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Purpose <p>To develop a dual-labeled PSMA-targeted tracer for radio- and fluorescence-guided surgery (RGS/FGS) with enhanced clinical utility due to optimized pharmacokinetics and tumor targeting.</p> Methods <p>Four novel hybrid PSMA ligands with varying cyanine-based fluorophores were comprehensively characterized preclinically. On the basis of its excellent in vitro (logD, plasma protein binding, PSMA-affinity, internalization) and in vivo (stability, clearance kinetics, tumor uptake in LNCaP and PC3-PIp tumor-bearing mice) profile, [<sup>99m</sup>Tc]Tc-PSMA-HSG was selected as the clinical lead compound. Five patients with primary and recurrent prostate cancer underwent [<sup>99m</sup>Tc]Tc-PSMA-HSG SPECT/CT and RGS. Tracer dosimetry was calculated using a MIRDcalc v1.22 protocol.</p> Results <p>The PSMA affinity (IC₅₀=38.4 ± 5.3 nM), hydrophilicity (logD =–2.94), and human plasma protein binding of [<sup>99m</sup>Tc]Tc-PSMA-HSG were all nearly identical to those of the non-fluorescent parent compound [<sup>99m</sup>Tc]Tc-PSMA-I&amp;S. Tumor uptake in mice was 11.8 ± 1.5%ID/g at 6&#xa0;h p.i. (vs. 6.4 ± 1.0%ID/g for [<sup>99m</sup>Tc]Tc-PSMA-I&amp;S). In and ex vivo fluorescence imaging in mice confirmed tumor localization with high signal-to-background ratios. In patients, [<sup>99m</sup>Tc]Tc-PSMA-HSG showed faster clearance and less background uptake than [<sup>99m</sup>Tc]Tc-PSMA-I&amp;S, with notably reduced salivary gland and intestinal accumulation, but a slightly higher whole body effective dose (0.011 ± 0.003 vs. 0.0052 mSv/MBq). Intraoperative gamma detection revealed lymph node metastases in 6/6 tracer-avid lesions, which were confirmed by PSMA-HSG fluorescence microscopy and histopathology. The specificity, selectivity, NPV and PPV of [<sup>99m</sup>Tc]Tc-PSMA-HSG in RGS were 100%, respectively.</p> Conclusions <p>The hybrid tracer [<sup>99m</sup>Tc]Tc-PSMA-HSG demonstrates high specificity and favorable pharmacokinetics. Its successful first-in-human application highlights its translational potential for precise intraoperative detection of PSMA-positive lymph node metastases.</p>

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[99mTc]Tc-PSMA-HSG for PSMA-targeted Hybrid Surgical Guidance: a new addition to the PSMA-I&S/I&T family

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Margret Schottelius,
  • David Viertl,
  • Tessa Buckle,
  • Hélène Koch,
  • Sebastian Martin,
  • Alexandra Litvinenko,
  • Marianne Patt,
  • D. M. van Willigen,
  • Fijs W. B. van Leeuwen,
  • Hans-Jürgen Wester,
  • Dorothea Weckermann,
  • Alessandro Liebich,
  • Alexander Gäble,
  • Nic G. Reitsam,
  • Bruno Märkl,
  • Johanna S. Enke,
  • Julia Brosch-Lenz,
  • Constantin Lapa

摘要

Purpose

To develop a dual-labeled PSMA-targeted tracer for radio- and fluorescence-guided surgery (RGS/FGS) with enhanced clinical utility due to optimized pharmacokinetics and tumor targeting.

Methods

Four novel hybrid PSMA ligands with varying cyanine-based fluorophores were comprehensively characterized preclinically. On the basis of its excellent in vitro (logD, plasma protein binding, PSMA-affinity, internalization) and in vivo (stability, clearance kinetics, tumor uptake in LNCaP and PC3-PIp tumor-bearing mice) profile, [99mTc]Tc-PSMA-HSG was selected as the clinical lead compound. Five patients with primary and recurrent prostate cancer underwent [99mTc]Tc-PSMA-HSG SPECT/CT and RGS. Tracer dosimetry was calculated using a MIRDcalc v1.22 protocol.

Results

The PSMA affinity (IC₅₀=38.4 ± 5.3 nM), hydrophilicity (logD =–2.94), and human plasma protein binding of [99mTc]Tc-PSMA-HSG were all nearly identical to those of the non-fluorescent parent compound [99mTc]Tc-PSMA-I&S. Tumor uptake in mice was 11.8 ± 1.5%ID/g at 6 h p.i. (vs. 6.4 ± 1.0%ID/g for [99mTc]Tc-PSMA-I&S). In and ex vivo fluorescence imaging in mice confirmed tumor localization with high signal-to-background ratios. In patients, [99mTc]Tc-PSMA-HSG showed faster clearance and less background uptake than [99mTc]Tc-PSMA-I&S, with notably reduced salivary gland and intestinal accumulation, but a slightly higher whole body effective dose (0.011 ± 0.003 vs. 0.0052 mSv/MBq). Intraoperative gamma detection revealed lymph node metastases in 6/6 tracer-avid lesions, which were confirmed by PSMA-HSG fluorescence microscopy and histopathology. The specificity, selectivity, NPV and PPV of [99mTc]Tc-PSMA-HSG in RGS were 100%, respectively.

Conclusions

The hybrid tracer [99mTc]Tc-PSMA-HSG demonstrates high specificity and favorable pharmacokinetics. Its successful first-in-human application highlights its translational potential for precise intraoperative detection of PSMA-positive lymph node metastases.