64Cu- and 68Ga-Labelled [Nle14,Lys40(Ahx-NODAGA)NH2]-Exendin-4 for Pancreatic Beta Cell Imaging in Rats

Mikkola, Kirsi; Yim, Cheng‐Bin; Fagerholm, Veronica; Ishizu, Tamiko; Elomaa, V.‐V.; Rajander, Johan; Jurttila, Jori; Saanijoki, Tiina; Tolvanen, Tuula; Tirri, Marko; Gourni, Eleni; Béhé, Martin; Gotthardt, Martin; Reubi, Jean Claude; Mäcke, Helmut R.; Roivainen, Anne; Solin, Olof; Nuutila, Pirjo

doi:10.1007/s11307-013-0691-2

Cited by 42 publications

(37 citation statements)

References 29 publications

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“…Owing to its fast binding kinetics, rapid uptake in target tissue, and ability to be stabilized to resist protease degradation, exendin and related peptides have been investigated as molecular imaging agents for measuring beta cell mass in vivo [24, 36, 43–44]. However, current approaches lack the sensitivity required for clinical application[25, 41, 45], so more development is needed. Modifications such as PEGylation have shown prolonged therapeutic effects[46–47], which may benefit a slower-clearing imaging agent if rapid distribution and blood clearance result in low targeting.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging

Zhang

Thurber

2015

Mol Imaging Biol

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Purpose Quantitative molecular imaging of beta cell mass (BCM) would enable early detection and treatment monitoring of type-1 diabetes. The glucagon like peptide-1 (GLP-1) receptor is an attractive target due to its beta cell specificity and cell surface location. We quantitatively investigated the impact of plasma clearance and receptor internalization on targeting efficiency in healthy B6 mice. Procedures Four exenatide-based probes were synthesized that varied in molecular weight, binding affinity, and plasma clearance. The GLP-1 receptor internalization rate and in vivo receptor expression were quantified. Results Receptor internalization (54,000 receptors/cell in vivo) decreased significantly within minutes, reducing the benefit of a slower clearing agent. The multimers and albumin binding probes had higher kidney and liver uptake, respectively. Conclusions Slow plasma clearance is beneficial for GLP-1 receptor peptide therapeutics. However, for exendin-based imaging of islets, downregulation of the GLP-1 receptor and non-specific background uptake result in a higher TBR for fast-clearing agents.

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Section: Introductionmentioning

confidence: 99%

Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging

Zhang

Thurber

2015

Mol Imaging Biol

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“…Several DOTA and DO3A functionalized exendin-4 analogues labeled with radionuclides have been reported [10, 26, 29]. However, the pancreas was not imaged in small animal models due to high kidney uptake and the low contrast between target tissue and background [27, 30]. In this report, we successfully imaged pancreatic β cells in normal SD male rats using DO3A and NODA functionalized exendin-4 analogues radiolabeled with Cu-64 and Ga-68 PET isotopes.…”

Section: Discussionmentioning

confidence: 99%

“…Recent publications have described the challenges of imaging β cells using GLP derivatives in small animal models [27, 30]. Several researchers have opted for models employing larger animals due to the ease of organ localization.…”

Section: Discussionmentioning

confidence: 99%

“…Over the years, various GLP-1R agonists/antagonists have been radiolabeled with I-125 [12, 15, 17, 19], In-111 [20–22], Tc-99 m [23], F-18 [24, 25], Cu-64 [10, 26–28], and Ga-68 [27, 29] to study BCM and also tumors of β cell origin. With the availability of medical cyclotrons and 68 Ge/ 68 Ga generators, there has been an increased interest in GLP-1 PET tracers [10, 27, 29]. Most of the above work has highlighted the challenges associated with imaging BCM using GLP-1 analogues in small animals [10, 29, 30].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Cu-64 and Ga-68 Radiolabeled Glucagon-Like Peptide-1 Receptor Agonists as PET Tracers for Pancreatic β cell Imaging

et al. 2015

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Purpose Copper-64 (Cu-64) and Galium-68 (Ga-68) radiolabeled DO3A and NODA conjugates of exendin-4 were used for preclinical imaging of pancreatic β cells via targeting of glucagon-like peptide-1 receptor (GLP-1R). Procedures DO3A-VS- and NODA-VS-tagged Cys40exendin-4 (DO3A-VS-Cys40-exendin-4 and NODA-VS-Cys40-exendin-4, respectively) were labeled with Cu-64 and Ga-68 using standard techniques. Biodistribution and dynamic positron emission tomography (PET) were carried out in normal Sprague–Dawley (SD) rats. Ex vivo autoradiography imaging was conducted with freshly frozen pancreatic thin sections. Results DO3A-VS- and NODA-VS-Cys40-exendin-4 analogues were labeled with Cu-64 and Ga-68 to a specific activity of 518.7±3.7 Ci/mmol (19.19±0.14 TBq/mmol) and radiochemical yield above 98 %. Biodistribution data demonstrated pancreatic uptake of 0.11±0.02 %ID/g for [64Cu]DO3A-VS-, 0.14±0.02 %ID/g for [64Cu]NODA-VS-, 0.11±0.03 for [68Ga]DO3A-VS-, and 0.26±0.03 for [68Ga]NODA-VS-Cys40-exendin-4. Excess exendin-4 and exendin-(9–39)-amide displaced all four Cu-64 and Ga-68 labeled exendin-4 derivatives in blocking studies. Conclusions [64Cu]/[68Ga]DO3A-VS-Cys40- and [64Cu]/[68Ga]NODA-VS-Cys40-exendin-4 can be used as PET imaging agents specific for GLP-1R expressed on β cells. Here, we report the first evidence of pancreatic uptake visualized with exendin-4 derivative in a rat animal model via in vivo dynamic PET imaging.

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“…These properties have led several investigators to explore the use of radiolabeled exendin molecules for tracking beta cell mass in diabetes 19–25 . However, the molecular properties of the radiolabeled peptide require further optimization before obtaining clinical utility 23, 25 . Using a novel dialkyne linker with a functional handle for attaching an imaging agent, we synthesized a dual-purpose linker to simultaneously stabilize and label alpha helices.…”

Section: Introductionmentioning

confidence: 99%

Dual-Purpose Linker for Alpha Helix Stabilization and Imaging Agent Conjugation to Glucagon-Like Peptide-1 Receptor Ligands

et al. 2015

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Peptides display many characteristics of efficient imaging agents such as rapid targeting, fast background clearance, and low non-specific cellular uptake. However, poor stability, low affinity, and loss of binding after labeling often preclude their use in vivo. Using the glucagon-like peptide-1 receptor (GLP-1R) ligands exendin and GLP-1 as a model system, we designed a novel alpha helix stabilizing linker to simultaneously address these limitations. The stabilized and labeled peptides showed an increase in helicity, improved protease resistance, negligible loss or an improvement in binding affinity, and excellent in vivo targeting. The ease of incorporating azidohomoalanine in peptides and efficient reaction with the dialkyne linker enables this technique to potentially be used as a general method for labeling alpha helices. This strategy should be useful for imaging beta cells in diabetes research and in developing and testing other peptide targeting agents.

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64Cu- and 68Ga-Labelled [Nle14,Lys40(Ahx-NODAGA)NH2]-Exendin-4 for Pancreatic Beta Cell Imaging in Rats

Cited by 42 publications

References 29 publications

Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging

Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging

Evaluation of Cu-64 and Ga-68 Radiolabeled Glucagon-Like Peptide-1 Receptor Agonists as PET Tracers for Pancreatic β cell Imaging

Dual-Purpose Linker for Alpha Helix Stabilization and Imaging Agent Conjugation to Glucagon-Like Peptide-1 Receptor Ligands

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