Development of a homotrimeric PSMA radioligand based on the NOTI chelating platform

Sebastian Martin; Moritz-Valentin Schreck; Tobias Stemler; Stephan Maus; Florian Rosar; Caroline Burgard; Andrea Schaefer-Schuler; Samer Ezziddin; Mark D Bartholomä

doi:10.1186/s41181-024-00314-7

Development of a homotrimeric PSMA radioligand based on the NOTI chelating platform

EJNMMI Radiopharm Chem. 2024 Dec 11;9(1):84. doi: 10.1186/s41181-024-00314-7.

Authors

Sebastian Martin¹, Moritz-Valentin Schreck², Tobias Stemler², Stephan Maus², Florian Rosar², Caroline Burgard², Andrea Schaefer-Schuler², Samer Ezziddin², Mark D Bartholomä^{3

4}

Affiliations

¹ Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Rue de Bugnon 25A, 1011, Lausanne, Switzerland.
² Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, 66421, Homburg, Germany.
³ Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, 66421, Homburg, Germany. mark.bartholomae@uks.eu.
⁴ Department of Nuclear Medicine, Saarland University, Kirrbergerstrasse, 66421, Homburg, Germany. mark.bartholomae@uks.eu.

Abstract

Background: The NOTI chelating scaffold can readily be derivatized for bioconjugation without impacting its metal complexation/radiolabeling properties making it an attractive building block for the development of multimeric/-valent radiopharmaceuticals. The objective of the study was to further explore the potential of the NOTI chelating platform by preparing and characterizing homotrimeric PSMA radioconjugates in order to identify a suitable candidate for clinical translation.

Results: Altogether, three PSMA conjugates based on the NOTI-TVA scaffold with different spacer entities between the chelating unit and the Glu-CO-Lys PSMA binding motif were readily prepared by solid phase-peptide chemistry. Cell experiments allowed the identification of the homotrimeric conjugate 9 comprising NaI-Amc spacer with high PSMA binding affinity (IC₅₀ = 5.9 nM) and high PSMA-specific internalization (17.8 ± 2.5%) compared to the clinically used radiotracer [⁶⁸Ga]Ga-PSMA-11 with a IC₅₀ of 18.5 nM and 5.2 ± 0.2% cell internalization, respectively. All ⁶⁸Ga-labeled trimeric conjugates showed high metabolic stability in vitro with [⁶⁸Ga]Ga-9 exhibiting high binding to human serum proteins (> 95%). Small-animal PET imaging revealed a specific tumor uptake of 16.0 ± 1.3% IA g^-1 and a kidney uptake of 67.8 ± 8.4% IA g^-1 for [⁶⁸Ga]Ga-9. Clinical PET imaging allowed identification of all lesions detected by [⁶⁸Ga]Ga-PSMA-11 together with a prolonged blood circulation as well as a significantly lower kidney and higher liver uptake of [⁶⁸Ga]Ga-9 compared to [⁶⁸Ga]Ga-PSMA-11.

Conclusions: Trimerization of the Glu-CO-Lys binding motif for conjugate 9 resulted in a ~ threefold higher binding affinity and cellular uptake as well as in an altered biodistribution profile compared to the control [⁶⁸Ga]Ga-PSMA-11 due to its intrinsic high binding to serum proteins. To fully elucidate its biodistribution, future studies in combination with long-lived radionuclides, such as ⁶⁴Cu, are warranted. Its prolonged biological half-life and favorable tumor-to-kidney ratio make this homotrimeric conjugate also a potential candidate for future radiotherapeutic applications in combination with therapeutic radionuclides such as ⁶⁷Cu.

Keywords: Bifunctional chelator; Gallium-68; Multimerization; NOTI; PSMA; Trimer.

Abstract

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