Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands
Prostate-specific membrane antigen (PSMA) is overexpressed in the majority of prostate cancer cells and is considered to be an important target for the molecular imaging and therapy of prostate cancer. Herein, we present the design, synthesis, and evaluation of 11 PSMA-binding radioligands with modi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/5/1098 |
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| author | Fanny Lundmark Gustav Olanders Sara Sophie Rinne Ayman Abouzayed Anna Orlova Ulrika Rosenström |
| author_facet | Fanny Lundmark Gustav Olanders Sara Sophie Rinne Ayman Abouzayed Anna Orlova Ulrika Rosenström |
| author_sort | Fanny Lundmark |
| collection | DOAJ |
| description | Prostate-specific membrane antigen (PSMA) is overexpressed in the majority of prostate cancer cells and is considered to be an important target for the molecular imaging and therapy of prostate cancer. Herein, we present the design, synthesis, and evaluation of 11 PSMA-binding radioligands with modified linker structures, focusing on the relationship between molecular structure and targeting properties. The linker design was based on 2-naphthyl-L-alanine-tranexamic acid, the linker structure of PSMA-617. X-ray crystal-structure analysis of PSMA and structure-based design were used to generate the linker modifications, suggesting that substitution of tranexamic acid could lead to interactions with Phe546, Trp541, and Arg43 within the binding cavity. After synthesis through SPPS, analogues were labelled with indium-111 and evaluated in vitro for their specific binding, affinity, and cellular retention. Selected compounds were further evaluated in vivo in PSMA-expressing tumour-bearing mice. Based on the results, 2-naphthyl-L-alanine appears to be crucial for good targeting properties, whereas tranexamic acid could be replaced by other substituents. [<sup>111</sup>In]In-BQ7859, consisting of a 2-naphthyl-L-alanine-L-tyrosine linker, demonstrated favourable targeting properties. The substitution of tranexamic acid for L-tyrosine in the linker led to an improved tumour-to-blood ratio, highlighting [<sup>111</sup>In]In-BQ7859 as a promising PSMA-targeting radioligand. |
| first_indexed | 2024-03-10T03:05:29Z |
| format | Article |
| id | doaj.art-42ee0b13d37d48cfbedd198fa981a7f1 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T03:05:29Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-42ee0b13d37d48cfbedd198fa981a7f12023-11-23T12:39:35ZengMDPI AGPharmaceutics1999-49232022-05-01145109810.3390/pharmaceutics14051098Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting RadioligandsFanny Lundmark0Gustav Olanders1Sara Sophie Rinne2Ayman Abouzayed3Anna Orlova4Ulrika Rosenström5Department 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 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, SwedenProstate-specific membrane antigen (PSMA) is overexpressed in the majority of prostate cancer cells and is considered to be an important target for the molecular imaging and therapy of prostate cancer. Herein, we present the design, synthesis, and evaluation of 11 PSMA-binding radioligands with modified linker structures, focusing on the relationship between molecular structure and targeting properties. The linker design was based on 2-naphthyl-L-alanine-tranexamic acid, the linker structure of PSMA-617. X-ray crystal-structure analysis of PSMA and structure-based design were used to generate the linker modifications, suggesting that substitution of tranexamic acid could lead to interactions with Phe546, Trp541, and Arg43 within the binding cavity. After synthesis through SPPS, analogues were labelled with indium-111 and evaluated in vitro for their specific binding, affinity, and cellular retention. Selected compounds were further evaluated in vivo in PSMA-expressing tumour-bearing mice. Based on the results, 2-naphthyl-L-alanine appears to be crucial for good targeting properties, whereas tranexamic acid could be replaced by other substituents. [<sup>111</sup>In]In-BQ7859, consisting of a 2-naphthyl-L-alanine-L-tyrosine linker, demonstrated favourable targeting properties. The substitution of tranexamic acid for L-tyrosine in the linker led to an improved tumour-to-blood ratio, highlighting [<sup>111</sup>In]In-BQ7859 as a promising PSMA-targeting radioligand.https://www.mdpi.com/1999-4923/14/5/1098prostate cancerPSMAlinker optimisationmolecular imagingSPPSstructure-based design |
| spellingShingle | Fanny Lundmark Gustav Olanders Sara Sophie Rinne Ayman Abouzayed Anna Orlova Ulrika Rosenström Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands Pharmaceutics prostate cancer PSMA linker optimisation molecular imaging SPPS structure-based design |
| title | Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands |
| title_full | Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands |
| title_fullStr | Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands |
| title_full_unstemmed | Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands |
| title_short | Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands |
| title_sort | design synthesis and evaluation of linker optimised psma targeting radioligands |
| topic | prostate cancer PSMA linker optimisation molecular imaging SPPS structure-based design |
| url | https://www.mdpi.com/1999-4923/14/5/1098 |
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