SuFEx and macrocyclic chelation define orthogonal reactivity domains enabling isotopically versatile...

The design of radiotheranostic agents has been constrained by a fundamental chemical incompatibility: existing strategies for fluorine-18 incorporation - nucleophilic substitution, silicon-fluoride exchange, aluminum fluoride chelation, and prosthetic conjugation - either require conditions incompatible with macrocyclic metal coordination, consume the chelator site needed for radiometal labeling, or introduce non-native structural appendages that alter pharmacokinetic behavior. Here we show that sulfur(VI) fluoride exchange (SuFEx) chemistry and macrocyclic metal coordination define non-overlapping reactivity domains co-embeddable within a single peptide precursor. An aryl fluorosulfate on tyrosine accepts ¹⁸F under mildly basic conditions; a spatially distinct macrocyclic chelator, DOTA, NOTA, NODAGA, or any compatible macrocycle, independently coordinates diagnostic (⁶⁸Ga, ⁶⁴Cu) or therapeutic (¹⁷⁷Lu) radiometals under mildly acidic conditions. The labeling pathways proceed independently under mutually compatible conditions, and both preserve receptor-binding affinity. Validated across PD-L1- and CD38-targeting scaffolds, this platform delivers nanomolar target affinity, high radiochemical yields, and matched pharmacokinetics, establishing isotopic orthogonality as a designable, intrinsic property of synthetic molecular radiopharmaceuticals.