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

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

doi:10.1007/s00259-025-07623-2

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

Eur J Nucl Med Mol Imaging. 2025 Nov 14. doi: 10.1007/s00259-025-07623-2. Online ahead of print.

Authors

Margret Schottelius^{1

2

3}, David Viertl⁴, Tessa Buckle⁵, Hélène Koch^{4

6

7}, Sebastian Martin^{4

6

7}, Alexandra Litvinenko^{4

6

7}, Marianne Patt⁸, D M van Willigen⁵, Fijs W B van Leeuwen⁵, Hans-Jürgen Wester⁹, Dorothea Weckermann¹⁰, Alessandro Liebich⁸, Alexander Gäble⁸, Nic G Reitsam^{11

12}, Bruno Märkl^{11

12}, Johanna S Enke^{8

12}, Julia Brosch-Lenz^{8

13}, Constantin Lapa^{8

12}

Affiliations

¹ Translational Radiopharmaceutical Sciences, Department of Nuclear Medicine, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne, 1011, Switzerland. margret.schottelius@chuv.ch.
² AGORA, Pôle de recherche sur le cancer, Lausanne, 1011, Switzerland. margret.schottelius@chuv.ch.
³ SCCL Swiss Cancer Center Leman, Lausanne, 1011, Switzerland. margret.schottelius@chuv.ch.
⁴ Translational Radiopharmaceutical Sciences, Department of Nuclear Medicine, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne, 1011, Switzerland.
⁵ Interventional Molecular Imaging Laboratory, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
⁶ AGORA, Pôle de recherche sur le cancer, Lausanne, 1011, Switzerland.
⁷ SCCL Swiss Cancer Center Leman, Lausanne, 1011, Switzerland.
⁸ Nuclear Medicine, University of Augsburg, 86156, Augsburg, Germany.
⁹ Chair for Pharmaceutical Radiochemistry, Faculties of Chemistry and Medicine, Technische Universität München, 85748, Garching, Germany.
¹⁰ Urology, Medical Faculty, University of Augsburg, 86156, Augsburg, Germany.
¹¹ Pathology, Medical Faculty, University of Augsburg, 86156, Augsburg, Germany.
¹² Bavarian Center for Cancer Research, 86156, Augsburg, Augsburg, Germany.
¹³ Institute of Nuclear Medicine, Glen Burnie, MD, USA.

PMID: 41233512
DOI: 10.1007/s00259-025-07623-2

Abstract

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.

Keywords: Fluorescence guided surgery; Hybrid tracer; PSMA; Prostate cancer (PCa); Radioguided surgery.