Design, Synthesis, and Preliminary Evaluation of [68Ga]Ga-NOTA-Insulin as a PET Probe in an Alzheimer's Disease Mouse Model

Jillissa C. Taubel, Nicholas R. Nelson, Aditya Bansal, Geoffrey L. Curran, Lushan Wang, Zengtao Wang, Heather M. Berg, Cynthia J. Vernon, Hoon Ki Min, Nicholas B. Larson, Timothy R. Degrado, Karunya K. Kandimalla, Val J. Lowe, Mukesh K Pandey

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant insulin signaling has been considered one of the risk factors for the development of Alzheimer's disease (AD) and has drawn considerable attention from the research community to further study its role in AD pathophysiology. Herein, we describe the development of an insulin-based novel positron emission tomography (PET) probe, [68Ga]Ga-NOTA-insulin, to noninvasively study the role of insulin in AD. The developed PET probe [68Ga]Ga-NOTA-insulin showed a significantly higher uptake (0.396 ± 0.055 SUV) in the AD mouse brain compared to the normal (0.140 ± 0.027 SUV) mouse brain at 5 min post injection and also showed a similar trend at 10, 15, and 20 min post injection. In addition, [68Ga]Ga-NOTA-insulin was found to have a differential uptake in various brain regions at 30 min post injection. Among the brain regions, the cortex, thalamus, brain stem, and cerebellum showed a significantly higher standard uptake value (SUV) of [68Ga]Ga-NOTA-insulin in AD mice as compared to normal mice. The inhibition of the insulin receptor (IR) with an insulin receptor antagonist peptide (S961) in normal mice showed a similar brain uptake profile of [68Ga]Ga-NOTA-insulin as it was observed in the AD case, suggesting nonfunctional IR in AD and the presence of an alternative insulin uptake route in the absence of a functional IR. The Gjedde-Patlak graphical analysis was also performed to predict the input rate of [68Ga]Ga-NOTA-insulin into the brain using MicroPET imaging data and supported the in vivo results. The [68Ga]Ga-NOTA-insulin PET probe was successfully synthesized and evaluated in a mouse model of AD in comparison with [18F]AV1451 and [11C]PIB to noninvasively study the role of insulin in AD pathophysiology.

Original languageEnglish (US)
JournalBioconjugate Chemistry
Volume33
Issue number5
DOIs
StateAccepted/In press - 2022

Bibliographical note

Funding Information:
This project was funded by the Minnesota Partnership for Biotechnology and Medical Genomics and the Department of Radiology, Mayo Clinic, Rochester, Minnesota, United States. The authors thank Dr. Surendra R. Gundam and Sujala Ghatamaneni for their assistance during the study.

Publisher Copyright:
©

Keywords

  • Alzheimer Disease/diagnostic imaging
  • Animals
  • Gallium Radioisotopes
  • Heterocyclic Compounds, 1-Ring
  • Insulin
  • Mice
  • Positron-Emission Tomography/methods
  • Receptor, Insulin

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article

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