1. Discovery of Glutamate Carboxypeptidase III Ligands to Compete the Uptake of [ 177 Lu]Lu-PSMA-617 in Healthy Organs.
- Author
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Müller M, Lucaroni L, Favalli N, Bassi G, Neri D, Cazzamalli S, and Oehler S
- Subjects
- Humans, Antigens, Surface, Autoradiography, Glutamate Carboxypeptidase II, Ligands, Prostate-Specific Antigen, Radioisotopes chemistry, Radioisotopes metabolism, Radiopharmaceuticals chemistry, Radiopharmaceuticals metabolism, Radiopharmaceuticals pharmacokinetics, Salivary Glands metabolism, Structure-Activity Relationship, Tissue Distribution, Dipeptides chemistry, Dipeptides metabolism, Heterocyclic Compounds, 1-Ring chemistry, Heterocyclic Compounds, 1-Ring metabolism, Lutetium chemistry, Lutetium metabolism
- Abstract
Prostate-specific membrane antigen (PSMA)-targeted radio ligand therapeutics (RLTs), such as [
177 Lu]Lu-PSMA-617 (Pluvicto), have been shown to accumulate in salivary glands and kidneys, potentially leading to undesired side effects. As unwanted accumulation in normal organs may derive from the cross-reactivity of PSMA ligands to glutamate carboxypeptidase III (GCPIII), it may be convenient to block this interaction with GCPIII-selective ligands. Parallel screening of a DNA-encoded chemical library (DEL) against GCPIII and PSMA allowed the identification of GCPIII binders. Structure-activity relationship (SAR) studies resulted in the identification of nanomolar GCPIII ligands with up to 1000-fold selectivity over PSMA. We studied the ability of GCPIII ligands to counteract the binding of [177 Lu]Lu-PSMA-617 to human salivary glands by autoradiography and could demonstrate a partial radioprotection.- Published
- 2024
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