Quinoline/Naphthalene-Embedded PSMA Probes for Precise PET Imaging with Minimized Undesired Retention

Accumulation in nontarget tissues, particularly the salivary glands, remains a major challenge for prostate-specific membrane antigen (PSMA)-targeted radiotherapeutics, narrowing the theranostic window. In this work, we developed quinoline/naphthalene-derived PSMA radiotracers ([18F]AlF-NNA8P1, [18F]AlF-NNB8P1, and [18F]AlF-NCB8P1) to minimize nontarget accumulation through systematic molecular optimization. All probes exhibited excellent stability in vitro and in vivo. In PSMA-positive PC3-PIP cells, a significant uptake was observed with nanomolar binding affinities. Visual drug screening and first-in-human studies were conducted. In PSMA-positive tumor models, micro-positron emission tomography (PET) imaging and biodistribution demonstrated high tumor uptake, significantly blocked by coinjection with PSMA inhibitors. The probes showed blood clearance primarily and a low background retention. In initial clinical evaluations, [18F]AlF-NCB8P1 outperformed the widely used [18F]PSMA-1007, enabling clear visualization of metastatic lesions. The preclinical and clinical results validate that these quinoline/naphthalene-based radiotracers hold promise for enriching the prostate cancer (PCa) precision oncology toolkit, paving the way for next-generation theranostic agents with improved precision and safety.