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Cancers (Basel). 2019 Sep 14;11(9). pii: E1371. doi: 10.3390/cancers11091371.

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

Author information

1
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden. bogdan.mitran@ilk.uu.se.
2
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden. zohreh.varasteh@tum.de.
3
Department of Nuclear Medicine, Klinikum rechts der Isar der TUM, 81675 Munich, Germany. zohreh.varasteh@tum.de.
4
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden. ayman.abouzayed@ilk.uu.se.
5
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden. sara.rinne@ilk.uu.se.
6
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden. emmi.puuvuori@ilk.se.
7
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden. mderosa@fondazionerimed.com.
8
Drug Discovery Unit, Ri.MED Foundation, 90133 Palermo, Italy. mderosa@fondazionerimed.com.
9
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden. mats.larhed@ilk.uu.se.
10
Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden. mats.larhed@ilk.uu.se.
11
Department of Immunology, Genetics and Pathology, Uppsala University, 751 23 Uppsala, Sweden. vladimir.tolmachev@igp.uu.se.
12
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden. anna.orlova@ilk.uu.se.
13
Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden. anna.orlova@ilk.uu.se.
14
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden. ulrika.rosenstrom@ilk.uu.se.

Abstract

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.

KEYWORDS:

GRPR; PET; PSMA; SPECT; heterodimer; molecular imaging; prostate cancer

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