Synthesis and Evaluation of Ga- and Lu-Labeled ()- vs ()-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives.

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, [Ga]Ga-PSMA-093 ([Ga]Ga-HBED-CC--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 ()- or ()-DOTAGA. This chelating group serves not only for chelating Ga but is also amendable for complexing other radioactive metals for radionuclide therapy. The corresponding optically pure ()- and ()-[Ga/Lu]-DOTAGA derivatives, ()-[Ga/Lu]- and ()-[Ga/Lu]-, were successfully prepared. Comparison of radiolabeling, binding affinity, cell uptake, and biodistribution between the two isomers was performed. Radiolabeling of ()-[Lu]Lu- and ()[Lu]Lu- at 50 °C suggested that rates of complex formation were time-dependent and the formation of ()-[Lu]Lu- was distinctly faster. The rates of complex formation for the corresponding Ga agents were comparable between structural isomers. The Ga and Lu equivalents showed high binding PSMA affinity (IC = 24-111 nM), comparable to that of the parent agent, [Ga]Ga-PSMA-093 (IC = 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 ()- and ()-isomers. This is the first time that a pair of [Ga/Lu]-()- and ()-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 Lu-DOTAGA-based radionuclide therapy agents in the future.