Development of Cyclic Peptide-Based Radiotracers for uPAR

Area of Science:

• Biomedical Imaging
• Radiochemistry
• Oncology

Background:

• The urokinase plasminogen activator (uPA) system, particularly its receptor (uPAR), is crucial in cancer progression and metastasis.
• uPAR-targeting radioligands are vital for early cancer diagnosis and treatment.
• Developing specific and effective radiotracers for uPAR imaging remains a key challenge.

Purpose of the Study:

• To synthesize and evaluate novel cyclic peptide-based positron emission tomography (PET) radioligands for uPAR imaging.
• To compare the performance of these novel radioligands with a clinically relevant tracer ([⁶⁴Cu]DOTA-AE105).
• To identify a lead candidate with optimal tumor uptake, specificity, and pharmacokinetic properties.

Main Methods:

• Development of three [⁶⁴Cu]-labeled cyclic peptide radioligands ([⁶⁴Cu]CARP-1, [⁶⁴Cu]CARP-2, [⁶⁴Cu]CARP-3) with varying disulfide bond configurations.
• In vivo evaluation in an MC38 tumor-bearing mouse model.
• Assessment of tumor uptake, specificity, biodistribution, and pharmacokinetics.
• Comparison with [⁶⁴Cu]DOTA-AE105.

Main Results:

• All three radioligands were successfully synthesized and radiolabeled with ⁶⁴Cu.
• [⁶⁴Cu]CARP-2 exhibited the highest tumor radioactivity accumulation and specificity among the novel candidates.
• Compared to [⁶⁴Cu]DOTA-AE105, [⁶⁴Cu]CARP-2 demonstrated reduced non-specific uptake and faster clearance from normal tissues.
• Favorable pharmacokinetics and biodistribution profiles were observed for [⁶⁴Cu]CARP-2.

Conclusions:

• [⁶⁴Cu]CARP-2 is a promising novel PET radioligand for uPAR imaging.
• Its enhanced tumor targeting and favorable pharmacokinetic profile suggest potential for improved diagnostic accuracy in cancer.
• [⁶⁴Cu]CARP-2 warrants further preclinical and clinical investigation for uPAR-targeted cancer imaging.