Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [¹⁷⁷Lu]Lu-PSMA-617

In recent years, radiolabeled tracers targeting prostate-specific membrane antigen (PSMA) have had a tremendous impact on prostate cancer management. Here, we report the formation of radioactive impurities formed during clinical production 177Lu-labeled PSMA-617. We provide compelling evidence that these are result spontaneous, thermally mediated condensation reaction Glu-CO-Lys moiety resulting in three different five-membered ring systems. Density functional theory (DFT) calculations show and cyclization is thermodynamically spontaneous. cell experiments, no affinity cyclized compounds toward PSMA was observed. HPLC analyses urine samples from patient studies showed rapid renal excretion species. Radiolabeling conditions were identified significantly reduced side products yielding PSMA-617 high radiochemical yield purity concordance with current good manufacturing practice (cGMP) requirements.