Fluorine-18 Labeled Urea-Based Ligands Targeting Prostate-Specific Membrane Antigen (PSMA) with Increased Tumor and Decreased Renal Uptake

High expression of prostate-specific membrane antigen (PSMA) in prostate cancers prompted the development of the PSMA-targeted PET-imaging agent [(18)F]DCFPyL, which was recently approved by the FDA. Fluorine-18-labeled Lys–Urea–Glu-based oxime derivatives of [(18)F]DCFPyL were prepared for the comparison of their in vitro and in vivo properties to potentially improve kidney clearance and tumor targeting. The oxime radiotracers were produced by condensation of an aminooxy functionalized PSMA-inhibitor Lys–Urea–Glu scaffold with fluorine-18-labeled aldehydes. The radiochemical yields were between 15–42% (decay uncorrected) in 50–60 min. In vitro saturation and competition binding assays with human prostate cancer cells transfected with PSMA, PC3(+), indicated similar high nM binding affinities to PSMA for all radiotracers. In vivo biodistribution studies with positive control PC3(+) tumor xenografts showed that the kidneys had the highest uptake followed by tumors at 60 min. The PC3(+) tumor uptake was blocked with non-radioactive DCFPyL, and PC3(−) tumor xenograft (negative control) tumor uptake was negligible indicating that PSMA targeting was preserved. The most lipophilic tracer, [(18)F]2a, displayed comparable tumor-targeting to [(18)F]DCFPyL and a desirable alteration in pharmacokinetics and metabolism, resulting in significantly lower kidney uptake with a shift towards hepatobiliary clearance and increased liver uptake.