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The nine-coordinate aza-macrocycle DO3Apic-NO2 and its kinetically inert rare earth complexes [M(DO3A-pic-NO2)]− (M = La, Tb, Eu, Lu, Y) can be readily bioconjugated to surface accessible thioles on peptides and proteins with a minimal structural footprint. All complexes express thioconjugation rate constants in the same order of magnitude ( k = 0.3 h −1 ) with the exception of Sc ( k = 0.89 h −1 ). Coupling to peptides and biologics with accessible cysteines also enables post-radiochelation bioconjugation at room temperature to afford injection-ready radiopharmaceuticals as demonstrated by formation of [ 177 Lu][Lu(DO3Apic-NO2)] − and [ 86 Y][Y(DO3Apic-NO2)] − , followed by post-labeling conjugation to a cysteine-functionalized peptide targeting the prostate specific membrane antigen. The 86 Y-labeled construct efficiently localizes in target tumors with no significant off-target accumulation as evidenced by positron emission tomography, biodistribution studies and metabolite analysis. 

Luminescent lanthanides possess ideal properties for biological imaging, including long luminescent lifetimes and emission within the optical window. Here, we report a novel approach to responsive luminescent Tb( iii ) probes that involves direct modulation of the antenna excited triplet state energy. If the triplet energy lies too close to the 5 D 4 Tb( iii ) excited state (20 500 cm −1 ), energy transfer to 5 D 4 competes with back energy transfer processes and limits lanthanide-based emission. To validate this approach, a series of pyridyl-functionalized, macrocyclic lanthanide complexes were designed, and the corresponding lowest energy triplet states were calculated using density functional theory (DFT). Subsequently, three novel constructs L3 (nitro-pyridyl), L4 (amino-pyridyl) and L5 (fluoro-pyridyl) were synthesized. Photophysical characterization of the corresponding Gd( iii ) complexes revealed antenna triplet energies between 25 800 and 30 400 cm −1 and a 500-fold increase in quantum yield upon conversion of Tb( L3 ) to Tb( L4 ) using the biologically relevant analyte H 2 S. The corresponding turn-on reaction can be monitored using conventional, small-animal optical imaging equipment in presence of a Cherenkov radiation emitting isotope as an in situ excitation source, demonstrating that antenna triplet state energy modulation represents a viable approach to biocompatible, Tb-based optical turn-on probes.