Preclinical Evaluation of ¹⁸F-VS-PSMAs as New Prostate-Specific Membrane Antigen Ligands for Prostate Cancer Imaging

Introduction: Radiolabeled prostate-specific membrane antigen (PSMA) (1) reagents have rapidly been used as part of the care of prostate cancer patients. Recently, ¹⁸F-labeled PSMA agents have attracted extensive attraction due to the ready availability of 18F from existing medical cyclotrons, the relatively low positron energy and high positron percentage of 18F, which may lead to improved contrast/resolution (2). In this study, we report the development of a series of new ¹⁸F-labeled PSMA PET agents whose tumor uptake and tumor/major organ ratio can be adjusted by intramolecular pharmacokinetic linkers.

Methods: Based on the high-affinity Glu-ureido-Lys scaffold (3), five novel ¹⁸F-labeled PSMA PET agents were constructed. The binding affinity and radiochemical purity of PSMA ligand were studied. In vivo imaging experiments and quantification were performed in the LNCaP tumor model (PSMA positive) to evaluate the impact of PK linker on tumor uptake and contrast. Blocking experiments were performed to confirm target specificity. The lead agents were then compared with ⁶⁸Ga-PSMA-11 (Fig. 1) in a side-by-side comparison.

Results: The isolation yields of ¹⁸F-VS-PSMAs range from 26% to 50% and the radiochemical purity are > 96%. Although significant tumor uptake was observed for all PET agents, ¹⁸F-VS3-PSMA showed the highest tumor uptake, while ¹⁸F-VS2-PSMA showed the highest the tumor-to-liver ratio (T/L = 4.8 ± 1.2 at 1.5 h p.i.). Compared with ⁶⁸Ga-PSMA-11 (9.5 ± 1.1 %ID/g, T/L = 13.5 ± 1.4 at 1.5 h p.i), ¹⁸F-VS2-PSMA (14.9 ± 1.8 %ID/g, T/L = 4.5 ± 1.5 at 1.5 h p.i), and ¹⁸F-VS3-PSMA (20.3 ± 1.5 %ID/g, T/L = 6.2 ± 1.9 at 1.5 h p.i), showed significantly higher tumor uptake (P <0.0001) on the same animal that was scanned on different days. Although the liver uptake of our newly developed agents are higher than ⁶⁸Ga-PSMA-11, high tumor to muscle ratio were still obtained for ¹⁸F-VS2-PSMA and ¹⁸F-VS3-PSMA.

Conclusions: The newly developed ¹⁸F-VS-PSMAs are promising PET agents for prostate cancer imaging. The excellent tumor uptake and tunable major organ uptake warrant further evaluation of lead agents in prostate cancer patients. Key Words: Prostate cancer; prostate-specific membrane antigen (PSMA); positron Emission Tomography (PET); ¹⁸F-labeling; vinyl sulfone (VS).REFERENCES1. Carter RE, Feldman AR, Coyle JT. Prostate-specific membrane antigen is a hydrolase with substrate and pharmacologic characteristics of a neuropeptidase. Proc Natl Acad Sci USA. 1996; 93: 749-753.2. Werner RA, Derlin T, Lapa C, et al. ¹⁸F-Labeled, PSMA-Targeted radiotracers: leveraging the advantages of radiofluorination for prostate cancer molecular imaging. Theranostics 2020; 10: 1-16.3. Kiess AP, Banerjee SR, Mease RC, et al. Prostate-specific membrane antigen as a target for cancer imaging and therapy. Q J Nucl Med Mol Imaging. 2015; 59: 241-268.

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