Synthesis and Evaluation of ^99mTc-Labeled _DPro-Gly-Containing Tracers Targeting PSMA

The specific expression of prostate-specific membrane antigen (PSMA) makes it an ideal target for the diagnosis and treatment of prostate cancer. Currently, many ^99mTc-labeled PSMA-targeted tracers have been developed. However, the high renal uptake of these ^99mTc-labeled tracers is a common problem that limits their clinical application. In this work, the ligand (EUKPG) using _DPro-Gly as the linker was synthesized and three ^99mTc-labeled complexes ([^99mTc]Tc-EUKPG-EDDA, [^99mTc]Tc-EUKPG-TPPTS, [^99mTc]Tc-EUKPG-TPPMS) with different coligands were prepared and evaluated. Among them, [^99mTc]Tc-EUKPG-EDDA showed the most favorable pharmacokinetic properties, with significantly reduced uptake in the kidney (14.04 ± 0.23% ID/g), rapid clearance and low uptake in nontarget organs, thus making it to exhibit high tumor-to-background ratios (tumor/blood: 7.47, tumor/muscle: 12.65). Affinity studies have shown that it has high specificity for PSMA both <i>in vivo</i> and <i>in vitro</i>. Therefore, [^99mTc]Tc-EUKPG-EDDA has great potential as a promising molecular tracer to target PSMA for tumor imaging.