Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer—Optimization of the Affinity towards PSMA by Linker Modification in Murine Model
Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are promising targets for molecular imaging of prostate cancer (PCa) lesions. Due to the heterogenic overexpression of PSMA and GRPR in PCa, a heterodimeric radiotracer with the ability to bind to both targets co...
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doaj-24e5fa420d624a7bb7e732ff267177c92020-11-25T03:33:02ZengMDPI AGPharmaceutics1999-49232020-07-011261461410.3390/pharmaceutics12070614Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer—Optimization of the Affinity towards PSMA by Linker Modification in Murine ModelFanny Lundmark0Ayman Abouzayed1Bogdan Mitran2Sara S. Rinne3Zohreh Varasteh4Mats Larhed5Vladimir Tolmachev6Ulrika Rosenström7Anna Orlova8Department 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, SwedenScience for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, 751 83 Uppsala, SwedenDepartment of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, SwedenDepartment of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, SwedenProstate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are promising targets for molecular imaging of prostate cancer (PCa) lesions. Due to the heterogenic overexpression of PSMA and GRPR in PCa, a heterodimeric radiotracer with the ability to bind to both targets could be beneficial. Recently, our group reported the novel heterodimer BQ7800 consisting of a urea-based PSMA inhibitor, the peptide-based GRPR antagonist RM26 and NOTA chelator. The study reported herein, aimed to improve the affinity of BQ7800 towards PSMA by changing the composition of the two linkers connecting the PSMA- and GRPR-targeting motifs. Three novel heterodimeric analogues were synthesized by incorporation of phenylalanine in the functional linker of the PSMA-binding motif and/or shortening the PEG-linker coupled to RM26. The heterodimers were labeled with indium-111 and evaluated in vitro. In the competitive binding assay, BQ7812, featuring phenylalanine and shorter PEG-linker, demonstrated a nine-fold improved affinity towards PSMA. In the in vivo biodistribution study of [<sup>111</sup>In]In-BQ7812 in PC3-pip tumor-bearing mice (PSMA and GRPR positive), the activity uptake was two-fold higher in the tumor and three-fold higher in kidneys than for [<sup>111</sup>In]In-BQ7800. Herein, we showed that the affinity of a bispecific PSMA/GRPR heterodimer towards PSMA could be improved by linker modification.https://www.mdpi.com/1999-4923/12/7/614prostate cancerPSMAGRPRheterodimermolecular imagingSPPS |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Fanny Lundmark Ayman Abouzayed Bogdan Mitran Sara S. Rinne Zohreh Varasteh Mats Larhed Vladimir Tolmachev Ulrika Rosenström Anna Orlova |
spellingShingle |
Fanny Lundmark Ayman Abouzayed Bogdan Mitran Sara S. Rinne Zohreh Varasteh Mats Larhed Vladimir Tolmachev Ulrika Rosenström Anna Orlova Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer—Optimization of the Affinity towards PSMA by Linker Modification in Murine Model Pharmaceutics prostate cancer PSMA GRPR heterodimer molecular imaging SPPS |
author_facet |
Fanny Lundmark Ayman Abouzayed Bogdan Mitran Sara S. Rinne Zohreh Varasteh Mats Larhed Vladimir Tolmachev Ulrika Rosenström Anna Orlova |
author_sort |
Fanny Lundmark |
title |
Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer—Optimization of the Affinity towards PSMA by Linker Modification in Murine Model |
title_short |
Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer—Optimization of the Affinity towards PSMA by Linker Modification in Murine Model |
title_full |
Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer—Optimization of the Affinity towards PSMA by Linker Modification in Murine Model |
title_fullStr |
Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer—Optimization of the Affinity towards PSMA by Linker Modification in Murine Model |
title_full_unstemmed |
Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer—Optimization of the Affinity towards PSMA by Linker Modification in Murine Model |
title_sort |
heterodimeric radiotracer targeting psma and grpr for imaging of prostate cancer—optimization of the affinity towards psma by linker modification in murine model |
publisher |
MDPI AG |
series |
Pharmaceutics |
issn |
1999-4923 |
publishDate |
2020-07-01 |
description |
Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are promising targets for molecular imaging of prostate cancer (PCa) lesions. Due to the heterogenic overexpression of PSMA and GRPR in PCa, a heterodimeric radiotracer with the ability to bind to both targets could be beneficial. Recently, our group reported the novel heterodimer BQ7800 consisting of a urea-based PSMA inhibitor, the peptide-based GRPR antagonist RM26 and NOTA chelator. The study reported herein, aimed to improve the affinity of BQ7800 towards PSMA by changing the composition of the two linkers connecting the PSMA- and GRPR-targeting motifs. Three novel heterodimeric analogues were synthesized by incorporation of phenylalanine in the functional linker of the PSMA-binding motif and/or shortening the PEG-linker coupled to RM26. The heterodimers were labeled with indium-111 and evaluated in vitro. In the competitive binding assay, BQ7812, featuring phenylalanine and shorter PEG-linker, demonstrated a nine-fold improved affinity towards PSMA. In the in vivo biodistribution study of [<sup>111</sup>In]In-BQ7812 in PC3-pip tumor-bearing mice (PSMA and GRPR positive), the activity uptake was two-fold higher in the tumor and three-fold higher in kidneys than for [<sup>111</sup>In]In-BQ7800. Herein, we showed that the affinity of a bispecific PSMA/GRPR heterodimer towards PSMA could be improved by linker modification. |
topic |
prostate cancer PSMA GRPR heterodimer molecular imaging SPPS |
url |
https://www.mdpi.com/1999-4923/12/7/614 |
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