| Summary: | 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 <sup>99m</sup>Tc can be utilized to facilitate the use of GRPR-targeting radiotracers for diagnostics of prostate cancers. Methods: Synthetically produced mercaptoacetyl-Ser-Ser-Ser (maSSS)-PEG<sub>2</sub>-RM26 and mercaptoacetyl-Ser-Glu-Ser (maSES)-PEG<sub>2</sub>-RM26 (RM26 = <span style="font-variant: small-caps;">d</span>-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH<sub>2</sub>) were radiolabeled with <sup>99m</sup>Tc 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 [<sup>99m</sup>Tc]Tc-maSSS-PEG<sub>2</sub>-RM26. Results: Peptides were radiolabeled with high yields (>98%), demonstrating GRPR specific binding and slow internalization in PC-3 cells. [<sup>99m</sup>Tc]Tc-maSSS-PEG<sub>2</sub>-RM26 outperformed [<sup>99m</sup>Tc]Tc-maSES-PEG<sub>2-</sub>RM26 in terms of GRPR affinity, with a lower dissociation constant (61 pM vs 849 pM) and demonstrating higher tumor uptake. [<sup>99m</sup>Tc]Tc-maSSS-PEG<sub>2</sub>-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 [<sup>99m</sup>Tc]Tc-maSSS-PEG<sub>2</sub>-RM26 clearly visualized the GRPR-overexpressing tumors. The dosimetry estimated for [<sup>99m</sup>Tc]Tc-maSSS-PEG<sub>2</sub>-RM26 showed the highest absorbed dose in the small intestine (1.65 × 10<sup>−3</sup> mGy/MBq), and the effective dose is 3.49 × 10<sup>−3</sup> mSv/MBq. Conclusion: The GRPR antagonist maSSS-PEG<sub>2</sub>-RM26 is a promising GRPR-targeting agent that can be radiolabeled through a single-step with the generator-produced <sup>99m</sup>Tc and used for imaging of GRPR-expressing prostate cancer.
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