Influence of Molecular Design on the Tumor Targeting and Biodistribution of PSMA-Binding Tracers Labeled with Technetium-99m
Previously, we designed the EuK-based PSMA ligand BQ0413 with an maE<sub>3</sub> chelator for labeling with technetium-99m. It showed efficient tumor targeting, but our preclinical data and preliminary clinical results indicated that the renal excretion levels need to be decreased. We hy...
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| Format: | Article |
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/7/3615 |
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| author | Ekaterina Bezverkhniaia Panagiotis Kanellopoulos Ulrika Rosenström Vladimir Tolmachev Anna Orlova |
| author_facet | Ekaterina Bezverkhniaia Panagiotis Kanellopoulos Ulrika Rosenström Vladimir Tolmachev Anna Orlova |
| author_sort | Ekaterina Bezverkhniaia |
| collection | DOAJ |
| description | Previously, we designed the EuK-based PSMA ligand BQ0413 with an maE<sub>3</sub> chelator for labeling with technetium-99m. It showed efficient tumor targeting, but our preclinical data and preliminary clinical results indicated that the renal excretion levels need to be decreased. We hypothesized that this could be achieved by a decrease in the ligand’s total negative charge, achieved by substituting negatively charged glutamate residues in the chelator with glycine. The purpose of this study was to evaluate the tumor targeting and biodistribution of two new PSMA inhibitors, BQ0411 and BQ0412, compared to BQ0413. Conjugates were radiolabeled with Tc-99m and characterized in vitro, using PC3-pip cells, and in vivo, using NMRI and PC3-pip tumor-bearing mice. [<sup>99m</sup>Tc]Tc-BQ0411 and [<sup>99m</sup>Tc]Tc-BQ0412 demonstrated PSMA-specific binding to PC3-pip cells with picomolar affinity. The biodistribution pattern for the new conjugates was characterized by rapid excretion. The tumor uptake for [<sup>99m</sup>Tc]Tc-BQ0411 was 1.6-fold higher compared to [<sup>99m</sup>Tc]Tc-BQ0412 and [<sup>99m</sup>Tc]Tc-BQ0413. [<sup>99m</sup>Tc]Tc-BQ0413 has demonstrated predominantly renal excretion, while the new conjugates underwent both renal and hepatobiliary excretion. In this study, we have demonstrated that in such small targeting ligands as PSMA-binding EuK-based pseudopeptides, the structural blocks that do not participate in binding could have a crucial role in tumor targeting and biodistribution. The presence of a glycine-based coupling linker in BQ0411 and BQ0413 seems to optimize biodistribution. In conclusion, the substitution of amino acids in the chelating sequence is a promising method to alter the biodistribution of [<sup>99m</sup>Tc]Tc-labeled small-molecule PSMA inhibitors. Further improvement of the biodistribution properties of BQ0413 is needed. |
| first_indexed | 2024-04-24T10:44:23Z |
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| id | doaj.art-565782fbe8ae4aa68a27718791984428 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T10:44:23Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-565782fbe8ae4aa68a277187919844282024-04-12T13:19:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01257361510.3390/ijms25073615Influence of Molecular Design on the Tumor Targeting and Biodistribution of PSMA-Binding Tracers Labeled with Technetium-99mEkaterina Bezverkhniaia0Panagiotis Kanellopoulos1Ulrika Rosenström2Vladimir Tolmachev3Anna Orlova4Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, SwedenDepartment of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, SwedenDepartment of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, 752 37 Uppsala, SwedenDepartment of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, SwedenPreviously, we designed the EuK-based PSMA ligand BQ0413 with an maE<sub>3</sub> chelator for labeling with technetium-99m. It showed efficient tumor targeting, but our preclinical data and preliminary clinical results indicated that the renal excretion levels need to be decreased. We hypothesized that this could be achieved by a decrease in the ligand’s total negative charge, achieved by substituting negatively charged glutamate residues in the chelator with glycine. The purpose of this study was to evaluate the tumor targeting and biodistribution of two new PSMA inhibitors, BQ0411 and BQ0412, compared to BQ0413. Conjugates were radiolabeled with Tc-99m and characterized in vitro, using PC3-pip cells, and in vivo, using NMRI and PC3-pip tumor-bearing mice. [<sup>99m</sup>Tc]Tc-BQ0411 and [<sup>99m</sup>Tc]Tc-BQ0412 demonstrated PSMA-specific binding to PC3-pip cells with picomolar affinity. The biodistribution pattern for the new conjugates was characterized by rapid excretion. The tumor uptake for [<sup>99m</sup>Tc]Tc-BQ0411 was 1.6-fold higher compared to [<sup>99m</sup>Tc]Tc-BQ0412 and [<sup>99m</sup>Tc]Tc-BQ0413. [<sup>99m</sup>Tc]Tc-BQ0413 has demonstrated predominantly renal excretion, while the new conjugates underwent both renal and hepatobiliary excretion. In this study, we have demonstrated that in such small targeting ligands as PSMA-binding EuK-based pseudopeptides, the structural blocks that do not participate in binding could have a crucial role in tumor targeting and biodistribution. The presence of a glycine-based coupling linker in BQ0411 and BQ0413 seems to optimize biodistribution. In conclusion, the substitution of amino acids in the chelating sequence is a promising method to alter the biodistribution of [<sup>99m</sup>Tc]Tc-labeled small-molecule PSMA inhibitors. Further improvement of the biodistribution properties of BQ0413 is needed.https://www.mdpi.com/1422-0067/25/7/3615prostate cancerprostate-specific membrane antigenPSMAtechnetium-99mcoupling linkerBQ0411 |
| spellingShingle | Ekaterina Bezverkhniaia Panagiotis Kanellopoulos Ulrika Rosenström Vladimir Tolmachev Anna Orlova Influence of Molecular Design on the Tumor Targeting and Biodistribution of PSMA-Binding Tracers Labeled with Technetium-99m International Journal of Molecular Sciences prostate cancer prostate-specific membrane antigen PSMA technetium-99m coupling linker BQ0411 |
| title | Influence of Molecular Design on the Tumor Targeting and Biodistribution of PSMA-Binding Tracers Labeled with Technetium-99m |
| title_full | Influence of Molecular Design on the Tumor Targeting and Biodistribution of PSMA-Binding Tracers Labeled with Technetium-99m |
| title_fullStr | Influence of Molecular Design on the Tumor Targeting and Biodistribution of PSMA-Binding Tracers Labeled with Technetium-99m |
| title_full_unstemmed | Influence of Molecular Design on the Tumor Targeting and Biodistribution of PSMA-Binding Tracers Labeled with Technetium-99m |
| title_short | Influence of Molecular Design on the Tumor Targeting and Biodistribution of PSMA-Binding Tracers Labeled with Technetium-99m |
| title_sort | influence of molecular design on the tumor targeting and biodistribution of psma binding tracers labeled with technetium 99m |
| topic | prostate cancer prostate-specific membrane antigen PSMA technetium-99m coupling linker BQ0411 |
| url | https://www.mdpi.com/1422-0067/25/7/3615 |
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