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.