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

Abstract

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. 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. 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 6nM reflecting very high affinity for PSMA. Compounds 4 and 8 showed IC50 values of 13 and 62nM, respectively. The IC50 value of reference compound DCFPyL was 13nM. 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). 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.