{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:09:12Z","timestamp":1787062152588,"version":"build-2736575974"},"reference-count":50,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,3,10]],"date-time":"2024-03-10T00:00:00Z","timestamp":1710028800000},"content-version":"vor","delay-in-days":69,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AG054960"],"award-info":[{"award-number":["R21AG054960"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&D Transl Res & Clin Interv"],"published-print":{"date-parts":[[2024,1]]},"abstract":"Abstract<\/jats:title>\n \n Introduction<\/jats:title>\n \n Nose\u2010to\u2010brain (N2B) insulin delivery has potential for Alzheimer's disease (AD) therapy. However, clinical implementation has been challenging without methods to follow N2B delivery non\u2010invasively. Positron emission tomography (PET) was applied to measure F\u201018\u2010labeled insulin ([\n 18<\/jats:sup>\n F]FB\u2010insulin) from intranasal dosing to brain uptake in non\u2010human primates following N2B delivery.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n [\n 18<\/jats:sup>\n F]FB\u2010insulin was prepared by reacting A\n 1<\/jats:sup>\n ,B\n 29<\/jats:sup>\n \u2010di(tert\u2010butyloxycarbonyl)insulin with [\n 18<\/jats:sup>\n F]\u2010\n N<\/jats:italic>\n \u2010succinimidyl\u20104\u2010fluorobenzoate. Three methods of N2B delivery for [\n 18<\/jats:sup>\n F]FB\u2010insulin were compared \u2013 delivery as aerosol via tubing (rhesus macaque,\n n<\/jats:italic>\n = 2), as aerosol via preplaced catheter (rhesus macaque,\n n<\/jats:italic>\n = 3), and as solution via preplaced catheter (cynomolgus macaque,\n n<\/jats:italic>\n = 3). Following dosing, dynamic PET imaging (120 min) quantified delivery efficiency to the nasal cavity and whole brain. Area under the time\u2010activity curve was calculated for 46 regions of the cynomolgus macaque brain to determine regional [\n 18<\/jats:sup>\n F]FB\u2010insulin levels.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Liquid instillation of [\n 18<\/jats:sup>\n F]FB\u2010insulin by catheter outperformed aerosol methods for delivery to the subject (39.89% injected dose vs 10.03% for aerosol via tubing, 0.17% for aerosol by catheter) and subsequently to brain (0.34% injected dose vs 0.00020% for aerosol via tubing, 0.05% for aerosol by catheter). [\n 18<\/jats:sup>\n F]FB\u2010insulin was rapidly transferred across the cribriform plate to limbic and frontotemporal areas responsible for emotional and memory processing. [\n 18<\/jats:sup>\n F]FB\u2010insulin half\u2010life was longer in olfactory nerve projection sites with high insulin receptor density compared to the whole brain.\n <\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n \n The catheter\u2010based liquid delivery approach combined with PET imaging successfully tracked the fate of N2B [\n 18<\/jats:sup>\n F]FB\u2010insulin and is thought to be broadly applicable for assessments of other therapeutic agents. This method can be rapidly applied in humans to advance clinical evaluation of N2B insulin as an AD therapeutic.\n <\/jats:p>\n <\/jats:sec>\n \n Highlights for<\/jats:title>\n \n \n \n \n [\n 18<\/jats:sup>\n F]FB\u2010insulin passage across the cribriform plate was detected by PET.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Intranasal [\n 18<\/jats:sup>\n F]FB\u2010insulin reached the brain within 13 min.\n <\/jats:p>\n <\/jats:list-item>\n \n \n [\n 18<\/jats:sup>\n F]FB\u2010insulin activity was highest in emotional and memory processing regions.\n <\/jats:p>\n <\/jats:list-item>\n \n Aerosol delivery was less efficient than liquid instillation by preplaced catheter.<\/jats:p>\n <\/jats:list-item>\n \n Insulin delivery to the cribriform plate was critical for arrival in the brain.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n 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