Evaluation of Bifunctional, PSMA-Targeted Triazamacrocycle-Picolinates Compatible with the ¹⁸ F/ ⁴⁴ Sc/ ¹⁷⁷ Lu Isotope Triad

The development of matched diagnostic and therapeutic radiopharmaceuticals─theranostic pairs─has emerged as a promising strategy to advance personalized nuclear medicine. However, many current systems rely on chemically distinct elements such as the ⁶⁸Ga³⁺/¹⁷⁷Lu³⁺ pair, leading to inconsistencies in the pharmacokinetics. Here, we evaluate bifunctional chelator platforms derived of triazamacrocycle picolinates, capable of stably incorporating three clinically relevant isotopes ¹⁸F⁻, ⁴⁴Sc³⁺, and ¹⁷⁷Lu³⁺. mpatcn supported the formation of [¹⁸F][ScF], [⁴⁴Sc][Sc], and [¹⁷⁷Lu][Lu] complexes when conjugated to a PSMA-targeting peptide (picaga-Met-hex-KuE). picaga-Met-hex-KuE displayed quantitative radiochemical yields and >95% formulation stability after 2 h. Biodistribution and metabolite analysis confirmed PSMA-targeting, minimal off-target uptake, and renal clearance for all picaga-Met-hex-KuE systems. Additionally, we demonstrate that a cartridge-based purification method formulates [¹⁸F][ScF(picaga-Met-hex-KuE)] in >95% radiochemical purity with nondecay corrected yields of 32% in under 110 min. These results establish picaga-Met-hex-KuE as a lead scaffold for the ¹⁸F/⁴⁴Sc/¹⁷⁷Lu triad, enabling single-kit radiopharmaceutical preparation for theranostic applications.