SuFEx and macrocyclic chelation define orthogonal reactivity domains enabling isotopically versatile radiopharmaceuticals from a single peptide precursor

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.