{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:12:04Z","timestamp":1792649524743,"version":"4.5.0"},"reference-count":41,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T00:00:00Z","timestamp":1753228800000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["T32 AG033534"],"award-info":[{"award-number":["T32 AG033534"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;amp;D Transl Res &amp;amp; Clin Interv"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Intranasal insulin (INI) is being explored to treat Alzheimer's disease and other conditions. The method of intranasal delivery has been shown to affect outcomes, requiring validation prior to clinical investigation. We conducted a first\u2010in\u2010human positron emission tomography (PET) study using a novel radiotracer, [\n                      <jats:sup>68<\/jats:sup>\n                      Ga]Ga\u2010NOTA\u2010insulin, administered intranasally with a specialized device (Aptar Cartridge Pump System) to evaluate the kinetics of insulin uptake and distribution in the brain.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      [\n                      <jats:sup>68<\/jats:sup>\n                      Ga]Ga\u2010NOTA\u2010insulin was intranasally administered (\u2248 0.037 \u00b1 0.001 GBq) to adults who were cognitively normal (CN,\n                      <jats:italic>n<\/jats:italic>\n                      = 7) or had mild cognitive impairment (MCI,\n                      <jats:italic>n<\/jats:italic>\n                      = 9). A dynamic 40 minute brain PET scan, followed by a 15 minute whole\u2010body PET\/computed tomography scan was acquired. Physiologic parameters were measured at baseline, during, and post\u2010scan. Brain uptake and time\u2010activity curves were determined for fused PET\/magnetic resonance imaging images.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Radiochemistry was optimized for producing [\n                      <jats:sup>68<\/jats:sup>\n                      Ga]Ga\u2010NOTA\u2010insulin with high radiochemical purity (&gt; 99%) and molar activity (95 GBq\/\u00b5mol). No safety issues were identified. PMOD analyses showed whole\u2010brain average standard uptake value (SUV;g\/mL) \u2248 0.68\u00a0\u00b1\u00a00.01; radioactivity in the brain and whole body were undetectable by 40 and 60 minutes post radiotracer administration respectively. Elevated (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.01) SUVs averaged over the 40 minute period after INI administration were observed for 11 regions: olfactory cortex, hippocampus, parahippocampus, amygdala, superior and middle temporal pole, insula, caudate, putamen, thalamus, and anterior cingulum. Time\u2010activity curves showed different uptake patterns for MCI and CN groups. Baseline pulse pressure, plasma insulin, and phosphorylated tau217 correlated with uptake for subgroups based on cognitive status and sex.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      [\n                      <jats:sup>68<\/jats:sup>\n                      Ga]Ga\u2010NOTA\u2010insulin is a safe and effective PET radiotracer for validating intranasal delivery of insulin to the brain in humans and revealed significant insulin uptake in multiple brain regions. Future studies should incorporate such validation before initiating clinical trials of intranasally administered agents. Further investigation of mechanisms underlying differences in INI uptake among clinical subgroups is also needed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Intranasal [\n                            <jats:sup>68<\/jats:sup>\n                            Ga]Ga\u2010NOTA\u2010insulin is a safe and effective positron emission tomography radiotracer in humans.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Intranasal insulin increased brain uptake in multiple regions for all participants.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Uptake varied by cognitive status, sex, vascular factors, and amyloid burden.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Our protocol provides a method to validate intranasal delivery devices for future trials.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70123","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T11:00:07Z","timestamp":1753268407000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["First\u2010in\u2010human positron emission tomography study of intranasal insulin in aging and MCI"],"prefix":"10.1002","volume":"11","author":[{"given":"Kiran K. Solingapuram","family":"Sai","sequence":"first","affiliation":[{"name":"Department of Radiology Wake Forest University School of Medicine Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M.","family":"Erichsen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Section on Gerontology and Geriatric Medicine Wake Forest University School of Medicine Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna K.","family":"Gollapelli","sequence":"additional","affiliation":[{"name":"Department of Radiology Wake Forest University School of Medicine Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Krizan","sequence":"additional","affiliation":[{"name":"Department of Radiology Wake Forest University School of Medicine Winston\u2010Salem North Carolina 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