Rational Design and Development of an Acyclic Chelator H₄pyox for Theranostic Radiometal Labeling under Mild...

Integrated diagnostic and therapeutic nuclear medicine requires chelators that coordinate multiple radionuclides efficiently under mild conditions. Herein, we developed H₄pyox, an acyclic chelator with a preorganized cavity designed to balance rapid kinetics with a high thermodynamic stability. H₄pyox achieves roughly quantitative radiochemical yields with various diagnostic and therapeutic radionuclides, ⁶⁸Ga, ⁸⁶Y, ¹⁷⁷Lu, etc., within 10 min at ambient temperature, whereas DOTA requires heating (>90 °C). Notably, H₄pyox maintains an ∼100% yield for ¹⁷⁷Lu at concentrations as low as 10^-7 M, significantly outperforming DOTA. To facilitate clinical translation, an activated ester, H₄pyox-NHS, was synthesized for efficient bioconjugation. The [¹⁷⁷Lu]Lu-pyox complex showed excellent stability in saline and mouse serum over 7 days of incubation, which is comparable to that of the [¹⁷⁷Lu]Lu-DOTA complex. Density functional theory calculations revealed that structural preorganization and high donor nucleophilicity underpin its rapid kinetics. Moreover, in vivo single-photon emission computed tomography/computed tomography imaging confirmed the stability of the [¹⁷⁷Lu]Lu-pyox complex and a dual metabolic excretion pathway (renal/hepatobiliary) without bone accumulation. These results support the potential of H₄pyox for radiopharmaceutical development and provide a complementary choice in the design of metal-based radiopharmaceuticals and in the tuning of their pharmacokinetic properties─especially for targeting vectors with poor thermal stability.