-activity relationships (SARs) of modafinil, a therapeutic drug of hypnolepsy, we designed and synthesized two series of compounds 2-[(diphenylmethane)sulfinyl] acetamides and 2-[(diphenylmethyl)thio] acetamides, and measured their biological activities. The target compounds (6a-6o) were synthesized beginning with diphenyl carbinol by substitution, oxidation, acylation and so on. Their structures were confirmed by ESI-MS, 1H NMR and elemental analysis. The central stimulatory effects of the target compounds were determined by the independent activity assay on mice. Compounds 6c, 6f and 6n have considerable activities, while the central stimulative effect of 6h is slightly better than the positive control modafinil.