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Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of (68)Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics
High kidney uptake is a common feature of peptide-based radiopharmaceuticals, leading to reduced detection sensitivity for lesions adjacent to kidneys and lower maximum tolerated therapeutic dose. In this study, we evaluated if the Met-Val-Lys (MVK) linker could be used to lower kidney uptake of (68...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503470/ https://www.ncbi.nlm.nih.gov/pubmed/32854201 http://dx.doi.org/10.3390/molecules25173854 |
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author | Bendre, Shreya Zhang, Zhengxing Kuo, Hsiou-Ting Rousseau, Julie Zhang, Chengcheng Merkens, Helen Roxin, Áron Bénard, François Lin, Kuo-Shyan |
author_facet | Bendre, Shreya Zhang, Zhengxing Kuo, Hsiou-Ting Rousseau, Julie Zhang, Chengcheng Merkens, Helen Roxin, Áron Bénard, François Lin, Kuo-Shyan |
author_sort | Bendre, Shreya |
collection | PubMed |
description | High kidney uptake is a common feature of peptide-based radiopharmaceuticals, leading to reduced detection sensitivity for lesions adjacent to kidneys and lower maximum tolerated therapeutic dose. In this study, we evaluated if the Met-Val-Lys (MVK) linker could be used to lower kidney uptake of (68)Ga-labeled DOTA-conjugated peptides and peptidomimetics. A model compound, [(68)Ga]Ga-DOTA-AmBz-MVK(Ac)-OH (AmBz: aminomethylbenzoyl), and its derivative, [(68)Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH, coupled with the PSMA (prostate-specific membrane antigen)-targeting motif of the previously reported HTK01166 were synthesized and evaluated to determine if they could be recognized and cleaved by the renal brush border enzymes. Additionally, positron emission tomography (PET) imaging, ex vivo biodistribution and in vivo stability studies were conducted in mice to evaluate their pharmacokinetics. [(68)Ga]Ga-DOTA-AmBz-MVK(Ac)-OH was effectively cleaved specifically by neutral endopeptidase (NEP) of renal brush border enzymes at the Met-Val amide bond, and the radio-metabolite [(68)Ga]Ga-DOTA-AmBz-Met-OH was rapidly excreted via the renal pathway with minimal kidney retention. [(68)Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH retained its PSMA-targeting capability and was also cleaved by NEP, although less effectively when compared to [(68)Ga]Ga-DOTA-AmBz-MVK(Ac)-OH. The kidney uptake of [(68)Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH was 30% less compared to that of [(68)Ga]Ga-HTK01166. Our data demonstrated that derivatives of [(68)Ga]Ga-DOTA-AmBz-MVK-OH can be cleaved specifically by NEP, and therefore, MVK can be a promising cleavable linker for use to reduce kidney uptake of radiolabeled DOTA-conjugated peptides and peptidomimetics. |
format | Online Article Text |
id | pubmed-7503470 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75034702020-09-23 Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of (68)Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics Bendre, Shreya Zhang, Zhengxing Kuo, Hsiou-Ting Rousseau, Julie Zhang, Chengcheng Merkens, Helen Roxin, Áron Bénard, François Lin, Kuo-Shyan Molecules Article High kidney uptake is a common feature of peptide-based radiopharmaceuticals, leading to reduced detection sensitivity for lesions adjacent to kidneys and lower maximum tolerated therapeutic dose. In this study, we evaluated if the Met-Val-Lys (MVK) linker could be used to lower kidney uptake of (68)Ga-labeled DOTA-conjugated peptides and peptidomimetics. A model compound, [(68)Ga]Ga-DOTA-AmBz-MVK(Ac)-OH (AmBz: aminomethylbenzoyl), and its derivative, [(68)Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH, coupled with the PSMA (prostate-specific membrane antigen)-targeting motif of the previously reported HTK01166 were synthesized and evaluated to determine if they could be recognized and cleaved by the renal brush border enzymes. Additionally, positron emission tomography (PET) imaging, ex vivo biodistribution and in vivo stability studies were conducted in mice to evaluate their pharmacokinetics. [(68)Ga]Ga-DOTA-AmBz-MVK(Ac)-OH was effectively cleaved specifically by neutral endopeptidase (NEP) of renal brush border enzymes at the Met-Val amide bond, and the radio-metabolite [(68)Ga]Ga-DOTA-AmBz-Met-OH was rapidly excreted via the renal pathway with minimal kidney retention. [(68)Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH retained its PSMA-targeting capability and was also cleaved by NEP, although less effectively when compared to [(68)Ga]Ga-DOTA-AmBz-MVK(Ac)-OH. The kidney uptake of [(68)Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH was 30% less compared to that of [(68)Ga]Ga-HTK01166. Our data demonstrated that derivatives of [(68)Ga]Ga-DOTA-AmBz-MVK-OH can be cleaved specifically by NEP, and therefore, MVK can be a promising cleavable linker for use to reduce kidney uptake of radiolabeled DOTA-conjugated peptides and peptidomimetics. MDPI 2020-08-25 /pmc/articles/PMC7503470/ /pubmed/32854201 http://dx.doi.org/10.3390/molecules25173854 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Bendre, Shreya Zhang, Zhengxing Kuo, Hsiou-Ting Rousseau, Julie Zhang, Chengcheng Merkens, Helen Roxin, Áron Bénard, François Lin, Kuo-Shyan Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of (68)Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics |
title | Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of (68)Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics |
title_full | Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of (68)Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics |
title_fullStr | Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of (68)Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics |
title_full_unstemmed | Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of (68)Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics |
title_short | Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of (68)Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics |
title_sort | evaluation of met-val-lys as a renal brush border enzyme-cleavable linker to reduce kidney uptake of (68)ga-labeled dota-conjugated peptides and peptidomimetics |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503470/ https://www.ncbi.nlm.nih.gov/pubmed/32854201 http://dx.doi.org/10.3390/molecules25173854 |
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