Design and Preclinical Evaluation of Two Prostate-Specific Membrane Antigen-Targeting Trifluoroborate Derivatives Suitable for One-Step Radiofluorination

Prostate cancer was the most frequently diagnosed cancer and the second leading cause of cancer-related death among men in the United States in 2025. Prostate-specific membrane antigen (PSMA)-targeted PET tracers have significantly improved the detection, visualization, and staging of prostate cancer. Recently, the novel prosthetic group [18F]AmBF3-Tz was introduced, combining simple isotopic 18F-radiolabeling of alkylammoniomethyltrifluoroborates (AmBF3) with efficient bioorthogonal tetrazine-trans-cyclooctene (TCO) conjugation. This study evaluated the suitability of [18F]AmBF3-Tz for radiolabeling PSMA-targeting urea derivatives and assessed its impact on PSMA-binding affinity in vitro and in vivo. Four precursors─TCO-PSMA, TCO-tranexamic acid-PSMA, AmBF3-PSMA, and AmBF3-tranexamic acid-PSMA─were synthesized and used for the preparation of [18F]AmBF3-PSMA and [18F]AmBF3-tranexamic acid-PSMA via one-step or two-step labeling strategies. Conjugation before radiolabeling gave radiochemical yields of 5.2–11.8%, whereas the two-step method gave 0.7–9.8%. Although these yields demonstrate feasibility, they are lower and more variable than the 33 ± 5% yield obtained for [18F]AmBF3-Tz and would require substantial optimization before clinical translation. Overall, [18F]AmBF3-PSMA and [18F]AmBF3-tranexamic acid-PSMA demonstrated PSMA-specific tumor uptake and enabled the visualization of C4-2 xenografts. The tranexamic acid-containing tracer showed higher tumor-to-background ratios than [18F]AmBF3-PSMA in this study, but the absolute tumor uptake was not significantly different between the two tracers. The moderate and variable radiochemical yields, microscale reaction sensitivity, and small animal group sizes indicate that this proof-of-concept platform warrants further optimization before its suitability for clinical translation can be assessed.