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Open AccessArticle

Bispecific GRPR-Antagonistic Anti-PSMA/GRPR Heterodimer for PET and SPECT Diagnostic Imaging of Prostate Cancer

1
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden
2
Department of Nuclear Medicine, Klinikum rechts der Isar der TUM, 81675 Munich, Germany
3
Drug Discovery Unit, Ri.MED Foundation, 90133 Palermo, Italy
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 23 Uppsala, Sweden
*
Author to whom correspondence should be addressed.
These authors contributed equally.
These authors contributed equally.
Cancers 2019, 11(9), 1371; https://doi.org/10.3390/cancers11091371
Received: 11 August 2019 / Revised: 3 September 2019 / Accepted: 9 September 2019 / Published: 14 September 2019
(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)
Simultaneous targeting of the prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) could improve the diagnostic accuracy in prostate cancer (PCa). The aim of this study was to develop a PSMA/GRPR-targeting bispecific heterodimer for SPECT and positron emission tomography (PET) diagnostic imaging of PCa. The heterodimer NOTA-DUPA-RM26 was produced by manual solid-phase peptide synthesis. NOTA-DUPA-RM26 was labeled with 111In and 68Ga, with yields >98%, and demonstrated a high stability and binding specificity to PSMA and GRPR. IC50 values for natIn-NOTA-DUPA-RM26 were 4 ± 1 nM towards GRPR and 824 ± 230 nM towards PSMA. An in vivo binding specificity 1 h pi of 111In-NOTA-DUPA-RM26 in PC3-PIP-xenografted mice demonstrated partially blockable tumor uptake when co-injected with an excess of PSMA- or GRPR-targeting agents. Simultaneous co-injection of both agents induced pronounced blocking. The biodistribution of 111In-NOTA-DUPA-RM26 and 68Ga-NOTA-DUPA-RM26 revealed fast activity clearance from the blood and normal organs via the kidneys. Tumor uptake exceeded normal organ uptake for both analogs 1 h pi. 68Ga-NOTA-DUPA-RM26 had a significantly lower tumor uptake (8 ± 2%ID/g) compared to 111In-NOTA-DUPA-RM26 (12 ± 2%ID/g) 1 h pi. Tumor-to-organ ratios increased 3 h pi, but decreased 24 h pi, for 111In-NOTA-DUPA-RM26. MicroPET/CT and microSPECT/CT scans confirmed biodistribution data, suggesting that 68Ga-NOTA-DUPA-RM26 and 111In-NOTA-DUPA-RM26 are suitable candidates for the imaging of GRPR and PSMA expression in PCa shortly after administration. View Full-Text
Keywords: PSMA; GRPR; heterodimer; molecular imaging; prostate cancer; PET; SPECT PSMA; GRPR; heterodimer; molecular imaging; prostate cancer; PET; SPECT
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MDPI and ACS Style

Mitran, B.; Varasteh, Z.; Abouzayed, A.; Rinne, S.S.; Puuvuori, E.; De Rosa, M.; Larhed, M.; Tolmachev, V.; Orlova, A.; Rosenström, U. Bispecific GRPR-Antagonistic Anti-PSMA/GRPR Heterodimer for PET and SPECT Diagnostic Imaging of Prostate Cancer. Cancers 2019, 11, 1371.

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