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Design, Synthesis, and Preclinical Evaluation of Novel Dimeric RM2-Based Radioligands for GRPR-Targeted Breast Cancer
P Paraïso1,2, A Savanovic1,2, L Li1,2
1Department of Radiology and Nuclear Medicine, Erasmus University Medical Center Rotterdam, 3015 GDRotterdam, The Netherlands.
Abstract:
The gastrin-releasing peptide receptor (GRPR) is an attractive target for breast cancer (BC) imaging, but the in vivo performance of GRPR-targeted radioligands, such as RM2 and NeoB, is limited by metabolic instability, which may compromise tumor retention. Here, we designed two dimeric RM2-based radioligands, hdPP-01 and hdPP-02, to investigate whether homodimerization could improve the preclinical profile of GRPR-targeted radiotracers. hdPP-01 was synthesized using a 1,3,5-triazine core, whereas hdPP-02 was obtained via a 2-cyanobenzothiazole/1,2-aminothiol click reaction. Both compounds were radiolabeled with indium-111 and evaluated in T47-D cells. The resulting radiotracers retained nanomolar GRPR-binding properties, showed higher GRPR-specific cellular uptake, and displayed improved stability in murine serum compared to [111In]In-RM2. In vivo, [111In]In-hdPP-01 demonstrated higher tumor uptake and prolonged retention time relative to [111In]In-RM2. These findings indicate that homodimerization can modulate stability, cellular uptake and tumor accumulation, supporting further optimization of dimeric RM2-based radioligands for GRPR-targeted BC imaging and therapy.
Insights
Dimeric gastrin-releasing peptide receptor (GRPR) radioligands, hdPP-01 and hdPP-02, show improved stability and tumor uptake for breast cancer (BC) imaging. Homodimerization enhances GRPR-targeted radiotracer performance.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Gastrin-releasing peptide receptor (GRPR) is a target for breast cancer (BC) imaging.
- Current GRPR-targeted radioligands like RM2 have limited in vivo performance due to metabolic instability, affecting tumor retention.
Purpose of the Study:
- To design and evaluate novel dimeric RM2-based radioligands (hdPP-01 and hdPP-02) to improve the preclinical profile of GRPR-targeted radiotracers.
- To investigate the impact of homodimerization on the stability, cellular uptake, and tumor accumulation of GRPR-targeted radioligands.
Main Methods:
- Synthesized two dimeric RM2 analogs, hdPP-01 (1,3,5-triazine core) and hdPP-02 (click chemistry).
- Radiolabeled compounds with indium-111 ([111In]).
- Evaluated GRPR binding, cellular uptake, serum stability, and in vivo tumor uptake/retention in preclinical models.
Main Results:
- Both [111In]In-hdPP-01 and [111In]In-hdPP-02 exhibited nanomolar GRPR-binding affinity.
- [111In]In-hdPP-01 and [111In]In-hdPP-02 showed enhanced GRPR-specific cellular uptake and improved stability in murine serum compared to [111In]In-RM2.
- [111In]In-hdPP-01 demonstrated significantly higher tumor uptake and prolonged retention in vivo.
Conclusions:
- Homodimerization of RM2-based radioligands can enhance metabolic stability, cellular uptake, and tumor accumulation.
- Dimeric GRPR-targeted radioligands represent a promising strategy for improving breast cancer imaging and therapy.
- Further optimization of dimeric RM2-based radioligands is warranted for clinical translation.
