PHARMACEUTICALS · Published 2026-07-29 · DOI 10.3390/ph19081187
Paul Minges, Jessica Matthias, Lisa-Charlotte Domogalla, Björn Thomas, Nils Steinacker, Nawal Ayada Amgar, Holger Müller, Antje Dietzel-Schaarschmidt, Philipp T. Meyer, Matthias Eder, Ann-Christin Eder
<b>Objectives</b>: Fluorescence-guided surgery (FGS) targeting prostate-specific membrane antigen (PSMA) holds promise for improving surgical precision in prostate cancer. Since conjugation of fluorescent dyes to targeting vectors can substantially alter pharmacokinetic properties, we systematically evaluated a library of fluorescent dyes conjugated to a PSMA-617-derived scaffold incorporating sarcosine-based spacers to identify candidates with favorable biodistribution and optical profiles for clinical translation. <b>Methods</b>: Nineteen fluorescent dyes spanning NIR, large Stokes shift, and STED-compatible categories were conjugated to a dual-labeled PSMA-617-derived precursor (Glu-urea-Lys-2Nal-TXA-Sar<sub>10</sub>-Lys(DOTA)-Sar<sub>5</sub>-βAla; hereafter DP). Compounds were radiolabeled with <sup>68</sup>Ga or <sup>177</sup>Lu and characterized for serum stability, lipophilicity, binding affinity, and internalization in LNCaP<sup>PSMA+</sup> cells. In vivo pharmacokinetics were assessed in LNCaP xenograft-bearing BALB/c nu/nu mice by µPET/MRI (1 and 2 h p.i., 500 pmol <sup>68</sup>Ga), organ distribution (0.5, 1, and 2 h p.i., 60 pmol <sup>177</sup>Lu), and clinical-grade endoscopic fluorescence imaging. <b>Results</b>: All conjugates retained hydrophilic character (logD: −3.72 to −1.79), low nanomolar binding affinity (K<sub>i</sub>: 18–87 nM), and high serum stability (94–100% intact at 24 h). Despite comparable in vitro properties, dye conjugation markedly influenced in vivo pharmacokinetics: tumor uptake at 2 h p.i. ranged from 1 to 23%ID/g and kidney accumulation from 3 to 82%ID/g. Visible-range dyes exhibited faster renal washout within the imaging window and higher tumor-to-background contrast than NIR fluorophores. Fluorescence signal intensity did not correlate with radiotracer-derived uptake, underscoring the importance of dye-specific photophysical properties. <b>Conclusions</b>: DP-12 (SulfoCy5), DP-15 (Alexa Fluor 647), and DP-18 (Tide Fluor 5WS) were identified as lead candidates combining favorable pharmacokinetics with strong fluorescence contrast, warranting further evaluation toward fluorescence-guided prostate cancer surgery.
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Minges, P., Matthias, J., Domogalla, L., et al. (2026). Sarcosine-Based Pharmacokinetic Optimization and Fluorescent Dye Library Evaluation of Dual-Labeled PSMA Inhibitors for Fluorescence-Guided Surgery. PHARMACEUTICALS. https://doi.org/10.3390/ph19081187