Gallium-68 P16-093

Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer cells and therefore is an attractive target for prostate cancer diagnosis and radionuclide therapy. Recently, published results from clinical studies using a new PSMA-targeting PET imaging agent, [⁶⁸Ga]Ga-PSMA-093 ([⁶⁸Ga]Ga-HBED-CC-O-carboxymethyl-Tyr-CO-NH-Glu), support the development of this agent for the diagnosis of prostate cancer. In this study, the HBED-CC chelating group in PSMA-093 was replaced by stereoselective (R)- or (S)-DOTAGA. This chelating group serves not only for chelating ⁶⁸Ga but is also amendable for complexing other radioactive metals for radionuclide therapy. The corresponding optically pure (R)- and (S)-[⁶⁸Ga/¹⁷⁷Lu]-DOTAGA derivatives, (R)-[⁶⁸Ga/¹⁷⁷Lu]-13 and (S)-[⁶⁸Ga/¹⁷⁷Lu]-13, were successfully prepared. Comparison of radiolabeling, binding affinity, cell uptake, and biodistribution between the two isomers was performed. Radiolabeling of (R)-[¹⁷⁷Lu]Lu-13 and (S)-[¹⁷⁷Lu]Lu-13 at 50 °C suggested that rates of complex formation were time-dependent and the formation of (S)-[¹⁷⁷Lu]Lu-13 was distinctly faster. The rates of complex formation for the corresponding ⁶⁸Ga agents were comparable between structural isomers. The ^natGa and ^natLu equivalents showed high binding PSMA affinity (IC₅₀ = 24-111 nM), comparable to that of the parent agent, [^natGa]Ga-PSMA-093 (IC₅₀ = 34.0 nM). Results of cell uptake and biodistribution studies in PSMA-expressing PC3-PIP tumor-bearing mice appeared to show no difference between the labeled (R)- and (S)-isomers. This is the first time that a pair of [⁶⁸Ga/¹⁷⁷Lu]-(R)- and (S)-DOTAGA isomers of PSMA agents were evaluated. Results of biological studies between the isomers showed no noticeable difference; however, the distinctions on the rate of Lu complex formation should be considered in the development of new ¹⁷⁷Lu-DOTAGA-based radionuclide therapy agents in the future.