Design, Synthesis, and Preclinical Evaluation of Novel Dimeric RM2-Based Radioligands for GRPR-Targeted Breast Cancer...

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.