134Ce/134La Radiotheranostics from PET Surrogation of 225Ac to Auger and Conversion-Electron Therapy

Abstract The development of 134Ce as both a positron-emitting surrogate for 225Ac and a therapeutic Auger and conversion-electron (ACE) emitter has accelerated rapidly in recent years, positioning it as one of the most versatile emerging radionuclides for targeted radiopharmaceuticals. Existing PET radionuclides used as imaging surrogates for 225Acincluding 64Cu, 68Ga, and 89Zrsuffer from kinetic, chemical, and dosimetric mismatches that limit their ability to accurately predict the biodistribution of the long-lived alpha emitter and the in vivo redistribution of its radioactive daughters. Lanthanum-based radionuclides (132La, 133La) offer improved chemical compatibility but face production challenges, imaging limitations, and sparse in vivo validation. In contrast, the 134Ce/134La pair offers the dual advantage of being an f-block element with chemistry closely mirroring that of 225Ac and whose high positron branching ratio (63.6%) and long half-life (t1/2 = 3.16 days) enable extended-time PET imaging, specifically with longer half-life macromolecules in vivo. Recent studies have demonstrated gigabecquerel (GBq) scale production of high-purity 134Ce, robust chelation strategies, and strong matched-pair performance with 225Ac across small molecules, antibodies, and pretargeting systems. Moreover, the first therapeutic application of 134Ce/134La therapies with ACEs and positrons has shown potent, PSMA-specific tumor repression with minimal off-target toxicity, highlighting its promise as a dual-function theranostic radionuclide. Collectively, the growing body of work on 134Ce establishes it as a compelling next-generation imaging surrogate for [225Ac]Ac-based radiopharmaceuticals and a potential therapeutic candidate through the utilization of its ACEs and positrons. In this review, we summarize the current progress in the development of [134Ce]Ce-based radiopharmaceuticals, highlighting studies reported to date for both imaging and therapeutic applications, and discuss the opportunities and challenges that must be addressed to advance this matched radionuclide pair toward clinical translation.