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Updated: Aug 16, 2025
Harnessing the Bioorthogonal Inverse Electron Demand Diels-Alder Cycloaddition for Pretargeted PET Imaging
Published on: February 3, 2015
Bioorthogonal Chemistry Approach for the Theranostics of GRPR-Expressing Cancers
Alice D'Onofrio1, Francisco Silva1, Lurdes Gano1,2
1Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Campus Tecnológico e Nuclear, Estrada Nacional 10, Km 139.7, 2695-066 Bobadela LRS, Portugal.
Abstract:
Several gastrin-releasing peptide receptor (GRPR) antagonists with improved in vivo behavior have been recently developed and tested in the clinic. However, despite the generally mild side effects of peptide receptor radionuclide therapy (PRRT), toxicity has been observed due to high doses delivered to nontarget tissues, especially in the kidneys and pancreas. Previous experiences with radiolabeled peptides opened a unique opportunity to explore GRPR pretargeting using clickable bombesin antagonists. Toward this goal, we used clickable DOTA-like radiocomplexes which have been previously evaluated by our group. We functionalized a potent GRPR antagonist with a clickable TCO moiety using two different linkers. These precursors were then studied to select the compound with the highest GRPR binding affinity and the best pharmacokinetics to finally explore the advantages of the devised pretargeting approach. Our results provided an important proof of concept toward the development of bioorthogonal approaches to GRPR-expressing cancers, which are worth investigating further to improve the in vivo results. Moreover, the use of clickable GRPR antagonists and DOTA/DOTAGA derivatives allows for fine-tuning of their pharmacokinetics and metabolic stability, leading to a versatile synthesis of new libraries of (radio)conjugates useful for the development of theranostic tools toward GRPR-expressing tumors.
Insights
Researchers developed clickable gastrin-releasing peptide receptor (GRPR) antagonists for targeted cancer therapy. This approach aims to reduce toxicity in non-target organs during peptide receptor radionuclide therapy (PRRT).
Area of Science:
- Nuclear Medicine
- Radiopharmaceutical Chemistry
- Oncology
Background:
- Peptide receptor radionuclide therapy (PRRT) shows promise for GRPR-expressing cancers but faces toxicity challenges in kidneys and pancreas.
- Existing GRPR antagonists require optimization for improved in vivo behavior and reduced off-target effects.
- Pretargeting strategies offer a potential solution to enhance therapeutic efficacy and minimize radiation dose to healthy tissues.
Purpose of the Study:
- To develop and evaluate novel clickable bombesin antagonists for gastrin-releasing peptide receptor (GRPR) pretargeting.
- To assess the GRPR binding affinity and pharmacokinetic properties of functionalized GRPR antagonists.
- To provide a proof of concept for bioorthogonal approaches in GRPR-targeted cancer theranostics.
Main Methods:
- Functionalization of a potent GRPR antagonist with a clickable TCO moiety using two distinct linkers.
- Utilized clickable DOTA-like radiocomplexes for potential radiolabeling.
- In vitro and in vivo evaluation of the developed precursors to determine GRPR binding affinity and pharmacokinetics.
Main Results:
- Successful synthesis and characterization of clickable GRPR antagonists.
- Identification of a lead compound with high GRPR binding affinity and favorable pharmacokinetic profile.
- Demonstrated proof of concept for the pretargeting strategy using clickable antagonists.
Conclusions:
- Clickable GRPR antagonists represent a promising avenue for developing advanced bioorthogonal pretargeting strategies in oncology.
- The developed compounds allow for fine-tuning of pharmacokinetic properties and metabolic stability.
- This versatile platform facilitates the synthesis of novel radioconjugates for theranostic applications targeting GRPR-expressing tumors.
