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New quinoline/naphthalene-based radiotracers targeting prostate-specific membrane antigen (PSMA) show reduced off-target accumulation. These agents offer improved visualization of prostate cancer (PCa) lesions in early clinical trials.

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Area of Science:

  • Radiochemistry
  • Nuclear Medicine
  • Oncology

Background:

  • Prostate-specific membrane antigen (PSMA)-targeted radiotherapeutics face challenges with nontarget tissue accumulation, limiting their therapeutic window.
  • Minimizing off-target uptake is crucial for enhancing the efficacy and safety of PSMA-targeted agents.

Purpose of the Study:

  • To develop novel quinoline/naphthalene-derived PSMA radiotracers with reduced nontarget accumulation.
  • To evaluate the preclinical and clinical performance of these new radiotracers for prostate cancer imaging.

Main Methods:

  • Systematic molecular optimization of quinoline/naphthalene scaffolds.
  • In vitro stability and cell binding assays using PSMA-positive cells.
  • In vivo micro-positron emission tomography (PET) imaging and biodistribution studies in tumor models.
  • Initial first-in-human clinical evaluations and comparisons with [18F]PSMA-1007.

Main Results:

  • Developed three novel radiotracers: [18F]AlF-NNA8P1, [18F]AlF-NNB8P1, and [18F]AlF-NCB8P1, all exhibiting excellent in vitro and in vivo stability.
  • Demonstrated high uptake in PSMA-positive cells and tumors, with significant blockade by PSMA inhibitors.
  • Probes showed rapid blood clearance and low background retention.
  • [18F]AlF-NCB8P1 outperformed [18F]PSMA-1007 in initial human studies, providing clearer visualization of metastatic lesions.

Conclusions:

  • Quinoline/naphthalene-based radiotracers represent a promising advancement in PSMA-targeted theranostics for prostate cancer.
  • These agents offer improved precision and safety, potentially enhancing the precision oncology toolkit for PCa.
  • Further development of these next-generation theranostic agents is warranted.