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Published on: January 7, 2019
Linker modifications in radiolabeled RM26-based antagonists to gastrin-releasing peptide receptor (GRPR) improved
Ekaterina Bezverkhniaia1, Ayman Abouzayed1, Panagiotis Kanellopoulos1
1Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden.
Abstract:
Radionuclide targeting of gastrin-releasing peptide receptor (GRPR) holds significant diagnostic and therapeutic potential, particularly in PSMA-negative/low-grade prostate cancer, estrogen receptor-positive breast cancer, and other malignancies. Recently, our group reported the development and results of the Phase I clinical evaluation of [99mTc]Tc-maSSS-PEG2-RM26, an antagonist GRPR-targeting SPECT imaging agent. This study focuses on developing the next generation of RM-26-based GRPR antagonists with enhanced metabolic stability and improved pharmacokinetics. Four new RM-26-based agents containing sarcosine (Sar) at position 11 to improve the in vivo stability and with more hydrophilic linkers were designed: Pep1 - maSSS-PEG2-[Sar11]RM26, Pep2 - maSSS-PEG6-[Sar11]RM26, Pep3 - maSSS-PEG2-Pip-[Sar11]RM26, and Pep4 - maSSS-EEE-[Sar11]RM26. These analogs were compared both in vitro and in vivo with [99mTc]Tc-maSSS-PEG2-RM26 as a reference. In PC-3 cells, [99mTc]Tc-Pep1, [99mTc]Tc-Pep2 and [99mTc]Tc-Pep3, but not [99mTc]Tc-Pep4, specifically bound to GRPR and exhibited low nanomolar affinity. When compared in vivo, [99mTc]Tc-Pep1, [99mTc]Tc-Pep2, and [99mTc]Tc-Pep3 demonstrated rapid blood clearance with different degrees of hepatobiliary excretion, particularly [99mTc]Tc-Pep2 and [99mTc]Tc-Pep3 had significantly lower activity uptake in the liver and gastrointestinal tract compared to [99mTc]Tc-maSSS-PEG2-RM26. Both [99mTc]Tc-Pep2 and [99mTc]Tc-Pep3 showed improved metabolic stability, bound specifically to GRPR in vivo, and demonstrated a tendency (not statistically significant) for higher tumor activity uptake compared to the reference peptide. Biodistribution data were confirmed by SPECT/CT imaging. In conclusion, the analogs with an elongation of the PEG2-linker either up to PEG6 (Pep2) or with the addition of a basic piperidine-containing moiety (Pep3) demonstrated an improvement of the pharmacokinetic properties of these agents and justify further investigations.
Insights
New gastrin-releasing peptide receptor (GRPR) antagonists show improved stability and pharmacokinetics for cancer imaging. These agents offer potential for better diagnostic and therapeutic applications in various malignancies.
Area of Science:
- Nuclear Medicine
- Radiopharmaceutical Chemistry
- Oncology
Background:
- Gastrin-releasing peptide receptor (GRPR) targeting has potential in diagnosing and treating cancers like prostate and breast cancer.
- Previous GRPR-targeting SPECT imaging agents like [99mTc]Tc-maSSS-PEG2-RM26 have shown promise.
- There is a need for GRPR antagonists with enhanced metabolic stability and improved pharmacokinetic profiles.
Purpose of the Study:
- To design and evaluate novel RM-26-based GRPR antagonists with improved in vivo stability and pharmacokinetics.
- To compare the performance of new analogs against the reference agent [99mTc]Tc-maSSS-PEG2-RM26.
- To assess the diagnostic and therapeutic potential of these next-generation GRPR antagonists.
Main Methods:
- Four new RM-26 analogs (Pep1-Pep4) were synthesized, incorporating sarcosine at position 11 and varying linker lengths/compositions.
- In vitro studies involved assessing specific binding to GRPR in PC-3 cells.
- In vivo evaluation included biodistribution studies, metabolic stability assessment, and SPECT/CT imaging in preclinical models.
Main Results:
- [99mTc]Tc-Pep1, [99mTc]Tc-Pep2, and [99mTc]Tc-Pep3 demonstrated specific GRPR binding and low nanomolar affinity in vitro.
- In vivo, these analogs exhibited rapid blood clearance and reduced uptake in the liver and gastrointestinal tract compared to the reference.
- [99mTc]Tc-Pep2 and [99mTc]Tc-Pep3 showed improved metabolic stability and a trend towards higher tumor uptake, confirmed by SPECT/CT imaging.
Conclusions:
- Elongating the PEG linker (Pep2) or adding a piperidine moiety (Pep3) to RM-26-based GRPR antagonists significantly improves pharmacokinetic properties.
- These optimized analogs, Pep2 and Pep3, demonstrate enhanced metabolic stability and favorable biodistribution profiles.
- The findings support further investigation of these next-generation GRPR antagonists for clinical applications in cancer imaging and therapy.
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