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 <i>in vitro</i> and <i>in vivo</i>. 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.