Preclinical Comparative Study of ⁶⁸Ga-Labeled DOTA, NOTA, and HBED-CC Chelated Radiotracers for Targeting PSMA

⁶⁸Ga-labeled, low-molecular-weight imaging agents that target the prostate-specific membrane antigen (PSMA) are increasingly used clinically to detect prostate and other cancers with positron emission tomography (PET). The goal of this study was to compare the pharmacokinetics of three PSMA-targeted radiotracers: ⁶⁸Ga-1, using DOTA-monoamide as the chelating agent; ⁶⁸Ga-2, containing the macrocyclic chelating agent p-SCN-Bn-NOTA; and ⁶⁸Ga-DKFZ-PSMA-11, currently in clinical trials, which uses the acyclic chelating agent, HBED-CC. The PSMA-targeting scaffold for all three agents utilized a similar Glu-urea-Lys-linker construct. Each radiotracer enabled visualization of PSMA+ PC3 PIP tumor, kidney, and urinary bladder as early as 15 min post-injection using small animal PET/computed tomography (PET/CT). ⁶⁸Ga-2 demonstrated the fastest rate of clearance from all tissues in this series and displayed higher uptake in PSMA+ PC3 PIP tumor compared to ⁶⁸Ga-1 at 1 h post-injection. There was no significant difference in PSMA+ PC3 PIP tumor uptake for the three agents at 2 and 3 h post-injection. ⁶⁸Ga-DKFZ-PSMA-11 demonstrated the highest uptake and retention in normal tissues, including kidney, blood, spleen, and salivary glands and PSMA-negative PC3 flu tumors up to 3 h post-injection. In this preclinical evaluation ⁶⁸Ga-2 had the most advantageous characteristics for PSMA-targeted PET imaging.