Pharmacokinetic Optimization of Radiocopper-Based Theranostic Pretargeting

Area of Science:

• Nuclear medicine
• Radiopharmaceutical chemistry
• Oncology

Background:

• In vivo pretargeting enhances tumor imaging and therapy by improving contrast and reducing healthy tissue radiation.
• The inverse electron-demand Diels-Alder (IEDDA) ligation between tetrazines (Tz) and trans-cyclooctenes (TCO) is a key pretargeting strategy.
• Radioligand pharmacokinetics critically influence pretargeting system performance.

Purpose of the Study:

• To synthesize and characterize sarcophagine-bearing tetrazines for copper-64 radiolabeling.
• To evaluate the performance of these radioligands in pretargeted immunoPET for colorectal cancer.
• To assess the therapeutic potential of the lead candidate radioligand labeled with copper-67.

Main Methods:

• Synthesis of sarcophagine-tetrazine conjugates (SarAr-Tz, SarAr-PEG5-Tz, SarAr-PEG10-Tz).
• Radiolabeling with Copper-64 (64Cu) and Copper-67 (67Cu).
• Pretargeted immunoPET imaging and biodistribution studies in a murine colorectal cancer model using huA33-TCO.

Main Results:

• All synthesized radioligands enabled excellent tumor-to-background contrast in immunoPET imaging.
• [64Cu]Cu-SarAr-PEG10-Tz demonstrated superior tumor-to-tissue activity concentration ratios.
• Pretargeted radioimmunotherapy with [67Cu]Cu-SarAr-PEG10-Tz showed promising efficacy and safety in vivo.

Conclusions:

• SarAr-PEG10-Tz is a highly effective radioligand for 64Cu-based pretargeted immunoPET.
• The developed [67Cu]Cu-SarAr-PEG10-Tz conjugate holds significant promise for colorectal cancer radioimmunotherapy.