The GRPR Antagonist [99mTc]Tc-maSSS-PEG2-RM26 towards Phase I Clinical Trial: Kit Preparation, Characterization and Toxicity

Abstract

Gastrin-releasing peptide receptors (GRPRs) are overexpressed in the majority of primary prostate tumors and in prostatic lymph node and bone metastases. Several GRPR antagonists were developed for SPECT and PET imaging of prostate cancer. We previously reported a preclinical evaluation of the GRPR antagonist [99mTc]Tc-maSSS-PEG2-RM26 (based on [D-Phe6, Sta13, Leu14-NH2]BBN(6-14)) which bound to GRPR with high affinity and had a favorable biodistribution profile in tumor-bearing animal models. In this study, we aimed to prepare and test kits for prospective use in an early-phase clinical study. The kits were prepared to allow for a one-pot single-step radiolabeling with technetium-99m pertechnetate. The kit vials were tested for sterility and labeling efficacy. The radiolabeled by using the kit GRPR antagonist was evaluated in vitro for binding specificity to GRPR on PC-3 cells (GRPR-positive). In vivo, the toxicity of the kit constituents was evaluated in rats. The labeling efficacy of the kits stored at 4 °C was monitored for 18 months. The biological properties of [99mTc]Tc-maSSS-PEG2-RM26, which were obtained after this period, were examined both in vitro and in vivo. The one-pot (gluconic acid, ethylenediaminetetraacetic acid, stannous chloride, and maSSS-PEG2-RM26) single-step radiolabeling with technetium-99m was successful with high radiochemical yields (>97%) and high molar activities (16–24 MBq/nmol). The radiolabeled peptide maintained its binding properties to GRPR. The kit constituents were sterile and non-toxic when tested in living subjects. In conclusion, the prepared kit is considered safe in animal models and can be further evaluated for use in clinics.

Gastrin-releasing peptide receptor (GRPR) as a novel biomarker and therapeutic target in prostate cancer

“…Gastrin-releasing peptide receptor (GRPR), a subtype of the bombesin (BBN) G protein-coupled receptor family, is overexpressed in prostate cancer, particularly in low-grade and smaller tumors [ 16 , 29 ]. RM2 is one of the extensively applied synthetic GRPR antagonists.…”

“…GRPR exhibits high expression, especially in early-stage prostate cancers, primarily within tumor cells [ 16 , 41 ]. Radiolabeled GRPR, particularly antagonists, offers precise localization of tumor cell localization, improving therapeutic outcomes.…”

“…Additionally, GRPR antagonists can bypass GRPR activation, which might otherwise stimulate tumor cell proliferation and growth. Furthermore, GRPR antagonists are small in size, allowing rapid tissue penetration and swift blood clearance [ 16 , 44–48 ]. GRPR radio antagonists, including but not limited to 68 Ga-RM2, 68 Ga-NeoBOMB1, 68 Ga- ProBOMB2, 177 Lu-ProBOMB2, 68 Ga-HZ220, 68 Ga-SB3, [ 68 Ga]Ga-DOTA-Ava-BBN2, [99 m Tc]Tc-DB15, [44 g Sc]Sc-DOTA-Ava-BBN2, 68 Ga-JMV4168/ 177 Lu-JMV4168, 68 Ga-AMBA/ 177 Lu-AMBA, and [99 m Tc]Tc-maSSS-PEG2-RM26, have demonstrated promising outcomes in both prostate cancer imaging and treatment [ 49–59 ].…”

“…To develop a more comprehensive imaging approach for prostate cancer, it is necessary to target other cellular markers besides PSMA. In this regard, GRPR has emerged as a significant and promising target [ 16 ].…”

Clinical application of 99mTc‐labeled peptides for tumor imaging: Current status and future directions

“…The results demonstrated that a single injection of 99m Tc‐maSSS‐PEG 2 ‐RM26 was well tolerated after administration. Multiple primary tumors and metastases were effectively visualized by SPECT/CT in both prostate and breast cancers [53, 54].…”