First Biodistribution Study of [ 68 Ga]Ga-NOTA-Insulin Following Intranasal Administration in Adult Vervet Monkeys

Abstract

Background:

Intranasal insulin (INI) is being explored as a treatment for Alzheimer’s disease (AD). Improved memory, functional ability, and cerebrospinal fluid (CSF) AD biomarker profiles have been observed following INI administration. However, the method of intranasal delivery may significantly affect outcomes.

Objective:

To show reliable delivery of insulin to the brain using the Aptar Cartridge Pump System (CPS) intranasal delivery system.

Methods:

To visualize INI biodistribution, we developed a novel PET radiotracer, Gallium 68-radiolabeled (NOTA-conjugated) insulin, [⁶⁸Ga]Ga-NOTA-insulin. We used the Aptar CPS to administer [⁶⁸Ga]Ga-NOTA-insulin to anesthetized healthy adult vervet monkeys and measured brain regional activity and whole-body dosimetry following PET/CT scans.

Results:

We observed brain penetration of [⁶⁸Ga]Ga-NOTA-insulin following intranasal administration with the Aptar CPS. Radioactive uptake was seen in multiple regions, including the amygdala, putamen, hypothalamus, hippocampus, and choroid plexus. A safety profile and whole-body dosimetry were also established in a second cohort of vervets. Safety was confirmed: vitals remained stable, blood glucose levels were unchanged, and no organ was exposed to more than 2.5 mSv of radioactivity. Extrapolations from vervet organ distribution allowed for estimation of the [⁶⁸Ga]Ga-NOTA-insulin absorbed dose in humans, and the maximum dose of [⁶⁸Ga]Ga-NOTA-insulin that can be safely administered to humans was determined to be 185 MBq.

Conclusions:

The use of [⁶⁸Ga]Ga-NOTA-insulin as a PET radiotracer is safe and effective for observing brain uptake in vervet monkeys. Further, the Aptar CPS successfully targets [⁶⁸Ga]Ga-NOTA-insulin to the brain. The data will be essential in guiding future studies of intranasal [⁶⁸Ga]Ga-NOTA-insulin administration in humans.

Keywords

Alzheimer’s disease insulin intranasal administration primates

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