Peptide-Based ROR1-Targeting PET Ligands for Melanoma Tumor Imaging: Design and Preclinical Evaluation

作者：Donglan Huang, Xingru Long, Li Zhong, Yajing Wang, Xuan Di, Zheng Wang, Shuhan Zhou, Xiaoyu Du, Yang Zhang, Hai Qian, Dawei Jiang, Hualong Fu · 发表于：Journal of Medicinal Chemistry · 年份：2026 · DOI：10.1021/acs.jmedchem.6c00570 · 被引用次数：3 · 研究领域：Melanoma and MAPK Pathways、HER2/EGFR in Cancer Research、Chemokine receptors and signaling

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in multiple cancers while remaining largely absent in adult tissues, which makes it an attractive target for both tumor diagnosis and therapy. To enable noninvasive imaging of ROR1, four peptide-based PET ligands [ 68 Ga] 1 – 4 were rationally designed and evaluated for melanoma imaging. In vitro assays confirmed reasonable ROR1 binding affinity ( K D = 481.0 and 44.9 nM, respectively) and specific cellular uptake of [ 68 Ga] 2 and [ 68 Ga] 3, which are functionalized with serum albumin-binding groups. Notably, microPET/CT imaging and biodistribution studies in B16F10, A375, and SK-MEL-28 tumor-bearing mice demonstrated that [ 68 Ga] 2 achieved the most favorable imaging performance, characterized by high tumor accumulation (up to 9.18% ID/g), sustained retention, and a relatively lower nonspecific background signal. These findings highlight [ 68 Ga] 2 as a promising candidate for ROR1-targeting PET imaging and underscore the potential of peptide-based ROR1 PET probes for tumor imaging and therapy guidance.