Acridine-Based [68Ga]Ga- and [18F]AlF-Labeled PSMA Radiotracers Enabling High-Contrast PET Imaging with Minimized Undesired Retention

Abstract Prostate-specific membrane antigen (PSMA)-targeted radioligands have achieved clinical success in prostate cancer imaging, yet nonspecific uptake in normal tissues remains a challenge. Here, we developed a series of acridine-based PSMA ligands and systematically investigated the effects of aromaticity and linker polarity on binding affinity and pharmacokinetics. Increased aromaticity improved predicted affinity but often resulted in unfavorable in vivo performance, whereas optimization of linker polarity enhanced tumor uptake and reduced off-target accumulation. Among the compounds, YD2 emerged as the optimal scaffold. Radiolabeled analogues, [68Ga]Ga-DOTA-YD2 and [18F]AlF-NOTA-YD2, showed high tumor uptake and improved tumor-to-background contrast compared with reference tracers. Preliminary clinical evaluation demonstrated lesion detectability comparable to [18F]PSMA-1007 while reducing nonspecific uptake and false-positive findings. These results provide evidence that acridine-based scaffold optimization represents a useful strategy for developing PSMA-targeted radiotracers with improved imaging specificity.