Distinct In Vitro Binding Profile of the Somatostatin Receptor Subtype 2 Antagonist [177Lu]Lu-OPS201 Compared to the Agonist [177Lu]Lu-DOTA-TATE

Rosalba Mansi; Pascale Plas; Georges Vauquelin; Melpomeni Fani

doi:10.3390/ph14121265

Distinct In Vitro Binding Profile of the Somatostatin Receptor Subtype 2 Antagonist [¹⁷⁷Lu]Lu-OPS201 Compared to the Agonist [¹⁷⁷Lu]Lu-DOTA-TATE

Pharmaceuticals (Basel). 2021 Dec 4;14(12):1265. doi: 10.3390/ph14121265.

Authors

Rosalba Mansi¹, Pascale Plas², Georges Vauquelin³, Melpomeni Fani¹

Affiliations

¹ Division of Radiopharmaceutical Chemistry, Clinic of Radiology and Nuclear Medicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
² Ipsen Innovation, Translational and Biomarkers Pharmacology, 91140 Les Ulis, France.
³ Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel, 1050 Brussels, Belgium.

Abstract

Treatment of neuroendocrine tumours with the radiolabelled somatostatin receptor subtype 2 (SST₂) peptide agonist [¹⁷⁷Lu]Lu-DOTA-TATE is effective and well-established. Recent studies suggest improved therapeutic efficacy using the SST₂ peptide antagonist [¹⁷⁷Lu]Lu-OPS201. However, little is known about the cellular mechanisms that lead to the observed differences. In the present in vitro study, we compared kinetic binding, saturation binding, competition binding, cellular uptake and release of [¹⁷⁷Lu]Lu-OPS201 versus [¹⁷⁷Lu]Lu-DOTA-TATE using HEK cells stably transfected with the human SST₂. While [¹⁷⁷Lu]Lu-OPS201 and [¹⁷⁷Lu]Lu-DOTA-TATE exhibited comparable affinity (K_D, 0.15 ± 0.003 and 0.08 ± 0.02 nM, respectively), [¹⁷⁷Lu]Lu-OPS201 recognized four times more binding sites than [¹⁷⁷Lu]Lu-DOTA-TATE. Competition assays demonstrated that a high concentration of the agonist displaced only 30% of [¹⁷⁷Lu]Lu-OPS201 bound to HEK-SST₂ cell membranes; an indication that the antagonist binds to additional sites that are not recognized by the agonist. [¹⁷⁷Lu]Lu-OPS201 showed faster association and slower dissociation than [¹⁷⁷Lu]Lu-DOTA-TATE. Whereas most of [¹⁷⁷Lu]Lu-OPS201 remained at the cell surface, [¹⁷⁷Lu]Lu-DOTA-TATE was almost completely internalised inside the cell. The present data identified distinct differences between [¹⁷⁷Lu]Lu-OPS201 and [¹⁷⁷Lu]Lu-DOTA-TATE regarding the recognition of receptor binding sites (higher for [¹⁷⁷Lu]Lu-OPS201) and their kinetics (faster association and slower dissociation of [¹⁷⁷Lu]Lu-OPS201) that explain, to a great extent, the improved therapeutic efficacy of [¹⁷⁷Lu]Lu-OPS201 compared to [¹⁷⁷Lu]Lu-DOTA-TATE.

Keywords: [177Lu]Lu-DOTA-TATE; [177Lu]Lu-OPS201; binding sites; dissociation; kinetics; radioligand binding; somatostatin receptor.