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Targeting Prostate-Specific Membrane Antigen (PSMA) with F-18-Labeled Compounds: the Influence of Prosthetic Groups on Tumor Uptake and Clearance Profile

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Abstract

Purpose

Prostate-specific membrane antigen (PSMA) is an important biomarker expressed in the majority of prostate cancers. The favorable positron emission tomography (PET) imaging profile of the PSMA imaging agent 2-(3-(1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentane-dioic acid [18F]DCFPyL in preclinical prostate cancer models and in prostate cancer patients stimulated the development and validation of other fluorine-containing PSMA inhibitors to further enhance pharmacokinetics and simplify production methods. Here, we describe the synthesis and radiopharmacological evaluation of various F-18-labeled PSMA inhibitors which were prepared through different prosthetic group chemistry strategies.

Procedures

Prosthetic groups N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB), 4-[18F]fluorobenzaldehyde, and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) were used for bioconjugation reactions to PSMA-binding lysine-urea-glutamate scaffold via acylation and oxime formation. All fluorine-containing PSMA inhibitors were tested for their PSMA inhibitory potency in an in vitro competitive binding assay in comparison to an established reference compound [125I]TAAG-PSMA. Tumor uptake and clearance profiles of three F-18-labeled PSMA inhibitors ([18F]4, [18F]7, and [18F]8) were studied with dynamic PET imaging using LNCaP tumor-bearing mice.

Results

F-18-labeled PSMA inhibitors were synthesized in 32–69 % radiochemical yields using (1) acylation reaction at the primary amino group of the lysine residue with [18F]SFB and (2) oxime formation with 4-[18F]fluorobenzaldehyde and [18F]FDG using the respective aminooxy-functionalized lysine residue. Compound 7 displayed an IC50 value of 6 nM reflecting very high affinity for PSMA. Compounds 4 and 8 showed IC50 values of 13 and 62 nM, respectively. The IC50 value of reference compound DCFPyL was 13 nM. Dynamic PET imaging revealed the following SUV60min for radiotracer uptake in PSMA(+) LNCaP tumors: 0.98 ([18F]DCFPyL), 2.11 ([18F]7), 0.40 ([18F]4), and 0.19 ([18F]8).

Conclusion

The observed tumor uptake and clearance profiles demonstrate the importance of the selected prosthetic group on the pharmacokinetic profile of analyzed PSMA-targeting radiotracers. Radiotracer [18F]7 displayed the highest uptake and retention in LNCaP tumors, which exceeded uptake values of reference compound [18F]DCFPyL by more than 100 %. Despite the higher kidney and liver uptake and retention of compound [18F]7, the simple radiosynthesis and the exceptionally high tumor uptake (SUV60min 2.11) and retention make radiotracer [18F]7 an interesting alternative to radiotracer [18F]DCFPyL for PET imaging of PSMA in prostate cancer.

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Acknowledgments

The authors would like to thank John Wilson, Dave Clendening, and Blake Lazurko from the Edmonton PET Centre for radionuclide production as well as Angela Westover and Jeff McPherson for providing [18F]FDG. The authors would like to thank Gail Hipperson and Dan McGinn from the Vivarium of the Cross Cancer Institute for supporting the animal work, as well as Dr. Hans-Soenke Jans from the Division of Medical Physics for the technical support of the animal imaging facility. We gratefully acknowledge the Dianne and Irving Kipnes Foundation, the Canadian Institute of Health Research (CIHR), The Ontario Institute for Cancer Research (OICR), and the National Science and Engineering Research Council of Canada (NSERC) with its Collaborative Research and Training Experience Program (CREATE – Molecular Imaging Probes) for supporting this work.

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Authors and Affiliations

  1. Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB, T6G 2X4, Canada

    Vincent Bouvet, Melinda Wuest, Justin J. Bailey, Cody Bergman & Frank Wuest

  2. Department of Chemistry and Chemical Biology, McMaster University, 1280 Main St., Hamilton, ON, L8S 4K1, Canada

    Nancy Janzen & John F. Valliant

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  1. Vincent Bouvet
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  2. Melinda Wuest
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  7. Frank Wuest
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Correspondence to Frank Wuest.

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Bouvet, V., Wuest, M., Bailey, J.J. et al. Targeting Prostate-Specific Membrane Antigen (PSMA) with F-18-Labeled Compounds: the Influence of Prosthetic Groups on Tumor Uptake and Clearance Profile. Mol Imaging Biol 19, 923–932 (2017). https://doi.org/10.1007/s11307-017-1102-x

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