ArticlePloS one2015
Evaluation of ¹¹¹in-labelled exendin-4 derivatives containing different meprin β-specific cleavable linkers.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 25 citations in OpenAlex.
- Towards the Magic Radioactive Bullet: Improving Targeted Radionuclide Therapy by Reducing the Renal Retention of Radioligands.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Reducing kidney uptake of radiolabelled exendin-4 using variants of the renally cleavable linker MVK.EJNMMI radiopharmacy and chemistry · 2023Article
- New Long-Acting [Journal of medicinal chemistry · 2023Article
- Radiolabeling Strategies of Nanobodies for Imaging Applications.Diagnostics (Basel, Switzerland) · 2021Review
- Small peptide-based GLP-1R ligands: an approach to reduce the kidney uptake of radiolabeled GLP-1R-targeting agents?EJNMMI radiopharmacy and chemistry · 2021Article
- Meprin β: A novel regulator of blood-brain barrier integrity.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2021Article
- Advances in GLP-1 receptor targeting radiolabeled agent development and prospective of theranostics.Theranostics · 2020Review
- Exendin-4 analogs in insulinoma theranostics.Journal of labelled compounds & radiopharmaceuticals · 2019Review
- Comparison of desferrioxamine and NODAGA for the gallium-68 labeling of exendin-4.EJNMMI radiopharmacy and chemistry · 2019Article
- An Efficient Method for Labeling Single Domain Antibody Fragments withBioconjugate chemistry · 2018Article
- Radiosynthesis and evaluation of anEJNMMI radiopharmacy and chemistry · 2018Article
- Targets and probes for non-invasive imaging of β-cells.European journal of nuclear medicine and molecular imaging · 2017Review
- Low kidney uptake of GLP-1R-targeting, beta cell-specific PET tracer,EJNMMI research · 2016Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCleavable linkers, which are specifically cleaved by defined conditions or enzymes, are powerful tools that can be used for various purposes. Amongst other things, they have been successfully used to deliver toxic payloads as prodrugs into target tissues. In this work novel linker sequences targeting meprin β, a metalloprotease expressed in the kidney brush-border membrane, were designed and included in the sequence of three radiolabelled exendin-4 derivatives. As radiolabelled exendin-4 derivatives strongly accumulate in the kidneys, we hypothesised that specific cleavage of the radiolabelled moiety at the kidney brush-border membrane would allow easier excretion of the activity into the urine and therefore improve the pharmacological properties of the peptide.
resultsThe insertion of a cleavable linker did not negatively influence the in vitro properties of the peptides. They showed a good affinity to the GLP-1 receptor expressed in CHL cells, a high internalisation and sufficiently high stability in fresh human blood plasma. In vitro digestion with recombinant meprin β rapidly metabolised the corresponding linker sequences. After 60 min the majority of the corresponding peptides were digested and at the same time the anticipated fragments were formed. The peptides were also quickly metabolised in CD1 nu/nu mouse kidney homogenates. Immunofluorescence staining of meprin β in kidney sections confirmed the expression of the protease in the kidney brush-border membrane. Biodistribution in GLP-1 receptor positive tumour-xenograft bearing mice revealed high specific uptake of the 111In-labelled tracers in receptor positive tissue. Accumulation in the kidneys, however, was still high and comparable to the lead compound 111In-Ex4NOD40.
conclusionIn conclusion, we show that the concept of cleavable linkers specific for meprin β is feasible, as the peptides are rapidly cleaved by the enzyme while retaining their biological properties.
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