SuFEx and Macrocyclic Chelation Enable Orthogonal Dual Radiopharmaceutical Labeling from Single Peptide Precursors

The development of radiotheranostic agents, which combine diagnostic imaging with targeted radionuclide therapy, faces a critical challenge: existing methods for incorporating fluorine-18 (¹⁸F) are often chemically incompatible with the macrocyclic chelators required for radiometal labeling (e.g., ⁶⁸Ga, ¹⁷⁷Lu). Current strategies either require harsh conditions, consume the chelator site, or introduce structural changes that alter the agent's pharmacokinetic profile. This fundamental incompatibility limits the design flexibility and clinical utility of next-generation radiopharmaceuticals, necessitating separate precursors or complex synthesis routes.

Researchers developed a platform leveraging sulfur(VI) fluoride exchange (SuFEx) chemistry for ¹⁸F incorporation and macrocyclic metal coordination for radiometals within a single peptide precursor. An aryl fluorosulfate group on a tyrosine residue was used to accept ¹⁸F under mildly basic conditions. Simultaneously, a spatially distinct macrocyclic chelator (e.g., DOTA, NOTA, NODAGA) was incorporated to coordinate diagnostic (e.g., ⁶⁸Ga, ⁶⁴Cu) or therapeutic (e.g., ¹⁷⁷Lu) radiometals under mildly acidic conditions. The method was validated across PD-L1- and CD38-targeting peptide scaffolds, assessing receptor-binding affinity and pharmacokinetics.

The study successfully demonstrated that SuFEx and macrocyclic metal coordination define non-overlapping reactivity domains, allowing independent labeling pathways under mutually compatible conditions. This orthogonal approach preserved receptor-binding affinity, delivering nanomolar target affinity across both PD-L1- and CD38-targeting scaffolds. The labeling reactions consistently achieved high radiochemical yields, ensuring efficient radionuclide incorporation. Importantly, the dual-labeled peptides exhibited matched pharmacokinetics, indicating that the additional labeling did not adversely affect their in vivo behavior. This establishes isotopic orthogonality as an intrinsic, designable property for synthetic molecular radiopharmaceuticals.

The independent labeling pathways proceeded under mutually compatible conditions, preserving receptor-binding affinity and delivering nanomolar target affinity with high radiochemical yields.