Development of a homotrimeric PSMA radioligand based on the NOTI chelating platform
Martin S, Schreck MV, Stemler T, Maus S, Rosar F, Burgard C, Schaefer-Schuler A, Ezziddin S, Bartholomä MD (2024)
Publication Type: Journal article
Publication year: 2024
Journal
Book Volume: 9
Article Number: 84
Journal Issue: 1
DOI: 10.1186/s41181-024-00314-7
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.
Involved external institutions
Universitätsklinikum des Saarlandes (UKS)
Germany (DE)
Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV)
Switzerland (CH)
Germany (DE)
Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV)
Switzerland (CH)
How to cite
APA:
Martin, S., Schreck, M.V., Stemler, T., Maus, S., Rosar, F., Burgard, C.,... Bartholomä, M.D. (2024). Development of a homotrimeric PSMA radioligand based on the NOTI chelating platform. EJNMMI Radiopharmacy and Chemistry, 9(1). https://doi.org/10.1186/s41181-024-00314-7
MLA:
Martin, Sebastian, et al. "Development of a homotrimeric PSMA radioligand based on the NOTI chelating platform." EJNMMI Radiopharmacy and Chemistry 9.1 (2024).
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