Synthesis, Radiolabelling and In Vitro Characterization of the Gallium-68-, Yttrium-90- and Lutetium-177-Labelled PSMA Ligand, CHX-A''-DTPA-DUPA-Pep

Benjamin Baur, Christoph Solbach, Elena Andreolli, Gordon Winter, Hans-Jürgen Machulla, Sven N Reske, Benjamin Baur, Christoph Solbach, Elena Andreolli, Gordon Winter, Hans-Jürgen Machulla, Sven N Reske

Abstract

Since prostate-specific membrane antigen (PSMA) has been identified as a diagnostic target for prostate cancer, many urea-based small PSMA-targeting molecules were developed. First, the clinical application of these Ga-68 labelled compounds in positron emission tomography (PET) showed their diagnostic potential. Besides, the therapy of prostate cancer is a demanding field, and the use of radiometals with PSMA bearing ligands is a valid approach. In this work, we describe the synthesis of a new PSMA ligand, CHX-A''-DTPA-DUPA-Pep, the subsequent labelling with Ga-68, Lu-177 and Y-90 and the first in vitro characterization. In cell investigations with PSMA-positive LNCaP C4-2 cells, KD values of ≤14.67 ± 1.95 nM were determined, indicating high biological activities towards PSMA. Radiosyntheses with Ga-68, Lu-177 and Y-90 were developed under mild reaction conditions (room temperature, moderate pH of 5.5 and 7.4, respectively) and resulted in nearly quantitative radiochemical yields within 5 min.

Figures

Scheme 1
Scheme 1
Synthesis of cyclohexyldiethylenetriamine pentaacetic acid (5S,8S,22S,26S)-1-amino-5,8-dibenzyl-4,7,10,19,24-pentaoxo-3,6,9,18,23,25-hexaazaoctacosane-22,26,28-tri-carboxylic acid trifluoroacetate (CHX-A''-DTPA-DUPA-Pep).
Figure 1
Figure 1
Exemplary chromatograms of [68Ga]Ga-CHX-A''-DTPA-DUPA-Pep in the radioactivity channel (upper signal; the first peak shows the total activity injected detector bypass for recovery rate calculation) and CHX-A''-DTPA-DUPA-Pep in the UV-channel (bottom signal; λ: 254 nm).
Figure 2
Figure 2
Dependence of the RCY of [68Ga]Ga-CHX-A''-DTPA-DUPA-Pep on the peptide amount (concentration) and reaction time at room temperature.
Figure 3
Figure 3
Dependence of the RCY of [90Y]Y-CHX-A''-DTPA-DUPA-Pep on peptide amount (concentration) and reaction time at room temperature.
Figure 4
Figure 4
Dependence of the RCY of [177Lu]Lu-CHX-A''-DTPA-DUPA-Pep on peptide amount (concentration) and reaction time at room temperature.
Figure 5
Figure 5
Stability study of [68Ga]Ga-CHX-A''-DTPA-DUPA-Pep in human serum: overlaid radio-HPLC chromatograms after 8 h (1), 4 h (2), 2 h (3) and 30 min (4). The first peak shows the total activity injected (the detector bypass for the recovery rate calculation).

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