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

doi:10.1021/acs.bioconjchem.2c00126

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

Pharmaceutics

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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 language	English (US)
Pages (from-to)	892-906
Number of pages	15
Journal	Bioconjugate Chemistry
Volume	33
Issue number	5
DOIs	https://doi.org/10.1021/acs.bioconjchem.2c00126
State	Published - May 18 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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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.bioconjchem.2c00126

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Cite this

Taubel, J. C., Nelson, N. R., Bansal, A., Curran, G. L., Wang, L., Wang, Z., Berg, H. M., Vernon, C. J., Min, H. K., Larson, N. B., Degrado, T. R., Kandimalla, K. K., Lowe, V. J., & Pandey, M. K. (2022). Design, Synthesis, and Preliminary Evaluation of [⁶⁸Ga]Ga-NOTA-Insulin as a PET Probe in an Alzheimer’s Disease Mouse Model. Bioconjugate Chemistry, 33(5), 892-906. https://doi.org/10.1021/acs.bioconjchem.2c00126

Taubel, JC, Nelson, NR, Bansal, A, Curran, GL, Wang, L, Wang, Z, Berg, HM, Vernon, CJ, Min, HK, Larson, NB, Degrado, TR, Kandimalla, KK, Lowe, VJ & Pandey, MK 2022, 'Design, Synthesis, and Preliminary Evaluation of [⁶⁸Ga]Ga-NOTA-Insulin as a PET Probe in an Alzheimer’s Disease Mouse Model', Bioconjugate Chemistry, vol. 33, no. 5, pp. 892-906. https://doi.org/10.1021/acs.bioconjchem.2c00126

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title = "Design, Synthesis, and Preliminary Evaluation of [68Ga]Ga-NOTA-Insulin as a PET Probe in an Alzheimer{\textquoteright}s Disease Mouse Model",

abstract = "Aberrant insulin signaling has been considered one of the risk factors for the development of Alzheimer{\textquoteright}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.",

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

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

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: {\textcopyright} ",

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doi = "10.1021/acs.bioconjchem.2c00126",

language = "English (US)",

volume = "33",

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T1 - Design, Synthesis, and Preliminary Evaluation of [68Ga]Ga-NOTA-Insulin as a PET Probe in an Alzheimer’s Disease Mouse Model

AU - Taubel, Jillissa C.

AU - Nelson, Nicholas R.

AU - Bansal, Aditya

AU - Curran, Geoffrey L.

AU - Wang, Lushan

AU - Wang, Zengtao

AU - Berg, Heather M.

AU - Vernon, Cynthia J.

AU - Min, Hoon Ki

AU - Larson, Nicholas B.

AU - Degrado, Timothy R.

AU - Kandimalla, Karunya K.

AU - Lowe, Val J.

AU - Pandey, Mukesh K

N1 - 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: ©

PY - 2022/5/18

Y1 - 2022/5/18

N2 - 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.

AB - 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.

KW - Alzheimer Disease/diagnostic imaging

KW - Animals

KW - Gallium Radioisotopes

KW - Heterocyclic Compounds, 1-Ring

KW - Insulin

KW - Mice

KW - Positron-Emission Tomography/methods

KW - Receptor, Insulin

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