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

Overview

Journal Bioconjug Chem

Publisher American Chemical Society

Specialty Biochemistry

Date 2022 Apr 14

PMID 35420782

Authors

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

Affiliations

Soon will be listed here.

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, [Ga]Ga-NOTA-insulin, to noninvasively study the role of insulin in AD. The developed PET probe [Ga]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, [Ga]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 [Ga]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 [Ga]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 [Ga]Ga-NOTA-insulin into the brain using MicroPET imaging data and supported the in vivo results. The [Ga]Ga-NOTA-insulin PET probe was successfully synthesized and evaluated in a mouse model of AD in comparison with [F]AV1451 and [C]PIB to noninvasively study the role of insulin in AD pathophysiology.

Citing Articles

Discovery of Glucose Metabolism-Associated Genes in Neuropathic Pain: Insights from Bioinformatics.

Yu Y, Cheung Y, Cheung C Int J Mol Sci. 2025; 25(24.

PMID: 39769264 PMC: 11679926. DOI: 10.3390/ijms252413503.

Aspects and prospects of preclinical theranostic radiopharmaceutical development.

Nelson B, Krol V, Bansal A, Andersson J, Wuest F, Pandey M Theranostics. 2024; 14(17):6446-6470.

PMID: 39479448 PMC: 11519794. DOI: 10.7150/thno.100339.

Synthesis and evaluation of anti-PD-L1-B11 antibody fragments for PET imaging of PD-L1 in breast cancer and melanoma tumor models.

Bansal A, Lavoie R, Lucien F, Kethamreddy M, Wootla B, Dong H Sci Rep. 2024; 14(1):19561.

PMID: 39174596 PMC: 11341854. DOI: 10.1038/s41598-024-70385-8.

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

Smith K, Fan J, Marriner G, Gerdes J, Kessler R, Zinn K Alzheimers Dement (N Y). 2024; 10(1):e12459.

PMID: 38469552 PMC: 10925727. DOI: 10.1002/trc2.12459.

State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer's Disease.

Rhea E, Leclerc M, Yassine H, Capuano A, Tong H, Petyuk V Aging Dis. 2023; 15(4):1688-1725.

PMID: 37611907 PMC: 11272209. DOI: 10.14336/AD.2023.0814.

References

Pandey M, Byrne J, Jiang H, Packard A, DeGrado T . Cyclotron production of (68)Ga via the (68)Zn(p,n)(68)Ga reaction in aqueous solution. Am J Nucl Med Mol Imaging. 2014; 4(4):303-10. PMC: 4074496. View

Gasparini L, Gouras G, Wang R, GROSS R, Beal M, Greengard P . Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001; 21(8):2561-70. PMC: 6762523. View

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View

Janson J, Laedtke T, Parisi J, OBrien P, Petersen R, Butler P . Increased risk of type 2 diabetes in Alzheimer disease. Diabetes. 2004; 53(2):474-81. DOI: 10.2337/diabetes.53.2.474. View

Craft S . Insulin resistance syndrome and Alzheimer's disease: age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging. 2005; 26 Suppl 1:65-9. DOI: 10.1016/j.neurobiolaging.2005.08.021. View

Pandey M, DeGrado T . Cyclotron Production of PET Radiometals in Liquid Targets: Aspects and Prospects. Curr Radiopharm. 2020; 14(4):325-339. PMC: 9909776. DOI: 10.2174/1874471013999200820165734. View

Peretti D, Garcia D, Reesink F, van der Goot T, De Deyn P, de Jong B . Relative cerebral flow from dynamic PIB scans as an alternative for FDG scans in Alzheimer's disease PET studies. PLoS One. 2019; 14(1):e0211000. PMC: 6336325. DOI: 10.1371/journal.pone.0211000. View

Hoxha E, Boda E, Montarolo F, Parolisi R, Tempia F . Excitability and synaptic alterations in the cerebellum of APP/PS1 mice. PLoS One. 2012; 7(4):e34726. PMC: 3325253. DOI: 10.1371/journal.pone.0034726. View

Akomolafe A, Beiser A, Meigs J, Au R, Green R, Farrer L . Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham Study. Arch Neurol. 2006; 63(11):1551-5. DOI: 10.1001/archneur.63.11.1551. View

10.

Minoshima S, Giordani B, Berent S, Frey K, Foster N, Kuhl D . Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Ann Neurol. 1997; 42(1):85-94. DOI: 10.1002/ana.410420114. View

11.

Goure W, Krafft G, Jerecic J, Hefti F . Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer's disease immunotherapeutics. Alzheimers Res Ther. 2014; 6(4):42. PMC: 4100318. DOI: 10.1186/alzrt272. View

12.

Zhou A, Swaminathan S, Curran G, Poduslo J, Lowe V, Li L . Apolipoprotein A-I Crosses the Blood-Brain Barrier through Clathrin-Independent and Cholesterol-Mediated Endocytosis. J Pharmacol Exp Ther. 2019; 369(3):481-488. PMC: 6538888. DOI: 10.1124/jpet.118.254201. View

13.

Havrankova J, Schmechel D, Roth J, Brownstein M . Identification of insulin in rat brain. Proc Natl Acad Sci U S A. 1978; 75(11):5737-41. PMC: 393044. DOI: 10.1073/pnas.75.11.5737. View

14.

Heras-Sandoval D, Ferrera P, Arias C . Amyloid-β protein modulates insulin signaling in presynaptic terminals. Neurochem Res. 2012; 37(9):1879-85. DOI: 10.1007/s11064-012-0800-7. View

15.

Vandal M, White P, Tremblay C, St-Amour I, Chevrier G, Emond V . Insulin reverses the high-fat diet-induced increase in brain Aβ and improves memory in an animal model of Alzheimer disease. Diabetes. 2014; 63(12):4291-301. DOI: 10.2337/db14-0375. View

16.

Gabbouj S, Ryhanen S, Marttinen M, Wittrahm R, Takalo M, Kemppainen S . Altered Insulin Signaling in Alzheimer's Disease Brain - Special Emphasis on PI3K-Akt Pathway. Front Neurosci. 2019; 13:629. PMC: 6591470. DOI: 10.3389/fnins.2019.00629. View

17.

Pandey M, DeGrado T, Qian K, Jacobson M, Hagen C, Duclos Jr R . Synthesis and preliminary evaluation of N-(16-18F-fluorohexadecanoyl)ethanolamine (18F-FHEA) as a PET probe of N-acylethanolamine metabolism in mouse brain. ACS Chem Neurosci. 2014; 5(9):793-802. DOI: 10.1021/cn400214j. View

18.

Pei J, Braak H, An W, Winblad B, Cowburn R, Iqbal K . Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer's disease. Brain Res Mol Brain Res. 2003; 109(1-2):45-55. DOI: 10.1016/s0169-328x(02)00488-6. View

19.

Swaminathan S, Ahlschwede K, Sarma V, Curran G, Omtri R, Decklever T . Insulin differentially affects the distribution kinetics of amyloid beta 40 and 42 in plasma and brain. J Cereb Blood Flow Metab. 2017; 38(5):904-918. PMC: 5987944. DOI: 10.1177/0271678X17709709. View

20.

Friedland R, Budinger T, Ganz E, Yano Y, Mathis C, Koss B . Regional cerebral metabolic alterations in dementia of the Alzheimer type: positron emission tomography with [18F]fluorodeoxyglucose. J Comput Assist Tomogr. 1983; 7(4):590-8. DOI: 10.1097/00004728-198308000-00003. View