Design, Synthesis, and Preclinical Evaluation of a Novel [ ¹⁸ F]AlF-Labeling Positron Emission Tomography Tracer Targeting Prostate-Specific Membrane Antigen

Prostate-specific membrane antigen (PSMA) is a promising target for the detection and treatment of prostate cancer (PCa). However, current PSMA-targeting probes still exhibit suboptimal tumor uptake and retention, which limits their performance in positron emission tomography (PET) imaging of PCa. In this study, we developed a series of novel PSMA-targeting probes, among which NOTA-SP₂A-PSMAL was selected. We then radiolabeled NOTA-SP₂A-PSMAL with ¹⁸F and evaluated the <i>in vitro</i> and <i>in vivo</i> characteristics of [¹⁸F]AlF-SP₂A-PSMAL. Subsequently, micro-PET/CT imaging and biodistribution studies were conducted in 22Rv1 and PC3 tumor-bearing mice to compare the <i>in vivo</i> distribution, tumor uptake, and retention of [¹⁸F]AlF-SP₂A-PSMAL with [¹⁸F]AlF-PSMA-BCH. [¹⁸F]AlF-SP₂A-PSMAL demonstrated favorable <i>in vivo</i> and <i>in vitro</i> properties. Micro-PET/CT imaging and biodistribution studies demonstrated that [¹⁸F]AlF-SP₂A-PSMAL had satisfying pharmacokinetic characteristics and excellent targeting specificity for PSMA. Compared with [¹⁸F]AlF-PSMA-BCH, [¹⁸F]AlF-SP₂A-PSMAL showed higher tumor uptake and better tumor retention. These results indicate that [¹⁸F]AlF-SP₂A-PSMAL is a promising PET/CT tracer for diagnosing PCa.