Preclinical Evaluation of 99mTc-Labeled GRPR Antagonists maSSS/SES-PEG2-RM26 for Imaging of Prostate Cancer

Ayman Abouzayed; Sara S Rinne; Hamideh Sabahnoo; Jens Sörensen; Vladimir Chernov; Vladimir Tolmachev; Anna Orlova

doi:10.3390/pharmaceutics13020182

Preclinical Evaluation of ^99mTc-Labeled GRPR Antagonists maSSS/SES-PEG₂-RM26 for Imaging of Prostate Cancer

Pharmaceutics. 2021 Jan 30;13(2):182. doi: 10.3390/pharmaceutics13020182.

Authors

Ayman Abouzayed¹, Sara S Rinne¹, Hamideh Sabahnoo¹, Jens Sörensen², Vladimir Chernov^{3

4}, Vladimir Tolmachev^{4

5}, Anna Orlova^{1

4

6}

Affiliations

¹ Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden.
² Division of Radiology and Nuclear Medicine, Department of Surgical Sciences, Uppsala University, 751 85 Uppsala, Sweden.
³ Department of Nuclear Medicine, Cancer Research Institute, Tomsk National Research Medical Center Russian Academy of Sciences, Tomsk 634009, Russia.
⁴ Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk 634050, Russia.
⁵ Department of Immunology, Genetics and Pathology, Uppsala University, 752 37 Uppsala, Sweden.
⁶ Science for Life Laboratory, Uppsala University, 752 37 Uppsala, Sweden.

Abstract

Background: Gastrin-releasing peptide receptor (GRPR) is an important target for imaging of prostate cancer. The wide availability of single-photon emission computed tomography/computed tomography (SPECT/CT) and the generator-produced ^99mTc can be utilized to facilitate the use of GRPR-targeting radiotracers for diagnostics of prostate cancers.

Methods: Synthetically produced mercaptoacetyl-Ser-Ser-Ser (maSSS)-PEG₂-RM26 and mercaptoacetyl-Ser-Glu-Ser (maSES)-PEG₂-RM26 (RM26 = d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂) were radiolabeled with ^99mTc and characterized in vitro using PC-3 cells and in vivo, using NMRI or PC-3 tumor bearing mice. SPECT/CT imaging and dosimetry calculations were performed for [^99mTc]Tc-maSSS-PEG₂-RM26.

Results: Peptides were radiolabeled with high yields (>98%), demonstrating GRPR specific binding and slow internalization in PC-3 cells. [^99mTc]Tc-maSSS-PEG₂-RM26 outperformed [^99mTc]Tc-maSES-PEG_2-RM26 in terms of GRPR affinity, with a lower dissociation constant (61 pM vs 849 pM) and demonstrating higher tumor uptake. [^99mTc]Tc-maSSS-PEG₂-RM26 had tumor-to-blood, tumor-to-muscle, and tumor-to-bone ratios of 97 ± 56, 188 ± 32, and 177 ± 79, respectively. SPECT/CT images of [^99mTc]Tc-maSSS-PEG₂-RM26 clearly visualized the GRPR-overexpressing tumors. The dosimetry estimated for [^99mTc]Tc-maSSS-PEG₂-RM26 showed the highest absorbed dose in the small intestine (1.65 × 10^-3 mGy/MBq), and the effective dose is 3.49 × 10^-3 mSv/MBq.

Conclusion: The GRPR antagonist maSSS-PEG₂-RM26 is a promising GRPR-targeting agent that can be radiolabeled through a single-step with the generator-produced ^99mTc and used for imaging of GRPR-expressing prostate cancer.

Keywords: RM26; gastrin-releasing peptide receptor antagonist; prostate cancer; single-photon emission computed tomography; technetium-99m.

Abstract

Grants and funding