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Improving GRPR-targeting peptides for radiotheranostics application: insights from chelator modifications and
Karim Obeid1, Ekaterina Bezverkhniaia1, Vladimir Tolmachev2
1Department of Medicinal Chemistry, Uppsala University, 75183, Uppsala, Sweden.
Background:
Targeting the gastrin-releasing peptide receptor (GRPR) is a promising approach for radionuclide therapy in prostate and breast cancers. GRPR-targeting peptides often have limited metabolic stability, which can compromise their clinical efficacy due to rapid degradation in the bloodstream, leading to reduced tumor uptake. We previously reported the GRPR-targeting peptide AU-RM26-M2 (DOTAGA-PEG2-Pip-[Sar11]RM26), which demonstrated promising pharmacokinetics in GRPR-expressing xenografts. In this study, we aimed to enhance the metabolic stability and targeting properties of AU-RM26-M2 by incorporating α-methyl-L-tryptophan (MetTrp) at position 8 in the pharmacophore, and to investigate the influence of chelator choice (DOTAGA vs. DOTA) for labeling with Lu-177, a β-emitting therapeutic nuclide.
Results:
Therefore, we designed two peptides: PKB2 (DOTAGA-PEG2-Pip-[MetTrp8, Sar11]RM26) and PKB3 (DOTA-PEG2-Pip-[MetTrp8, Sar11]RM26). For comparison, we also evaluated the DOTA-bearing analogue of AU-RM26-M2, PKB1 (DOTA-PEG2-Pip-[Sar11]RM26). PKB1, PKB2, and PKB3 were labeled with Lu-177, achieving high radiochemical yields (> 97%) and purities (> 93%). In PC-3 cells, [177Lu]Lu-PKB1, [177Lu]Lu-PKB2, and [177Lu]Lu-PKB3 showed affinity in the sub-nanomolar range and high specificity for GRPR, with a slow internalization rate. The radiopeptides with MetTrp8 modification had high metabolic stability against peptidases in vivo. In PC-3 xenografts, [177Lu]Lu-PKB2 and [177Lu]Lu-PKB3 demonstrated rapid background clearance and high GRPR-mediated tumor activity uptake at 2 h pi, exceeding activity uptake in the kidneys. Activity uptake in the tumor was highly retained at 24 h pi.
Conclusions:
This study led to the development of two metabolically stable GRPR-targeting radiopeptides, [177Lu]Lu-PKB2 and [177Lu]Lu-PKB3, with a high potential for targeted radionuclide therapy.
Insights
New gastrin-releasing peptide receptor (GRPR)-targeting radiopeptides, [177Lu]Lu-PKB2 and [177Lu]Lu-PKB3, show enhanced metabolic stability and tumor uptake for targeted radionuclide therapy.
Area of Science:
- Nuclear medicine
- Radiopharmaceutical chemistry
- Oncology
Background:
- Gastrin-releasing peptide receptor (GRPR) targeting is a promising strategy for prostate and breast cancer radionuclide therapy.
- Current GRPR-targeting peptides face challenges with metabolic stability, limiting their clinical effectiveness due to rapid blood degradation and reduced tumor accumulation.
- Previous work established the GRPR-targeting peptide AU-RM26-M2, showing potential in GRPR-expressing xenografts.
Purpose of the Study:
- To enhance the metabolic stability and targeting capabilities of the GRPR-targeting peptide AU-RM26-M2.
- To investigate the impact of incorporating α-methyl-L-tryptophan (MetTrp) at position 8 on peptide pharmacophore.
- To evaluate the influence of chelator choice (DOTAGA vs. DOTA) for Lutetium-177 (Lu-177) labeling.
Main Methods:
- Design and synthesis of two novel peptides: PKB2 (DOTAGA-PEG2-Pip-[MetTrp8, Sar11]RM26) and PKB3 (DOTA-PEG2-Pip-[MetTrp8, Sar11]RM26).
- Preparation of a comparative DOTA-analogue, PKB1 (DOTA-PEG2-Pip-[Sar11]RM26).
- Labeling of PKB1, PKB2, and PKB3 with Lu-177, followed by in vitro characterization (binding affinity, specificity, internalization) and in vivo evaluation in PC-3 xenografts (metabolic stability, biodistribution).
Main Results:
- High radiochemical yields (>97%) and purities (>93%) were achieved for [177Lu]Lu-PKB1, [177Lu]Lu-PKB2, and [177Lu]Lu-PKB3.
- [177Lu]Lu-PKB1, [177Lu]Lu-PKB2, and [177Lu]Lu-PKB3 exhibited sub-nanomolar affinity and high specificity for GRPR in PC-3 cells, with slow internalization.
- Radiopeptides incorporating MetTrp8 demonstrated significant in vivo metabolic stability against peptidases.
- In PC-3 xenografts, [177Lu]Lu-PKB2 and [177Lu]Lu-PKB3 showed rapid background clearance, high GRPR-mediated tumor uptake at 2 hours post-injection (exceeding kidney uptake), and sustained tumor retention at 24 hours post-injection.
Conclusions:
- Successful development of two metabolically stable GRPR-targeting radiopeptides, [177Lu]Lu-PKB2 and [177Lu]Lu-PKB3.
- These novel radiopeptides hold significant potential for targeted radionuclide therapy in GRPR-expressing cancers.
- The MetTrp8 modification and chelator choice influenced the pharmacokinetic and targeting properties of the GRPR-targeting peptides.
