Preclinical Evaluation of a Novel High-Affinity Radioligand [^99mTc]Tc-BQ0413 Targeting Prostate-Specific Membrane Antigen (PSMA)

Radionuclide imaging using radiolabeled inhibitors of prostate-specific membrane antigen (PSMA) can be used for the staging of prostate cancer. Previously, we optimized the Glu-urea-Lys binding moiety using a linker structure containing 2-napththyl-L-alanine and L-tyrosine. We have now designed a molecule that contains mercaptoacetyl-triglutamate chelator for labeling with Tc-99m (designated as BQ0413). The purpose of this study was to evaluate the imaging properties of [Tc-99m]Tc-BQ0413. PSMA-transfected PC3-pip cells were used to evaluate the specificity and affinity of [Tc-99m]Tc-BQ0413 binding in vitro. PC3-pip tumor-bearing BALB/C nu/nu mice were used as an in vivo model. [Tc-99m]Tc-BQ0413 bound specifically to PC3-pip cells with an affinity of 33 +/- 15 pM. In tumor-bearing mice, the tumor uptake of [Tc-99m]Tc-BQ0413 (38 +/- 6 %IA/g in PC3-pip 3 h after the injection of 40 pmol) was dependent on PSMA expression (3 +/- 2 %IA/g and 0.9 +/- 0.3 %IA/g in PSMA-negative PC-3 and SKOV-3 tumors, respectively). We show that both unlabeled BQ0413 and the commonly used binder PSMA-11 enable the blocking of [Tc-99m]Tc-BQ0413 uptake in normal PSMA-expressing tissues without blocking the uptake in tumors. This resulted in an appreciable increase in tumor-to-organ ratios. At the same injected mass (5 nmol), the use of BQ0413 was more efficient in suppressing renal uptake than the use of PSMA-11. In conclusion, [Tc-99m]Tc-BQ0413 is a promising probe for the visualization of PSMA-positive lesions using single-photon emission computed tomography (SPECT).