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Peptide Radioligands in Cancer Theranostics: Agonists and Antagonists

Berthold A Nock¹, Panagiotis Kanellopoulos¹, Lieke Joosten²

¹Molecular Radiopharmacy, INRaSTES, NCSR "Demokritos", 15310 Athens, Greece.

Pharmaceuticals (Basel, Switzerland)

|May 27, 2023

Abstract:

The clinical success of radiolabeled somatostatin analogs in the diagnosis and therapy-"theranostics"-of tumors expressing the somatostatin subtype 2 receptor (SST₂R) has paved the way for the development of a broader panel of peptide radioligands targeting different human tumors. This approach relies on the overexpression of other receptor-targets in different cancer types. In recent years, a shift in paradigm from internalizing agonists to antagonists has occurred. Thus, SST₂R-antagonist radioligands were first shown to accumulate more efficiently in tumor lesions and clear faster from the background in animal models and patients. The switch to receptor antagonists was soon adopted in the field of radiolabeled bombesin (BBN). Unlike the stable cyclic octapeptides used in the case of somatostatin, BBN-like peptides are linear, fast to biodegradable and elicit adverse effects in the body. Thus, the advent of BBN-like antagonists provided an elegant way to obtain effective and safe radiotheranostics. Likewise, the pursuit of gastrin and exendin antagonist-based radioligands is advancing with exciting new outcomes on the horizon. In the present review, we discuss these developments with a focus on clinical results, commenting on challenges and opportunities for personalized treatment of cancer patients by means of state-of-the-art antagonist-based radiopharmaceuticals.

Insights

Radiolabeled antagonists targeting cancer receptors offer improved tumor accumulation and faster clearance compared to agonists. This shift enhances the safety and efficacy of targeted cancer theranostics.

Area of Science:

Nuclear medicine and molecular imaging.
Oncology and targeted cancer therapy.
Radiopharmaceutical development.

Background:

Clinical success of somatostatin receptor subtype 2 (SST2R) radioligands for cancer theranostics.
Exploitation of receptor overexpression in various cancer types for targeted therapies.
Emerging trend towards receptor antagonists over agonists in radiopharmaceutical design.

Purpose of the Study:

To review the advancements in antagonist-based radiopharmaceuticals for cancer theranostics.
To highlight the clinical results and potential of novel peptide radioligands.
To discuss challenges and opportunities in personalized cancer treatment using these agents.

Main Methods:

Review of recent literature on antagonist radioligands targeting various cancer receptors.
Analysis of preclinical and clinical data for somatostatin, bombesin, gastrin, and exendin analogs.
Focus on receptor antagonist efficacy, tumor accumulation, and background clearance.

Main Results:

SST2R antagonist radioligands demonstrate superior tumor targeting and faster clearance than agonists.
Bombesin (BBN)-like antagonists offer improved safety and efficacy over linear BBN peptides.
Advancements in gastrin and exendin antagonist radioligands show promising clinical outcomes.

Conclusions:

Antagonist-based radiopharmaceuticals represent a significant paradigm shift in cancer theranostics.
These agents offer enhanced tumor targeting, improved safety profiles, and potential for personalized cancer treatment.
Further development holds promise for more effective and tailored oncological therapies.

Read full analysis

Keywords:

exendin gastrin radioligands peptide theranostics radiolabeled BBN-analogs radiotheranostics receptor antagonist somatostatin radioligands

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