Advances in GLP-1 receptor targeting radiolabeled agent development and prospective of theranostics

Velikyan, Irina; Eriksson, Olof

doi:10.7150/thno.38366

Cited by 30 publications

(26 citation statements)

References 156 publications

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“…To further validate the pRO method, it will be crucial to extend the approach to measuring target engagement using advanced tracer approaches that ultimately may offer insights into pRO across tissues. There is progress in this area with the recent description of both GLP-1 and glucagon receptor PET ligands ( 41 , 42 ).…”

Section: Discussionmentioning

confidence: 99%

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

Willard¹,

Douros²,

Gabe³

et al. 2020

JCI Insight

258

192

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Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.

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Section: Discussionmentioning

confidence: 99%

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

Willard¹,

Douros²,

Gabe³

et al. 2020

JCI Insight

258

192

View full text Add to dashboard Cite

show abstract

“…However, preclinical and clinical studies of 18 F-labeled exendin-4 derivatives are still relatively limited (94). Against expectations, most previous reports on 8 F-labeled exendin-4 derivatives have demonstrated high non-specific uptake even in the kidneys (39,89,94). For example, [ 18 F]FBexendin-4 showed relatively high liver and kidney uptake, leading to low contrast in in vivo PET images (95).…”

Section: Visualization Of B Cells: Glucagon-like Peptide-1 Receptor-targeted Imagingmentioning

confidence: 98%

“…In this context, nuclear medicine imaging techniques such as SPECT and PET have attracted attention (20,37) due to their ability to detect their radioisotope-labeled probes at picomolar ranges, despite their limited spatial resolutions (38). The high specificity to b cells of high-sensitivity imaging modalities combined with radioisotopelabeled probes outweighs the shortcomings of their spatial resolution (17,39). Accordingly, SPECT and PET have been investigated for the application to in vivo b-cell-specific imaging.…”

Section: Challenges Of Non-invasive B-cell-specific Imagingmentioning

confidence: 99%

“…In most of the designs of exendin-3 probes for SPECT and PET, the residue Lys 40 of exendin-3 was conjugated with the radioisotope-labeling structures. Although exendin-3 probes showed successful in vivo visualization of the pancreas, further research to improve the stability is warranted (39).…”

Section: Visualization Of B Cells: Glucagon-like Peptide-1 Receptor-targeted Imagingmentioning

confidence: 99%

“…As for PET imaging, 68 Ga, 18 F, 64 Cu, and zirconium-89 ( 89 Zr)-labeled exendin-4 derivatives have been developed (39). In particular, 68 Ga-labeled exendin-4 derivatives have been well researched in preclinical and clinical studies, with the goal of overcoming the low spatial resolution and relatively high kidney uptake of SPECT probes by using 68 Ga for PET imaging.…”

Section: Visualization Of B Cells: Glucagon-like Peptide-1 Receptor-targeted Imagingmentioning

confidence: 99%

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Non-invasive Beta-cell Imaging: Visualization, Quantification, and Beyond

2021

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Pancreatic beta (β)-cell dysfunction and reduced mass play a central role in the development and progression of diabetes mellitus. Conventional histological β-cell mass (BCM) analysis is invasive and limited to cross-sectional observations in a restricted sampling area. However, the non-invasive evaluation of BCM remains elusive, and practical in vivo and clinical techniques for β-cell-specific imaging are yet to be established. The lack of such techniques hampers a deeper understanding of the pathophysiological role of BCM in diabetes, the implementation of personalized BCM-based diabetes management, and the development of antidiabetic therapies targeting BCM preservation and restoration. Nuclear medical techniques have recently triggered a major leap in this field. In particular, radioisotope-labeled probes using exendin peptides that include glucagon-like peptide-1 receptor (GLP-1R) agonist and antagonist have been employed in positron emission tomography and single-photon emission computed tomography. These probes have demonstrated high specificity to β cells and provide clear images accurately showing uptake in the pancreas and transplanted islets in preclinical in vivo and clinical studies. One of these probes, 111indium-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4), has captured the longitudinal changes in BCM during the development and progression of diabetes and under antidiabetic therapies in various mouse models of type 1 and type 2 diabetes mellitus. GLP-1R-targeted imaging is therefore a promising tool for non-invasive BCM evaluation. This review focuses on recent advances in non-invasive in vivo β-cell imaging for BCM evaluation in the field of diabetes; in particular, the exendin-based GLP-1R-targeted nuclear medicine techniques.

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Multivalent γ‐PGA‐Exendin‐4 Conjugates to Target Pancreatic β‐Cells

Rossi

Kerekes²,

Kovács-Kocsi³

et al. 2022

ChemBioChem

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Targeting of glucagon-like peptide 1 receptor (GLP-1R), expressed on the surface of pancreatic β-cells, is of great interest for the development of advanced therapies for diabetes and diagnostics for insulinoma. We report the conjugation of exendin-4 (Ex-4), an approved drug to treat type 2 diabetes, to poly-γ-glutamic acid (γ-PGA) to obtain more stable and effective GLP-1R ligands. Exendin-4 modified at Lysine-27 with PEG4-maleimide was conjugated to γ-PGA functionalized with furan, in different molar ratios, exploiting a chemoselective Diels-Alder cycloaddition. The γ-PGA presenting the highest number of conjugated Ex-4 molecules (average 120 per polymeric chain) showed a double affinity towards GLP-1R with respect to exendin per se, paving the way to improved therapeutic and diagnostic applications.

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Advances in GLP-1 receptor targeting radiolabeled agent development and prospective of theranostics

Cited by 30 publications

References 156 publications

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

Non-invasive Beta-cell Imaging: Visualization, Quantification, and Beyond

Multivalent γ‐PGA‐Exendin‐4 Conjugates to Target Pancreatic β‐Cells

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