Harnessing the Radiochelation Chemistry of Theranostic, Rare Earth Isotopes

Abstract public domain (NIH RePORTER)

Theranostic isotope pairs—combining diagnostic and therapeutic radionuclides that target the same biochemical pathway—are transforming personalized medicine. Diagnostic imaging (via SPECT or PET) enables non- invasive disease localization, patient stratification, and treatment monitoring, while therapeutic isotopes deliver targeted cytotoxic radiation. Clinically, these pairs have improved treatment efficacy, reduced side effects, and enhanced patient outcomes. The positron-emitting rare earths 44Sc (Eβ⁺ avg = 632 keV, t1/2 = 4 h) and 86Y (Eβ⁺ avg = 660 keV, t1/2 = 14.7 h), along with the beta-emitting 177Lu (Eβ⁻ avg = 134 keV, t1/2 = 159.6 h) and 161Tb (Eβ⁻ avg = 154 keV, t1/2 = 166 h), have shown growing clinical impact and global demand. These isotopes are accessible: PET isotopes can be produced in commercial low-energy cyclotrons, and therapeutic isotopes are already available from high-flux reactors. To fully realize their potential, next-generation chelation strategies are urgently needed. Current radiochelation methods are incompatible with one-step, kit-based radiosynthesis or require different chemical precursor materials to accommodate isotopes of interest. This challenges clinical adoption, patient access and prevents accurate prediction of therapeutic dosing regimens based on diagnostic imaging. During the previous funding period, our research group has pioneered coordination chemistry approaches that are compatible with one-step, room temperature radiosynthesis of 44Sc, 86Y, 177Lu and 161Tb chelates, while simultaneously accommodating aqueous radiofluorination with the clinical PET isotope 18F (E<β+> = 476 keV, t1/2= 1.82 h). Together, this establishes an unprecedented theranostic pentad consisting of 18F, 44Sc, 86Y, 177Lu and 161Tb. Building on these advances, we propose a systematic, coordination chemistry-driven strategy to create functional radiopharmaceuticals for the F/Sc/Y/Lu/Tb pentad. Our specific aims are to: 1.) Identify chemical linkage strategies to conjugate cancer-targeting peptides without disrupting favorable radiochelation properties; 2.) Implement a photochemical solid-phase radiosynthesis platform to afford ready-to-inject radiopharmaceuticals 3.) Apply self-immolative amide bond chemistry to fine-tune pharmacokinetics through selective, in vivo hydrolysis. Validation of each Aim will be pursued using relevant preclinical mouse models of prostate, neuroendocrine, pancreatic cancer/glioblastoma.

Public health relevance public domain (NIH RePORTER)

The diagnostic positron-emitting isotope ¹⁸F, along with the rare earth elements ⁴⁴Sc and ⁸⁶Y, and the therapeutic beta-emitting isotopes ¹⁷⁷Lu and ¹⁶¹Tb, have demonstrated significant clinical utility, with global demand rising rapidly. To fully realize the potential of these isotopes in clinical applications, the development of next-generation radiolabeling strategies is essential, as current methods remain underdeveloped and limit their effectiveness. This proposal aims to address these critical limitations by advancing coordination chemistry approaches compatible with the theranostic pentad ¹⁸F, ⁴⁴Sc, ⁸⁶Y, ¹⁷⁷Lu, and ¹⁶¹Tb, and applying them to the design of functional, clinically translatable radiopharmaceuticals.