Distribution of insulin in primate brain following nose-to-brain transport

Kylie Smith; Jinda Fan; Gwendolyn A Marriner; John Gerdes; Robert Kessler; Kurt R Zinn

doi:10.1002/trc2.12459

Distribution of insulin in primate brain following nose-to-brain transport

Alzheimers Dement (N Y). 2024 Mar 10;10(1):e12459. doi: 10.1002/trc2.12459. eCollection 2024 Jan-Mar.

Authors

Kylie Smith^{1

2}, Jinda Fan^{2

3

4}, Gwendolyn A Marriner⁵, John Gerdes⁶, Robert Kessler⁴, Kurt R Zinn^{1

2

4

7}

Affiliations

¹ Department of Biomedical Engineering Michigan State University East Lansing Michigan USA.
² Institute for Quantitative Health Science and Engineering, Michigan State University East Lansing Michigan USA.
³ Department of Chemistry Michigan State University East Lansing Michigan USA.
⁴ Department of Radiology Michigan State University East Lansing Michigan USA.
⁵ Department of Molecular Imaging Charles River Laboratories Mattawan Michigan USA.
⁶ Department of Biomedical and Pharmaceutical Sciences University of Montana Missoula Montana USA.
⁷ Department of Small Animal Clinical Sciences Michigan State University East Lansing Michigan USA.

Abstract

Introduction: Nose-to-brain (N2B) insulin delivery has potential for Alzheimer's disease (AD) therapy. However, clinical implementation has been challenging without methods to follow N2B delivery non-invasively. Positron emission tomography (PET) was applied to measure F-18-labeled insulin ([¹⁸F]FB-insulin) from intranasal dosing to brain uptake in non-human primates following N2B delivery.

Methods: [¹⁸F]FB-insulin was prepared by reacting A¹,B²⁹-di(tert-butyloxycarbonyl)insulin with [¹⁸F]-N-succinimidyl-4-fluorobenzoate. Three methods of N2B delivery for [¹⁸F]FB-insulin were compared - delivery as aerosol via tubing (rhesus macaque, n = 2), as aerosol via preplaced catheter (rhesus macaque, n = 3), and as solution via preplaced catheter (cynomolgus macaque, n = 3). Following dosing, dynamic PET imaging (120 min) quantified delivery efficiency to the nasal cavity and whole brain. Area under the time-activity curve was calculated for 46 regions of the cynomolgus macaque brain to determine regional [¹⁸F]FB-insulin levels.

Results: Liquid instillation of [¹⁸F]FB-insulin 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). [¹⁸F]FB-insulin was rapidly transferred across the cribriform plate to limbic and frontotemporal areas responsible for emotional and memory processing. [¹⁸F]FB-insulin half-life was longer in olfactory nerve projection sites with high insulin receptor density compared to the whole brain.

Discussion: The catheter-based liquid delivery approach combined with PET imaging successfully tracked the fate of N2B [¹⁸F]FB-insulin 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.

Highlights for: [¹⁸F]FB-insulin passage across the cribriform plate was detected by PET.Intranasal [¹⁸F]FB-insulin reached the brain within 13 min.[¹⁸F]FB-insulin activity was highest in emotional and memory processing regions.Aerosol delivery was less efficient than liquid instillation by preplaced catheter.Insulin delivery to the cribriform plate was critical for arrival in the brain.

Keywords: Alzheimer's disease; cranial nerves; cribriform plate; dementia; dynamic imaging; image‐guided delivery; intervention; intranasal insulin; neuroprotection; non‐invasive imaging; positron emission tomography (PET).