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Article

Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer—Optimization of the Affinity towards PSMA by Linker Modification in Murine Model

1
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden
2
Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, 171 77 Stockholm, Sweden
3
Department of Nuclear Medicine, Klinikum rechts der Isar der TUM, 80802 Munich, Germany
4
Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden
5
Department of Immunology, Genetics and Pathology, Uppsala University, 751 83 Uppsala, Sweden
6
Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia
*
Author to whom correspondence should be addressed.
These authors contributed equally.
These authors contributed equally.
Pharmaceutics 2020, 12(7), 614; https://doi.org/10.3390/pharmaceutics12070614
Received: 8 June 2020 / Revised: 27 June 2020 / Accepted: 28 June 2020 / Published: 1 July 2020
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 [111In]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 [111In]In-BQ7800. Herein, we showed that the affinity of a bispecific PSMA/GRPR heterodimer towards PSMA could be improved by linker modification. View Full-Text
Keywords: prostate cancer; PSMA; GRPR; heterodimer; molecular imaging; SPPS prostate cancer; PSMA; GRPR; heterodimer; molecular imaging; SPPS
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MDPI and ACS Style

Lundmark, F.; Abouzayed, A.; Mitran, B.; Rinne, S.S.; Varasteh, Z.; Larhed, M.; Tolmachev, V.; Rosenström, U.; Orlova, A. Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer—Optimization of the Affinity towards PSMA by Linker Modification in Murine Model. Pharmaceutics 2020, 12, 614. https://doi.org/10.3390/pharmaceutics12070614

AMA Style

Lundmark F, Abouzayed A, Mitran B, Rinne SS, Varasteh Z, Larhed M, Tolmachev V, Rosenström U, Orlova A. Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer—Optimization of the Affinity towards PSMA by Linker Modification in Murine Model. Pharmaceutics. 2020; 12(7):614. https://doi.org/10.3390/pharmaceutics12070614

Chicago/Turabian Style

Lundmark, Fanny, Ayman Abouzayed, Bogdan Mitran, Sara S. Rinne, Zohreh Varasteh, Mats Larhed, Vladimir Tolmachev, Ulrika Rosenström, and Anna Orlova. 2020. "Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer—Optimization of the Affinity towards PSMA by Linker Modification in Murine Model" Pharmaceutics 12, no. 7: 614. https://doi.org/10.3390/pharmaceutics12070614

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