Radiotheranostic landscape: A review of clinical and preclinical development

Radiotheranostics combines diagnostic imaging with targeted radionuclide therapy, representing a transformative approach in precision oncology. Landmark approvals of Lutathera^® and Pluvicto^® have catalyzed significant advancements in this field, driving research into novel radionuclides, targeting strategies, and clinical applications. This review evaluates the evolving clinical and preclinical landscape of radiotheranostics, highlighting advancements, emerging trends, and persistent challenges in radionuclide therapy.

A comprehensive analysis was performed, encompassing active clinical trials as of December 2024, sourced from ClinicalTrials.gov and TheranosticTrials.org. Preclinical developments were evaluated through a review of recent literature, focusing on innovations in radionuclide production, targeting molecules, and radiochemistry.

In reviewing the clinical landscape, agents targeting somatostatin receptors (SSTR) and prostate-specific membrane antigen (PSMA) still dominate the field, but new targets such as fibroblast activation protein (FAP), integrins, and gastrin-releasing peptide receptors (GRPR) are gaining traction in both clinical and preclinical development. While small molecules and peptides remain the most common radionuclide carriers, antibody-based carriers including bispecific antibodies, immunoglobin-derived antigen-binding fragments, and antibody-mimetic proteins are on the rise due to their specificity and adaptability. Innovations in radioligand design are driving a shift from agonists to antagonists, accompanied by the development of modified peptides with enhanced pharmacokinetics and tumor-targeting properties. Next-generation therapeutic radionuclides, such as the beta-emitter terbium-161 and alpha-emitters actinium-225 and lead-212, are under investigation to complement or replace lutetium-177, addressing the need for improved efficacy and reduced toxicity. Paired isotopic radionuclides are gaining popularity for their ability to optimize imaging and therapeutic dosimetry as they offer near-identical specificity, biodistribution, and metabolism. Additionally, radiohybrid systems represent an innovative approach to chelating chemically distinct radionuclide pairs within a single molecule, further enhancing flexibility in radiotheranostic design.

Radiotheranostics has transformed cancer care through its precision and adaptability, but challenges in radionuclide production, regulatory frameworks, and workforce training hinder broader adoption. Advances in isotopic pairing, next-generation radionuclides, and radiohybrid systems in preclinical and clinical settings hold promise to overcome these barriers. Collaborative efforts among academia, industry, and regulatory bodies are critical to accelerating innovation and optimizing clinical outcomes.