In vitro and in vivo comparative study of 68 Ga-labeled DOTA-, NOTA-, and HBEDCC-chelated radiotracers targeting prostate-specific membrane antigen

68 Ga-radiolabeled small molecules targeting prostate-specific membrane antigen (PSMA) have been extensively investigated as 68 Ga-positron emission tomography ( 68 Ga-PET) tracers. Nevertheless, current 68 Ga-labeled radiotracers suffer from either fair detection rates for metastatic prostate cancer lesions or a high uptake by the kidneys. This study synthesizes new PSMA-targeted radiotracers, [ 68 Ga]SC691-DOTA, [ 68 Ga]SC691-NOTA, and [ 68 Ga]SC691-HBEDCC, and explores the in vitro and in vivo properties. These three radiotracers enabled PSMA-positive LNCaP tumors to be visualized by micro-PET/CT as early as 5 min post-injection. Biodistribution studies revealed that all three compounds could accumulate in the tumor with high affinity. The kidney’s uptake of [ 68 Ga]SC691-DOTA and [ 68 Ga]SC691-NOTA was comparable but lower than [ 68 Ga]SC691-HBEDCC. [ 68 Ga]SC691-HBEDCC demonstrated the most increased uptake and retention in the tumor over 2 h post-injection and a lower tumor-to-tissue ratio than [ 68 Ga]SC691-DOTA, and [ 68 Ga]SC691-NOTA.