Development of [^99mTc]TcO-ABX474: Design, Synthesis, and Biological Evaluation of PSMA-Binding Technetium-99m Radioligands for SPECT Imaging of Prostate Cancer

A current global limitation to the timely and equitable patient access to PSMA-based therapies for prostate cancer (PCa) is the insufficient PET capacity for pretreatment imaging. However, the extensive global availability of SPECT cameras renders this imaging technology as an attractive alternative. The lack of regulatory approved PSMA radioligands for SPECT imaging of PCa prompted us to design new ^99mTc-labeled radioligands with a fast pharmacokinetic profile by harnessing proven complexation of the [^99mTc][TcO]³⁺ core by a bis(aminoethanethiol) chelator. Six ^99mTc-labeled PSMA radioligands were synthesized and biologically characterized in cell-based assays and by SPECT imaging in LNCaP tumor-bearing mice. From this series, [^99mTc]TcO-<b>5</b> ([^99mTc]TcO-ABX474, <i>K</i>_d(PSMA) = 6.1 ± 1.7 nM) displayed the most advantageous properties for SPECT imaging of PCa: high and fast tumor uptake accompanied by rapid clearance from nontarget tissues, leading to faster pharmacokinetics than observed for the reference [^99mTc]Tc-PSMA-I&S. Furthermore, [^99mTc]TcO-<b>5</b> performed similar to the established PSMA-PET radioligand [⁶⁸Ga]Ga-PSMA-11.