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Pharmacokinetic Optimization of Radiocopper-Based Theranostic Pretargeting.

Mike A Cornejo1,2,3, Zachary V Samuels1,2,3, Gina Dehlavi1,2,4,5

  • 1Department of Chemistry, Hunter College, The City University of New York, New York, New York 10021, United States.

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This study developed novel copper-64 and copper-67 radioligands for in vivo pretargeting in colorectal cancer imaging and therapy. The PEGylated tetrazine, SarAr-PEG10-Tz, showed superior tumor targeting and efficacy in preclinical models.

Keywords:
PEGylationPETcopper-64copper-67multistep targetingpositron emission tomographypretargeted radioimmunotherapypretargetingradiocopperradioimmunotherapyradiopharmaceutical therapysarcophaginetargeted radionuclide therapy

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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.