Development and Evaluation of a Vinyl Sulfone-Based Fluorine-18 Labeling Method for Constructing PSMA-targeted Prostate Cancer Imaging Agents.

Purpose: Since prostate-specific membrane antigen (PSMA) is widely expressed in nearly all stages of prostate cancer (PCa), PSMA tracers can be considered a viable diagnostic tool for PCa. Compared to Ga-labeled PSMA agents, F-labeled analogues have various advantages, including the ability to achieve large scale production; easy to commercialize due to its longer half-life; and the ability to image late time points. Because [F]vinyl sulfone (VS) is a good intermediate for labeling thiol groups in mild conditions with high labeling yield, we explored the use of various VS groups for PSMA modifications in this study.

Procedures: We developed six F-labeled radiotracers targeting PSMA from radioactive intermediates to explore targeting ability and distribution in vivo in LNCaP and 22RV1 tumor-bearing mice. Different labeling methods were compared on their ability to lead to PSMA agents with high contrast and uptake.

Results: In vitro stability assay showed that the tracer [F]4a had high stability, with more than 95% of the radiochemical purities remaining as intact forms after 0.5, 1, and 2 h incubation, respectively. In vitro binding assays showed that [F]4a has a low-micromole binding affinity of 9.45 µM. Cell uptake and internalization assays found that [F]4a exhibited the highest cell uptake and internalization in 22RV1 cells (1.25 ± 0.06, 1.32 ± 0.11, 1.73 ± 0.08, and 2.03 ± 0.14%ID/10 cells after 10 min, 30 min, 1 h, and 2 h incubation, respectively for cell uptake assay; 0.52 ± 0.02, 0.70 ± 0.11, 0.78 ± 0.04, and 0.98 ± 0.15%ID/10 cells after 10 min, 30 min, 1 h, and 2 h incubation, respectively for cell internalization assay.) Analysis of the PET images showed that the tracer [F]4a had the highest tumor uptake (3.38 ± 0.35%ID/g at 2 h p. i. in 22RV1 tumor-bearing mice; 30.16 ± 13.00%ID/g at 2 h p. i. in LNCaP tumor-bearing mice.) Of note, the tracer [F]4a showed an approximately threefold increase in tumor uptake compared to [Ga]PSMA-11 in LNCaP tumor-bearing mice at 2 h p. i. The biodistribution experiment verified the accuracy of the in vivo distribution of [F]4a in LNCaP and 22RV1 tumor-bearing mice by PET/CT imaging.

Conclusions: PSMA-targeted radiotracer [F]4a is a promising PET agent for prostate cancer diagnosis.