A New Rapid Bioorthogonal Cyanopyridothiazole/1,2-Aminothiol Click Reaction for Radiolabeling Applications

Abstract A new cyanopyridothiazole (CPT)/1,2-aminothiol click reaction was developed through DFT-guided scaffold design, exhibiting substantially enhanced reaction kinetics while maintaining excellent bioorthogonality under catalyst-free conditions. The utility of this chemistry was demonstrated by the synthesis of [67Ga]Ga-labeled PSMA-targeted probes. In vivo preclinical SPECT/CT imaging studies showed specific uptake in PSMA-positive tumors and clear tumor visualization, supporting the application of the CPT chemistry as a versatile bioconjugation strategy for radiopharmaceutical development.