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

Area of Science:

• Oncology
• Radiochemistry
• Molecular Imaging

Background:

• Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in various cancers, making it a promising diagnostic and therapeutic target.
• ROR1's absence in most adult tissues enhances its specificity for cancer detection.
• Noninvasive imaging of ROR1 is crucial for guiding cancer therapy.

Purpose of the Study:

• To design and evaluate novel peptide-based positron emission tomography (PET) ligands for noninvasive ROR1 imaging.
• To assess the in vitro and in vivo performance of these ROR1-targeting PET probes, particularly in melanoma models.
• To identify a lead candidate for ROR1-targeted PET imaging and potential therapeutic applications.

Main Methods:

• Rational design of four peptide-based PET ligands ([⁶⁸Ga]1-4) targeting ROR1.
• In vitro evaluation of ROR1 binding affinity and specific cellular uptake.
• In vivo microPET/CT imaging and biodistribution studies in melanoma xenograft mouse models (B16F10, A375, SK-MEL-28).

Main Results:

• Ligands [⁶⁸Ga]2 and [⁶⁸Ga]3, functionalized with serum albumin-binding groups, demonstrated specific cellular uptake and reasonable ROR1 binding affinity (K_D = 481.0 and 44.9 nM).
• [⁶⁸Ga]2 exhibited superior imaging performance in vivo, with high tumor accumulation (up to 9.18% ID/g), sustained retention, and low background signal in multiple melanoma models.
• Biodistribution studies confirmed the tumor-specific accumulation and retention of [⁶⁸Ga]2.

Conclusions:

• The peptide-based PET ligand [⁶⁸Ga]2 is a highly promising candidate for noninvasive ROR1-targeted PET imaging of melanoma.
• The developed ROR1 PET probes demonstrate significant potential for tumor imaging and therapy guidance in clinical oncology.
• Serum albumin-binding groups enhance the performance of peptide-based PET ligands for ROR1 imaging.