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

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.